Systematic analysis, comparison, and integration of disease based human genetic association data and mouse genetic phenotypic information

  • Yonqing Zhang1Email author,

    Affiliated with

    • Supriyo De1Email author,

      Affiliated with

      • John R Garner1,

        Affiliated with

        • Kirstin Smith1,

          Affiliated with

          • S Alex Wang2 and

            Affiliated with

            • Kevin G Becker1Email author

              Affiliated with

              BMC Medical Genomics20103:1

              DOI: 10.1186/1755-8794-3-1

              Received: 13 April 2009

              Accepted: 21 January 2010

              Published: 21 January 2010

              Abstract

              Background

              The genetic contributions to human common disorders and mouse genetic models of disease are complex and often overlapping. In common human diseases, unlike classical Mendelian disorders, genetic factors generally have small effect sizes, are multifactorial, and are highly pleiotropic. Likewise, mouse genetic models of disease often have pleiotropic and overlapping phenotypes. Moreover, phenotypic descriptions in the literature in both human and mouse are often poorly characterized and difficult to compare directly.

              Methods

              In this report, human genetic association results from the literature are summarized with regard to replication, disease phenotype, and gene specific results; and organized in the context of a systematic disease ontology. Similarly summarized mouse genetic disease models are organized within the Mammalian Phenotype ontology. Human and mouse disease and phenotype based gene sets are identified. These disease gene sets are then compared individually and in large groups through dendrogram analysis and hierarchical clustering analysis.

              Results

              Human disease and mouse phenotype gene sets are shown to group into disease and phenotypically relevant groups at both a coarse and fine level based on gene sharing.

              Conclusion

              This analysis provides a systematic and global perspective on the genetics of common human disease as compared to itself and in the context of mouse genetic models of disease.

              Background

              Common complex diseases such as cardiovascular disease, cancer, and autoimmune disorders; metabolic conditions such as diabetes and obesity, as well as neurological and psychiatric disorders make up a majority of health morbidity and mortality in developed countries. The specific genetic contributions to disease etiology and relationships to environmental factors in common disorders are unclear; complicated by many factors such as gene-gene interactions, the balance between susceptibility and protective alleles, copy number variation, low relative risk contributed by each gene, and a myriad of complex environmental inputs.

              Genetic association studies using a candidate gene approach and more recently whole genome association studies (GWAS) have produced a large and rapidly increasing amount of information on the genetics of common disease. In parallel, mouse genetic models for human disease have provided a wealth of genetic and phenotypic information. While not always perfect models for human common complex disorders, the genetic purity and experimental flexibility of mouse disease models have produced valuable insights relevant to human disease.

              Gene nomenclature standardization[1], database efforts [24], and phenotype ontology projects[5] in both human and mouse over the past decade have provided the foundation for integration of information on genetic contributions to disease and phenotypes. This allows the opportunity for systematic comparison and higher order systems analysis of disease and phenotypic information. In this report, we summarize and integrate large scale information on human genetic association information and mouse genetically determined phenotypic information with the goal of identifying fundamental relationships in human disease and mouse models of human disease.

              Methods

              The Genetic Association Database

              The Genetic Association Database [2] (GAD) http://​geneticassociati​ondb.​nih.​gov is an archive of summary data of published human genetic association studies of many common disease types. GAD is primarily focused on archiving information on common complex human disease rather than rare Mendelian disorders as found in the Online Mendelian Inheritance in Man (OMIM)[6]. GAD contains curated information on candidate gene studies and more recently on genome wide association studies. It builds on the curation of the CDC HuGENet info literature database [3] in part by adding molecular and ontological annotation creating a bridge between epidemiological and molecular information. This allows the large-scale integration of disease based genetic association information with genomic and molecular information as well as with the software tools and computational approaches and that use genomic information [712]. This report is a summary and analysis of the genes and diseases with positive associations in the Genetic Association Database with regard to replication, comparisons between diseases, and within broad phenotypic disease classes. Although GAD contains information on gene variation, this report is at the gene level only and does not consider specific gene variation or genetic polymorphism.

              The Genetic Association Database (GAD) currently contains approximately 40,000 individual gene records of genetic association studies taken from over 23,000 independent publications. Importantly, a large number (11,568) of the records in GAD have a designation of whether the gene of record was reported to be associated (Y) or was not (N) associated with the disease phenotype for that specific record. Many records, for various reasons, do not have such a designation. In addition, a portion of the database records have been annotated with standardized disease phenotype keywords from the MeSH http://​www.​nlm.​nih.​gov/​mesh/​ vocabulary. The GAD summations shown below are a subset of the records in GAD. They only include those records that are both; a) positively associated with a disease phenotype, and b) have a MeSH disease phenotype annotation. This represents a subset of 10,324 records having both positive associations to disease and records with MeSH annotations. Records designated as not associated (N) with a disease phenotype and those without MeSH disease annotation are not considered at this time in this report.

              Mouse phenotypic database

              The mouse phenotypic information described here was obtained from the Mouse Genome Informatics (MGI) database [4]http://​www.​informatics.​jax.​org/​ Phenotypes, Alleles and Disease Models section. The file used for mouse phenotypic information (see methods) is comprised of 5011 unique genes and 5142 unique phenotypic terms derived from information from specific gene mutations in multiple mouse strains. The mouse phenotypic information had been annotated to the mouse gene mutation records using Mammalian Phenotype terms and codes in the mouse phenotype database as a component of the Mouse Phenotyping Project [5, 13].

              Quantitation of genes and disease phenotypes

              Quantitation of how often a disease phenotype was positively associated with a gene was performed as follows. GAD records having both recorded positive associations and annotated MeSH disease keywords were extracted and stored in a database according to their relationships. Using a perl script, the number of times of co-occurrence of a MeSH disease keyword was positively associated with a specific gene was recorded as found in the GAD database. These counts were sorted in declining order for each unique gene grouped by the disease MeSH term with which they are associated.

              Mouse phenotypic information

              The mouse phenotypic information described here was obtained from the Mouse Genome Informatics (MGI) http://​www.​informatics.​jax.​org/​; Phenotypes, Alleles and Disease Models section; ftp://​ftp.​informatics.​jax.​org/​pub/​reports/​index.​html#pheno

              Using these three files downloaded on 4-4-2008

              ftp://​ftp.​informatics.​jax.​org/​pub/​reports/​MPheno_​OBO.​ontology

              ftp://​ftp.​informatics.​jax.​org/​pub/​reports/​MGI_​PhenotypicAllele​.​rpt

              ftp://​ftp.​informatics.​jax.​org/​pub/​reports/​MGI_​PhenoGenoMP.​rpt

              The mouse phenotype files were extracted using a perl script annotating each gene with the phenotype term associated with each Mammalian Phenotype (MP) code.

              Venn Diagram overlap of individual gene lists

              Individual GAD primary gene sets were analyzed using Venny[14]http://​bioinfogp.​cnb.​csic.​es/​tools/​venny/​index.​html. Pathway Venn Diagram comparisons were performed by placing individual GAD primary gene sets into WebGestalt [15]http://​bioinfo.​vanderbilt.​edu/​webgestalt/​ to identify KEGG pathways, then placing the resulting pathway names into Venny.

              Dendrogram analysis of gene sets

              Relationships between diseases were identified by a unique method similar to phyologenetic classification. First the distance between the diseases were calculated by pairwise comparison of the diseases by finding the common genes between the pairs and dividing it by the smallest group of the pair. This number was then subtracted from 1. This step was done because if two lists are identical (100% match) then the resultant distance should be 0. This is represented in the formula:
              http://static-content.springer.com/image/art%3A10.1186%2F1755-8794-3-1/MediaObjects/12920_2009_Article_136_Equa_HTML.gif

              Where: C k : Genes in each disease set (where k = i, j); N(C k ): Number of genes in each disease set (where k = i, j); dij is the pairwise distance; i, j: index of genes in each disease set where; i = 1, 2, 3, ........., n; j = 1, 2, 3, ........., m

              The disease relationships were calculated from the distance matrix using the Fitch program from the Phylip package[16]. It calculates the relationships based on the Fitch and Margoliash method of constructing the phylogenetic trees[17] using the following formula (from the Phylip manual):
              http://static-content.springer.com/image/art%3A10.1186%2F1755-8794-3-1/MediaObjects/12920_2009_Article_136_Equb_HTML.gif

              where D is the observed distance between gene sets i and j and d is the expected distance, computed as the sum of the lengths of the segments of the tree from gene set i to gene set j. The quantity n is the number of times each distance has been replicated. In simple cases n is taken to be one. If n is chosen more than 1, the distance is then assumed to be a mean of those replicates. The power P is what distinguished between the Fitch and Neighbor-Joining methods. For the Fitch-Margoliash method P is 2.0 and for Neighbor-Joining method it is 0.0. As running Fitch took a long time when the gene-set size was huge (weeks for the human gene-sets and months for the mouse gene-sets), Neighbor-Joining method was used to create the replicate dendrograms (not shown) after randomizing the input order for greater confidence. The resulting coefficient matrix files were displayed using the Phylodraw graphics program[18].

              Hierarchical clustering of gene sets

              Ward's minimum variance method[19] was used to find the distance between two diseases. The distance between the clusters is the ANOVA sum of squares between the two clusters added up over all the variables. At each generation, the within-cluster sum of squares is minimized over all partitions obtainable by merging two clusters from the previous generation. Ward's method joins clusters to maximize the likelihood at each level of the hierarchy under the assumptions of multivariate normal mixtures, spherical covariance matrices, and equal sampling probabilities. Distance for Ward's method is: http://static-content.springer.com/image/art%3A10.1186%2F1755-8794-3-1/MediaObjects/12920_2009_Article_136_IEq1_HTML.gif (taken from JMP Manual) where NK is the number of observations in CK (which is the Kth cluster, subset of {1, 2, ..., n) where n is the number of observations). http://static-content.springer.com/image/art%3A10.1186%2F1755-8794-3-1/MediaObjects/12920_2009_Article_136_IEq2_HTML.gif is the mean vector for cluster CK.

              Results

              Each record in GAD represents a specific gene from a unique publication of a human population based genetic association study and is categorized into one of 24 general disease classes corresponding to broad MeSH disease or disease phenotypic groupings. Table 1 is a summary of the number of positively associated human genes in each MeSH human disease class. As represented by these disease classes the GAD database covers a broad selection of diseases falling into major disease classes including; aging studies, cancer, immune disorders, psychiatric diseases, metabolic conditions, pharmacogenomic studies, and studies of chemical dependency, among others. Similarly, each record in the phenotype files from the MGI phenotype database represents a unique mouse gene specific genetic model. Table 2 shows the general categories represented by the mouse phenotype summary files and the number of mouse genes found in each top level phenotype class. The mouse files contain a greater number of intermediate developmental and morphological phenotypes (e.g. insulin resistance, absent CD4+ T cells, abnormal spatial learning) while the human files tend to comprise a greater number of end stage clinical disease phenotypes (e.g. Type 2 Diabetes, multiple sclerosis, autism).
              Table 1

              Number of human genes associated in each Disease Class

              DISEASE CLASS

              # of human genes in each disease class

              Neoplasms

              1835

              Cardiovascular Diseases

              1112

              Pathological Conditions, Signs and Symptoms

              938

              Nervous System Diseases

              902

              Nutritional and Metabolic Diseases

              838

              Mental Disorders

              554

              Digestive System Diseases

              407

              Male Urogenital Diseases

              396

              Musculoskeletal Diseases

              366

              Respiratory Tract Diseases

              362

              Bacterial Infections and Mycoses

              256

              Disorders of Environmental Origin

              243

              Female Urogenital Diseases and Pregnancy Complications

              226

              Virus Diseases

              224

              Skin and Connective Tissue Diseases

              212

              Hemic and Lymphatic Diseases

              183

              Eye Diseases

              176

              Congenital, Hereditary, and Neonatal Diseases and Abnormalities

              142

              Stomatognathic Diseases

              130

              Immune System Diseases

              116

              Endocrine System Diseases

              98

              Parasitic Diseases

              57

              Otorhinolaryngologic Diseases

              35

              Animal Diseases

              4

              Table 2

              Number of Mouse genes in each General Phenotypic Class

              PHENOTYPIC CLASS

              # of Mouse genes in each class

              unassigned top level

              19186

              nervous system phenotype

              8149

              immune system phenotype

              6414

              homeostasis/metabolism phenotype

              5976

              skeleton phenotype

              5559

              growth/size phenotype

              5556

              behavior/neurological phenotype

              5417

              cardiovascular system phenotype

              5221

              hematopoietic system phenotype

              5163

              reproductive system phenotype

              4762

              lethality-prenatal/perinatal

              4409

              embryogenesis phenotype

              3416

              skin/coat/nails phenotype

              3048

              vision/eye phenotype

              2710

              hearing/vestibular/ear phenotype

              2447

              muscle phenotype

              2370

              cellular phenotype

              2335

              normal phenotype

              2120

              renal/urinary system phenotype

              2104

              endocrine/exocrine gland phenotype

              1871

              life span-post-weaning/aging

              1857

              respiratory system phenotype

              1832

              digestive/alimentary phenotype

              1780

              lethality-postnatal

              1777

              liver/biliary system phenotype

              1498

              limbs/digits/tail phenotype

              1282

              tumorigenesis

              1268

              adipose tissue phenotype

              1067

              craniofacial phenotype

              1016

              pigmentation phenotype

              634

              touch/vibrissae phenotype

              625

              no phenotypic analysis

              403

              other phenotype

              343

              taste/olfaction phenotype

              156

              Table 3 introduces examples of human genes from fundamental biological pathways that have been consistently associated with major disease phenotypes highlighting the sometimes-broad pleiotropic effects that major regulatory molecules have on multiple disease phenotypes. Genes such as NOS3, nitric oxide synthase 3, regulating nitrous oxide production; HLA-DQB1, the MHC class II molecule DQ beta 1, involved in antigen presentation; ACE, angiotensin I converting enzyme, central to the renin-angiotensin system and PPARG, peroxisome proliferator-activated receptor gamma, regulating transcription in pathways important in lipid metabolism are examples of genes that affect multiple tissues and different organ systems through the complex course of disease progression. Importantly, all the mouse orthologs of the human genes in Table 3 have experimentally determined phenotypes that are similar or broadly overlapping with human clinical disease phenotypes (see below).
              Table 3

              Selected Major Genes and Disease Phenotypes

              Gene

               

              Gene

               

              APOE

              ALZHEIMER DISEASE (70)

              VDR

              PROSTATIC NEOPLASMS (10)

               

              CORONARY DISEASE (8)

               

              OSTEOPOROSIS, POSTMENOPAUSAL (8)

               

              CARDIOVASCULAR DISEASES (7)

               

              BREAST NEOPLASMS (7)

               

              MYOCARDIAL INFARCTION (6)

               

              DIABETES MELLITUS, TYPE 1 (6)

               

              DIABETES MELLITUS, TYPE 2 (6)

               

              OSTEOPOROSIS (6)

              ACE

              HYPERTENSION (47)

              MTHFR

              NEURAL TUBE DEFECTS (6)

               

              DIABETES MELLITUS, TYPE 2 (25)

               

              COLORECTAL NEOPLASMS (5)

               

              MYOCARDIAL INFARCTION (17)

               

              DIABETES MELLITUS, TYPE 2 (5)

               

              CORONARY DISEASE (16)

               

              ESOPHAGEAL NEOPLASMS (5)

               

              DIABETIC NEPHROPATHIES (15)

               

              ADENOCARCINOMA (4)

              HLA-DQB1

              DIABETES MELLITUS, TYPE 1 (30)

              CYP17A1

              BREAST NEOPLASMS (10)

               

              PAPILLOMAVIRUS INFECTIONS (7)

               

              PROSTATIC NEOPLASMS (9)

               

              CELIAC DISEASE (6)

               

              PROSTATIC HYPERPLASIA (4)

               

              AUTOIMMUNE DISEASES (5)

               

              OSTEOPOROSIS, POSTMENOPAUSAL (3)

               

              TUBERCULOSIS, PULMONARY (5)

               

              ENDOMETRIAL NEOPLASMS (2)

              DRD2

              ALCOHOLISM (17)

              ADRB2

              ASTHMA (12)

               

              SCHIZOPHRENIA (14)

               

              OBESITY (10)

               

              PERSONALITY DISORDER (2)

               

              HYPERTENSION (8)

               

              DEPRESSIVE DISORDER (2)

               

              DIABETES MELLITUS, TYPE 2 (4)

               

              DYSKINESIA, DRUG INDUCED (2)

               

              BRONCHIAL HYPERREACTIVITY (4)

              PPARG

              DIABETES MELLITUS, TYPE 2 (18)

              NOS3

              HYPERTENSION (20)

               

              OBESITY (11)

               

              MYOCARDIAL INFARCTION (18)

               

              DIABETES MELLITUS (6)

               

              CORONARY ARTERY DISEASE (15)

               

              INSULIN RESISTANCE (4)

               

              CORONARY DISEASE (12)

               

              GLUCOSE INTOLERANCE (2)

               

              DIABETES MELLITUS, TYPE 2 (10)

              Summaries of genes and phenotypes in human and mouse

              The majority of this report is built upon large non-redundant general summary lists for both human and mouse, shown below. These lists take two complimentary forms in both human and mouse. The first sets are GENE-to-Disease/Phenotype lists. These are non-redundant lists of genes showing the diseases or phenotypes that have been associated with each gene (Table 4 human, table 5 mouse, and table 6 human-mouse). The second sets of basic lists are DISEASE/PHENOTYPE-to-Gene lists. These are non redundant lists of diseases or phenotypes with the genes that have been associated with that disease or phenotype (Table 7 human and table 8 mouse).
              Table 4

              Selected Human Genes and Disease Phenotype (MeSH counts), positive associations

              Gene ID

              HUGO Gene Sym.

              MESH TERM 1

              MESH TERM 2

              MESH TERM 3

              MESH TERM 4

              348

              APOE

              Alzheimer Disease(70)

              Coronary Disease(8)

              Cardiovascular Diseases(7)

              Diabetes Mellitus, Type 2(6)

              1636

              ACE

              Hypertension(47)

              Diabetes Mellitus, Type 2(25)

              Myocardial Infarction(17)

              Coronary Disease(16)

              3119

              HLA-DQB1

              Diabetes Mellitus, Type 1(30)

              Papillomavirus Infections(7)

              Celiac Disease(6)

              Tuberculosis, Pulmonary(5)

              1493

              CTLA4

              Diabetes Mellitus, Type 1(28)

              Graves Disease(21)

              Thyroiditis, Autoimmune(10)

              Autoimmune Diseases(8)

              183

              AGT

              Hypertension(24)

              Coronary Disease(6)

              Diabetic Nephropathies(5)

              Myocardial Infarction(5)

              1814

              DRD3

              Schizophrenia(24)

              Dyskinesia, Drug-Induced(6)

              Psychotic Disorders(5)

              Alcoholism(2)

              4846

              NOS3

              Hypertension(20)

              Myocardial Infarction(18)

              Coronary Artery Disease(15)

              Coronary Disease(12)

              3075

              CFH

              Macular Degeneration(19)

              Choroidal Neovascularization(3)

              Hemolytic-Uremic Syndrome(2)

              Atrophy(2)

              3077

              HFE

              Hemochromatosis(18)

              Cardiovascular Diseases(1)

              Colorectal Neoplasms(1)

              Liver Cirrhosis(1)

              3356

              HTR2A

              Schizophrenia(18)

              Alzheimer Disease(4)

              Depressive Disorder(4)

              Depressive Disorder, Major(4)

              1585

              CYP11B2

              Hypertension(18)

              Cardiovascular Diseases(2)

              Ventricular Dysfunction, Left(2)

              Cardiomyopathy, Dilated(2)

              5468

              PPARG

              Diabetes Mellitus, Type 2(18)

              Obesity(11)

              Diabetes Mellitus(6)

              Insulin Resistance(4)

              2784

              GNB3

              Hypertension(18)

              Insulin Resistance(4)

              Diabetes Mellitus, Type 2(3)

              Obesity(3)

              1815

              DRD4

              Attention Def. Dis. with Hyperact. (17)

              Schizophrenia(8)

              Substance-Related Disorders(4)

              Mood Disorders(4)

              1813

              DRD2

              Alcoholism(17)

              Schizophrenia(14)

              Personality Disorders(2)

              Depressive Disorder(2)

              155

              ADRB3

              Obesity(17)

              Diabetes Mellitus, Type 2(9)

              Insulin Resistance(6)

              Endometrial Neoplasms(2)

              9370

              ADIPOQ

              Diabetes Mellitus, Type 2(17)

              Insulin Resistance(11)

              Obesity(8)

              Hypertension(4)

              3123

              HLA-DRB1

              Arthritis, Rheumatoid(16)

              Diabetes Mellitus, Type 1(16)

              Multiple Sclerosis(8)

              Lupus Erythematosus, Systemic(7)

              118

              ADD1

              Hypertension(16)

              Cardiovascular Diseases(3)

              Cerebral Hemorrhage(1)

              Diabetic Angiopathies(1)

              3117

              HLA-DQA1

              Diabetes Mellitus, Type 1(15)

              Graves Disease(4)

              Autoimmune Diseases(4)

              Celiac Disease(4)

              1956

              EGFR

              Lung Neoplasms(15)

              Carcinoma, Non-SC Lung(10)

              Adenocarcinoma(6)

              Neoplasm Recurrence, Local(3)

              6690

              SPINK1

              Pancreatitis(15)

              Chronic Disease(11)

              Acute Disease(3)

              Pancreatitis, Alcoholic(3)

              6934

              TCF7L2

              Diabetes Mellitus, Type 2(15)

              Insulin Resistance(4)

              Diabetes Mellitus(2)

              Liver Neoplasms(1)

              1234

              CCR5

              HIV Infections(14)

              Diabetes Mellitus, Type 2(4)

              Diabetic Nephropathies(4)

              Asthma(3)

              5663

              PSEN1

              Alzheimer Disease(14)

              Down Syndrome(2)

              Dementia(1)

              Cerebral Amyloid Angiopathy(1)

              11132

              CAPN10

              Diabetes Mellitus, Type 2(14)

              Insulin Resistance(3)

              Polycystic Ovary Syndrome(2)

              Obesity(2)

              3553

              IL1B

              Stomach Neoplasms(14)

              Helicobacter Infections(6)

              Alzheimer Disease(5)

              Periodontitis(3)

              6532

              SLC6A4

              Depressive Disorder, Major(13)

              Depressive Disorder(13)

              Bipolar Disorder(10)

              Alcoholism(8)

              4210

              MEFV

              Familial Mediterranean Fever(13)

              Amyloidosis(4)

              Behcet Syndrome(3)

              Colitis, Ulcerative(2)

              3172

              HNF4A

              Diabetes Mellitus, Type 2(13)

              Glucose Intolerance(2)

              Birth Weight(1)

              Fetal Macrosomia(1)

              7157

              TP53

              Carcinoma, Squamous Cell(13)

              Lung Neoplasms(12)

              Breast Neoplasms(10)

              Carcinoma, Non-SC Lung(9)

              672

              BRCA1

              Breast Neoplasms(12)

              Ovarian Neoplasms(5)

              Carcinoma, Endometrioid(1)

              DNA Damage(1)

              185

              AGTR1

              Hypertension(12)

              Myocardial Infarction(3)

              Coronary Disease(3)

              Pregnancy Comp., Cardiovascular(2)

              154

              ADRB2

              Asthma(12)

              Obesity(10)

              Hypertension(8)

              Diabetes Mellitus, Type 2(4)

              3953

              LEPR

              Obesity(12)

              Body Weight(4)

              Insulin Resistance(4)

              Glucose Intolerance(3)

              2169

              FABP2

              Diabetes Mellitus, Type 2(12)

              Insulin Resistance(10)

              Obesity(7)

              Hyperlipidemias(4)

              929

              CD14

              Asthma(12)

              Myocardial Infarction(5)

              Arteriosclerosis(4)

              Colitis, Ulcerative(4)

              26191

              PTPN22

              Arthritis, Rheumatoid(11)

              Diabetes Mellitus, Type 1(9)

              Lupus Erythematosus, Systemic(5)

              Arthritis, Psoriatic(2)

              3596

              IL13

              Asthma(11)

              Hypersensitivity, Immediate(4)

              Pulmonary Dis., Chronic Obstr. (4)

              Respiratory Hypersensitivity(2)

              1080

              CFTR

              Cystic Fibrosis(10)

              Pancreatitis(5)

              Chronic Disease(3)

              Acute Disease(2)

              Table 5

              Selected Mouse Genes-Disease Phenotypes

              Mouse Gene Sym.

              Human Ortholog Gene Sym.

              Mouse Phenotype 1

              Mouse Phenotype 2

              Mouse Phenotype 3

              Mouse Phenotype 4

              Mouse Phenotype 5

              A4galt

              A4GALT

              abnormal induced morb./mort.

              abnormal resp./metab. to xenobiotics

              life span-post-weaning/aging

              homeostasis/metab. phenotype

               

              Abca2

              ABCA2

              tremors

              decreased body weight

              behavior/neurological phenotype

              hyperactivity

              increased startle reflex

              Abcc2

              ABCC2

              abnormal blood chemistry

              abnormal liver physiology

              abnormal urine chemistry

              abnormal kidney physiology

              Abn. resp./metabolism to xenobiotics

              Abi2

              ABI2

              abn. corpus callosum morph.

              abnormal cerebral cortex morph.

              abnormal hippocampus morph.

              abnormal dentate gyrus morph.

              microphthalmia

              Acaca

              ACACA

              abnormal liver physiology

              abnormal lipid level

              incr. circulating free fatty acid level

              hyperglycemia

              embryonic growth arrest

              Acads

              ACADS

              hypoglycemia

              behavior/neurological phenotype

              abnormal drinking behavior

              abnormal food preference

              abnormal urine chemistry

              Accn1

              ACCN1

              retinal degeneration

              vision/eye phenotype

              abnormal eye electrophysiology

                

              Adad1

              ADAD1

              impaired fertilization

              male infertility

              asthenozoospermia

              oligozoospermia

              reproductive system phenotype

              Adam23

              ADAM23

              tremors

              behavior/neurological phenotype

              ataxia

              postnatal lethality

              lethality-postnatal

              Adarb1

              ADARB1

              behavior/neurological phenot.

              seizures

              postnatal lethality

              behavior/neurological phenotype

              normal phenotype

              Adipoq

              ADIPOQ

              vasculature congestion

              increased body weight

              decreased body weight

              abnormal CNS syn. transmission

              abnormal coat appearance

              Adora1

              ADORA1

              behavior/neurological phenot.

              increased anxiety-related response

              abnormal body temperature regulation

              abnormal angiogenesis

              abnormal nervous system electrophys.

              Ager

              AGER

              increased bone density

              abnormal cancellous bone morph.

              abnormal blood chemistry

              reproductive system phenotype

              abnormal cell proliferation

              Akap1

              AKAP1

              reduced female fertility

              decreased litter size

              abnormal female meiosis

              increased cholesterol level

               

              Apoc1

              APOC1

              abnormal circ. cholesterol level

              abnormal lipid level

              increased circulating triglyceride level

              abnormal immune sys. Morph.

              abnormal bile composition

              B2m

              B2M

              decreased hematocrit

              abnormal interleukin-10 physiology

              rectal prolapse

              abnormal dorsal root gang. morph.

              enlarged spleen

              Bax

              BAX

              enlarged spleen

              increased thymocyte number

              abnormal motor neuron morph.

              short snout

              abnormal sympathetic neuron morph.

              Bcl2

              BCL2

              small ears

              absent melanin granules in hair follicle

              abnormal snout morph.

              herniated abdominal wall

              abnormal small intestine morph.

              Bmp1

              BMP1

              abnormal heart morph.

              abnormal aorta morph.

              abnormal ventricular septum morph.

              abnormal awl hair

              prenatal lethality

              Brca1

              BRCA1

              abnormal cell death

              increased cell proliferation

              decreased cell proliferation

              decreased anxiety-related resp.

              kinked tail

              Capn10

              CAPN10

              abnormal pancreas physiology

              endocrine/exocrine gland phenotype

              digestive/alimentary phenotype

              decreased inflammatory response

               

              Casp1

              CASP1

              abnormal apoptosis

              abnormal induced morbidity/mortality

              abnormal inflammatory response

              decr. suscep. to endotoxin shock

              tumorigenesis

              Ccr4

              CCR4

              immune system phenotype

              decreased tumor necrosis factor secr.

              decreased interleukin-1 beta secretion

              abnormal induced morbid./mort.

               

              Dusp1

              DUSP1

              thick alveolar septum

              abnormal circ. alanine transaminase

              hypotension

              increased thymocyte number

              lung inflammation

              E2f1

              E2F1

              abnormal cell death

              decreased salivation

              enlarged thymus

              pale liver

              exencephaly

              Epo

              EPO

              abnormal erythropoiesis

              abnormal pericardium morph.

              small liver

              postnatal growth retardation

              abnormal hepatocyte morph.

              Ercc4

              ERCC4

              abnormal cell content/morph.

              abnormal liver morph.

              decreased body weight

              absent blood islands

              liver/biliary system phenotype

              F5

              F5

              behavior/neurological phenot.

              abnormal somite development

              abnormal yolk sac morph.

              increased suscep. to bact. Infect.

              hemorrhage

              Fcgr1

              FCGR1A

              impaired macrophage phagocyt.

              abnormal inflammatory response

              decreased inflammatory response

              abnormal yolk sac morph.

              abnormal cell-mediated immunity

              Foxo1

              FOXO1

              absent organized vascular net.

              abnormal looping morphogenesis

              abnormal vasculature

              exencephaly

              absent vitelline blood vessels

              Gadd45a

              GADD45A

              decreased leukocyte cell num.

              increased cell proliferation

              increased thymocyte number

              postnatal lethality

              skin irradiation sensitivity

              Gap43

              GAP43

              decreased body weight

              abnormal optic nerve innervation

              absent optic tract

              abnormal erythropoiesis

              nervous system phenotype

              Gata1

              GATA1

              decreased hematocrit

              abnormal thrombopoiesis

              extramedullary hematopoiesis

              overexpanded resp. alveoli

              liver hypoplasia

              Grin1

              GRIN1

              abn. trigeminal nerve morph.

              atelectasis

              lung hemorrhage

              abnormal tympanic ring morph.

              decreased body weight

              Hoxa1

              HOXA1

              small ears

              abnormal inner ear morph.

              abnormal malleus morph.

              increased susceptibility to injury

              abnormal cochlea morph.

              Hspa1a

              HSPA1A

              decreased body weight

              increased cell. Sens. to gamma-irrad.

              chromosome breakage

              increased body weight

              homeostasis/metabolism phenotype

              Icam1

              ICAM1

              increased leukocyte cell number

              increased neutrophil cell number

              increased monocyte cell number

              abnormal spatial learning

              abnormal retina morph.

              Igbp1

              IGBP1

              decreased thymocyte number

              behavior/neurological phenotype

              abnormal cued conditioning behavior

              intestinal ulcer

              abnormal thymus lobule morph.

              Table 6

              Selected Human-Mouse Phenotype Overlap

              Mouse Gene Sym

              Human Gene Sym

              Human Gene ID #

              Human Disease MeshTerm

              Mouse Phenotype Term

              Npc1l1

              NPC1L1

              29881

              Hypercholesterolemia(1)

              abnormal circulating LDL cholesterol level;

              decreased circulating HDL cholesterol level;

              abnormal triglyceride level;

              abnormal lipid homeostasis; ...

              Nkx2-5

              NKX2-5

              1482

              Heart Defects, Congenital(1),

              Heart Block(1)

              abnormal heart development;

              abnormal looping morphogenesis;

              abnormal heart tube morphology;

              abnormal heart shape;

              thin ventricular wall; ...

              Oprm1

              OPRM1

              4988

              Alcoholism(9),

              Substance-Related Disorders(5),

              Heroin Dependence(2), Pain,

              Postoperative(2),

              Epilepsy, Generalized(1),

              Substance Withdrawal Syndrome(1),

              Cocaine-Related Disorders(1),

              Diabetes Mellitus, Type 2(1),

              Kidney Failure, Chronic(1),

              Pain(1), Ischemia(1),

              Opioid-Related Disorders(1),

              Postoperative Nausea and Vomiting(1)

              abnormal response to addictive substance;

              preference for addictive substance;

              abnormal touch/nociception;

              abnormal pain threshold;

              decreased chemically-elicited antinociception;

              sensitivity to addictive substance;

              excitatory postsyn. potential;

              resistance to addictive substance;

              altered response to anesthetics; ...

              Homer1

              HOMER1

              9456

              Cocaine-Related Disorders(1)

              cocaine preference;

              abnormal conditioning behavior;

              abnormal response to addictive substance;

              nervous system phenotype;

              abnormal nervous system physiology;

              behavior/neurological phenotype, ...

              Insl3

              INSL3

              3640

              Cryptorchidism(3),

              Abnormalities, Multiple(1),

              Hypospadias(1),

              Gonadal Dysgenesis(1),

              Infertility, Male(1),

              Testicular Diseases(1)

              abnormal male reproductive anatomy;

              small testis;

              abnormal spermatogenesis;

              behavior/neurological phenotype;

              male infertility;

              female infertility;

              abnormal estrous cycle;

              abnormal gametogenesis;

              decreased germ cell number;

              cryptorchism; ...

              Stat6

              STAT6

              6778

              Asthma(3),

              Hypersensitivity(3),

              Dermatitis, Atopic(2),

              Anaphylaxis(2),

              Nut Hypersensitivity(1),

              Nephrotic Syndrome(1),

              Infertility(1),

              Hypersensitivity, Immediate(1),

              Graves Disease(1),

              Endometriosis(1), ...

              abnormal humoral immune response;

              decreased IgM level;

              decreased IgA level;

              decreased susceptibility to viral infection;

              decreased IgE level;

              increased IgG level;

              increased IgA level;

              abnormal interleukin physiology;

              abnormal interferon physiology;

              abnormal CD8-positive T cell morphology; ...

              En2

              EN2

              2020

              Autistic Disorder(1),

              Asperger Syndrome(1)

              abnormal social investigation;

              abnormal spatial learning;

              abnormal social/conspecific interaction;

              abnormal cerebellum morphology;

              abnormal cerebellar foliation;

              abnormal vermis morphology;

              abnormal cerebellar granule layer;

              abnormal colliculi morphology;

              hyperactivity;

              impaired coordination;

              abnormal grooming behavior; ...

              Hsd11b1

              HSD11B1

              3290

              Diabetes Mellitus, Type 2(2),

              Obesity(2),

              Hypertension(2),

              Insulin Resistance(2),

              Polycystic Ovary Syndrome(1),

              Hyperandrogenism(1)

              abnormal abdominal fat pads;

              abnormal circulating cholesterol level;

              decreased circulating LDL cholesterol level;

              enlarged adrenal glands;

              increased circulating HDL cholesterol level;

              abnormal glucose homeostasis;

              decreased circulating triglyceride level;

              abnormal corticosterone level;

              improved glucose tolerance; ...

              Msh3

              MSH3

              4437

              Lung Neoplasms(1),

              Head and Neck Neoplasms(1),

              Colonic Neoplasms(1),

              Carcinoma, Squamous Cell(1),

              Carcinoma, Small Cell(1)

              tumorigenesis;

              increased tumor incidence;

              premature death;

              life span-post-weaning/aging

              Crb1

              CRB1

              23418

              Optic Atrophies, Hereditary(1),

              Blindness(1)

              abnormal retinal photoreceptor morphology;

              abnormal retina morphology;

              retinal degeneration;

              decreased retinal photoreceptor cell number;

              photosensitivity;

              abnormal ocular fundus morphology;

              nervous system phenotype;

              abnormal retinal photoreceptor layer;

              abnormal photoreceptor inner segment morph; ...

              Chrna7

              CHRNA7

              1139

              Schizophrenia(3),

              Auditory Perceptual Disorders(1),

              Memory Disorders(1)

              pharmacologically induced seizures;

              decreased anxiety-related response;

              abnormal spatial learning;

              abnormal hippocampus function;

              abnormal tumor necrosis factor physiology;

              homeostasis/metabolism phenotype

              Inha

              INHA

              3623

              Ovarian Failure, Premature(2),

              Amenorrhea(1)

              kyphoscoliosis;

              abnormal liver morphology;

              abnormal ovarian follicle morphology;

              enlarged testes;

              abnormal spermatogenesis;

              increased circulating follicle stimulating hormone;

              male infertility;

              female infertility;

              tumorigenesis;

              ovary hemorrhage;

              cachexia;

              diffuse hepatic necrosis;

              pancytopenia;

              liver/biliary system phenotype; ...

              Slc6a3

              SLC6A3

              6531

              Attention Deficit Disorder w/Hyp.(7),

              Tobacco Use Disorder(3),

              Schizophrenia(2),

              Alcohol Withdrawal Delirium(2),

              Eating Disorders(1),

              Substance Withdrawal Syndrome(1),

              Stress Disorders, Post-Traumatic(1),

              Child Behavior Disorders(1),

              Bulimia(1),

              Alcoholism(1),

              abnormal maternal nurturing;

              hyperactivity; hypoactivity;

              impaired coordination;

              increased exploration in new environment;

              decreased exploration in new environment;

              abnormal spatial learning;

              abnormal pituitary secretion;

              abnormal lactation;

              increased dopamine level;

              cocaine preference; ...

              Cyp11b2

              CYP11B2

              1585

              Hypertension(18),

              Cardiovascular Diseases(2),

              Ventricular Dysfunction, Left(2),

              Cardiomyopathy, Dilated(2),

              Arteriosclerosis(1),

              Acromegaly(1),

              Fibrosis(1),

              Arthritis, Rheumatoid(1),

              Polycystic Ovary Syndrome(1),

              Metabolic Syndrome X(1),

              decreased body size;

              hypotension;

              increased circulating corticosterone level;

              decreased circulating aldosterone level;

              decreased circulating chloride level;

              increased circulating renin level;

              abnormal enzyme/coenzyme level;

              lethality-postnatal;

              homeostasis/metabolism phenotype;

              growth/size phenotype; ...

              Ptpn22

              PTPN22

              26191

              Arthritis, Rheumatoid(11),

              Diabetes Mellitus, Type 1(9),

              Lupus Erythematosus, Systemic(5),

              Arthritis, Psoriatic(2),

              Autoimmune Diseases(2),

              Arthritis, Juvenile Rheumatoid(2),

              Nephritis(1),

              Multiple Sclerosis(1),

              Asthma(1),

              Cholangitis, Sclerosing(1),

              enlarged spleen;

              enlarged lymph nodes;

              abnormal Peyer's patch germinal center morph;

              abnormal T cell physiology;

              increased IgE level;

              increased B cell number;

              immune system phenotype;

              hematopoietic system phenotype;

              increased follicular B cell number;

              increased spleen germinal center number;

              increased IgG1 level;

              increased IgG2a level; ...

              Table 7

              Selected Human Disease Phenotypes (MeSH) and Gene counts, positive associations

              Disease Mesh Term

              Gene Rank 1

              Gene Rank 2

              Gene Rank 3

              Gene Rank 4

              Gene Rank 5

              Gene Rank 6

              Gene Rank 7

              Gene Rank 8

              DISEASE CLASS - CARDIOVASCULAR

                      

              Hypertension

              ACE(47)

              AGT(24)

              NOS3(20)

              CYP11B2(18)

              GNB3(18)

              ADD1(16)

              AGTR1(12)

              ADRB2(8)

              Myocardial Infarction

              NOS3(18)

              ACE(17)

              SERPINE1(11)

              ITGA2(7)

              LPL(6)

              APOE(6)

              GP1BA(5)

              F7(5)

              Coronary Disease

              ACE(16)

              NOS3(12)

              PON1(11)

              APOB(11)

              APOE(8)

              LPL(7)

              AGT(6)

              SERPINE1(6)

              Coronary Artery Disease

              NOS3(15)

              PON1(9)

              ACE(7)

              APOA5(6)

              APOE(5)

              AGT(4)

              ABCA1(4)

              APOA1(4)

              Hypertrophy, Left Ventricular

              ACE(15)

              GNB3(3)

              AGTR2(2)

              EDN1(2)

              TNNT2(2)

              NOS3(2)

              ENPP1(1)

              ACE2(1)

              Venous Thrombosis

              F5(8)

              F2(5)

              SERPINE1(4)

              MTHFR(3)

              ABO(2)

              F8(2)

              JAK2(2)

              PROCR(2)

              Cardiovascular Diseases

              APOE(7)

              CETP(6)

              ACE(5)

              NOS3(5)

              PON1(4)

              APOA5(4)

              APOC3(4)

              SERPINE1(3)

              Myocardial Ischemia

              ACE(6)

              LPL(5)

              NOS3(2)

              ITGB3(2)

              APOB(2)

              AGT(1)

              AGTR1(1)

              SELPLG(1)

              Arteriosclerosis

              ACE(5)

              CD14(4)

              PON1(3)

              FGB(3)

              MTHFR(3)

              NOS3(3)

              APOE(3)

              TLR4(2)

              Cardiomyopathies

              TTR(5)

              HFE(1)

              APOA1(1)

              HLADQB1(1)

              SOD2(1)

              CCR2(1)

              SELE(1)

              MMP9(1)

              Heart Failure

              ADRA2C(5)

              ADRB1(5)

              ACE(3)

              NOS3(3)

              ADRB2(3)

              AMPD1(2)

              SCNN1B(1)

              EDN1(1)

              DISEASE CLASS - DIGESTIVE SYS. DISEASES

                      

              Pancreatitis

              SPINK1(15)

              CFTR(5)

              PRSS1(3)

              HLA-DRB1(2)

              HLA-A(1)

              TLR4(1)

              UGT1A7(1)

              KRT8(1)

              Cystic Fibrosis

              CFTR(10)

              NOS1(2)

              SERPINA1(2)

              SPINK1(1)

              CAPN10(1)

              SFTPA2(1)

              GCLC(1)

              FCGR2A(1)

              Celiac Disease

              HLADQB1(6)

              CTLA4(6)

              HLADQA1(4)

              TNF(2)

              PTPN22(1)

              IFNG(1)

              TIPARP(1)

              IL21(1)

              Crohn Disease

              IL23R(6)

              NOD2(5)

              TNF(5)

              ABCB1(4)

              CD14(4)

              IBD5(3)

              DLG5(3)

              MIF(3)

              Liver Cirrhosis, Alcoholic

              ALDH2(6)

              ACE(1)

              TNF(1)

              SOD2(1)

              ADH1C(1)

              ADH1B(1)

              DRD2(1)

              CYP2E1(1)

              Colitis, Ulcerative

              ABCB1(5)

              IL23R(5)

              TNF(4)

              CD14(4)

              TLR4(3)

              ICAM1(3)

              IL1RN(3)

              CTLA4(3)

              Gastritis, Atrophic

              MPO(3)

              TLR4(1)

              IL13(1)

              PTPN11(1)

              TNF(1)

              ABO(1)

              CMA1(1)

              IL1B(1)

              Inflammatory Bowel Diseases

              TNF(3)

              ABCB1(3)

              IL23R(3)

              ITPA(2)

              NOD2(2)

              DLG5(2)

              HP(2)

              PON1(1)

              Cholangitis, Sclerosing

              HLADRB1(2)

              HP(2)

              PTPN22(1)

              MMP1(1)

              HLADQA1(1)

              TNF(1)

              HLADQB1(1)

              MMP3(1)

              DISEASE CLASS - DIS. OF ENVIRONMENTAL ORIGIN

                      

              Alcoholism

              DRD2(17)

              OPRM1(9)

              SLC6A4(8)

              ALDH2(7)

              MAOA(6)

              GABRA2(4)

              NPY(4)

              ADH1B(3)

              DNA Damage

              XRCC1(7)

              TP53(3)

              CYP1A1(3)

              GSTM1(3)

              OGG1(3)

              LIG4(2)

              APEX1(2)

              BRCA2(2)

              Substance-Related Disorders

              SLC6A4(5)

              OPRM1(5)

              DRD4(4)

              DRD5(2)

              BDNF(2)

              ADH4(2)

              CNR1(2)

              DRD2(2)

              Fractures, Bone

              ESR1(4)

              ESR2(2)

              COL1A1(2)

              CYP19A1(1)

              IGF1(1)

              TNFRSF11B(1)

              P2RX7(1)

              TGFB1(1)

              Tobacco Use Disorder

              CYP2A6(3)

              SLC6A3(3)

              CHRNA4(2)

              TH(2)

              BDNF(1)

              PPP1R1B(1)

              SLC18A2(1)

              PTEN(1)

              Cocaine-Related Disorders

              PDYN(2)

              HOMER1(1)

              TTC12(1)

              ANKK1(1)

              DBH(1)

              GSTP1(1)

              OPRM1(1)

               

              Heroin Dependence

              OPRM1(2)

              BDNF(1)

              OPRD1(1)

              SLC6A4(1)

              COMT(1)

              MAOA(1)

                

              Spinal Fractures

              COL1A1(2)

              CYP19A1(1)

              TNFRSF11B(1)

              GC(1)

              PLXNA2(1)

              AR(1)

              NOS3(1)

               

              DISEASE CLASS - IMMUNE SYSTEM

                      

              Autoimmune Diseases

              CTLA4(8)

              HLADQB1(5)

              HLADRB1(4)

              HLADQA1(4)

              PTPN22(2)

              HLA-A(2)

              CYP2D6(2)

              CIITA(2)

              Hypersensitivity, Immediate

              IL4R(8)

              IL13(4)

              CD14(4)

              IL4(2)

              SERPINE1(2)

              CCL5(2)

              NOS2A(2)

              CTLA4(2)

              Graft vs Host Disease

              IFNG(3)

              TNF(2)

              TLR4(1)

              NOD2(1)

              HLA-DPB1(1)

              HLA-A(1)

              IL10(1)

              IL1R1(1)

              Hypersensitivity

              IL4(3)

              STAT6(3)

              IL4R(2)

              IFNG(1)

              IFNGR1(1)

              TLR2(1)

              FADS1(1)

              IL13(1)

              Antiphospholipid Syndrome

              F2(2)

              SELPLG(1)

              SERPINE1(1)

              FCGR2A(1)

              HLADMA(1)

                 

              Food Hypersensitivity

              IL4(1)

              IL4R(1)

              STAT6(1)

              IL13(1)

              HLADQB1(1)

              CD14(1)

                

              DISEASE CLASS - MENTAL DISORDERS

                      

              Schizophrenia

              DRD3(24)

              HTR2A(18)

              DRD2(14)

              COMT(10)

              HTR2C(8)

              BDNF(8)

              DRD4(8)

              NOTCH4(8)

              Attention Deficit Disorder with Hyperactivity

              DRD4(17)

              SLC6A3(7)

              SLC6A4(6)

              ADRA2A(4)

              MAOA(3)

              SNAP25(3)

              SLC6A2(2)

              DRD5(2)

              Depressive Disorder

              SLC6A4(13)

              HTR2A(4)

              TPH1(3)

              CYP2D6(2)

              CYP2C19(2)

              MAOA(2)

              BDNF(2)

              DRD2(2)

              Depressive Disorder, Major

              SLC6A4(13)

              TPH1(5)

              HTR2A(4)

              TPH2(3)

              BDNF(2)

              DRD2(2)

              GNB3(2)

              DTNBP1(1)

              Bipolar Disorder

              SLC6A4(10)

              BDNF(6)

              MAOA(5)

              COMT(5)

              XBP1(3)

              GABRA5(3)

              HTR2A(3)

              TPH2(3)

              Anxiety Disorders

              SLC6A4(7)

              MAOA(3)

              PLXNA2(1)

              BDNF(1)

              DBI(1)

              MED12(1)

              GABRB3(1)

              DRD2(1)

              Mood Disorders

              SLC6A4(5)

              DRD4(4)

              CLOCK(2)

              MAOA(2)

              BDNF(2)

              ACE(1)

              CRH(1)

              DRD3(1)

              Psychotic Disorders

              DRD3(5)

              SLC6A4(3)

              DRD4(3)

              HTR2A(3)

              DTNBP1(2)

              DISC1(2)

              DRD2(2)

              MAOA(1)

              Obsessive-Compulsive Disorder

              SLC6A4(4)

              HTR2A(3)

              COMT(3)

              SLC1A1(2)

              DRD4(2)

              HTR1B(1)

              BDNF(1)

              NRCAM(1)

              Panic Disorder

              CCK(4)

              HTR1A(2)

              MAOA(2)

              HTR2A(2)

              DBI(1)

              CCKAR(1)

              ADORA2A(1)

              PGR(1)

              Cognition Disorders

              APOE(3)

              BDNF(3)

              DRD4(2)

              COMT(2)

              HMGCR(1)

              DTNBP1(1)

              SLC6A4(1)

              NQO1(1)

              DISEASE CLASS - NERVOUS SYSTEM DISEASES

                      

              Alzheimer Disease

              APOE(70)

              PSEN1(14)

              A2M(10)

              CYP46A1(8)

              ACE(7)

              BCHE(7)

              IL1A(7)

              BDNF(6)

              Parkinson Disease

              PARK2(9)

              LRRK2(9)

              CYP2D6(7)

              MAOB(7)

              BDNF(5)

              SNCA(5)

              PON1(4)

              PINK1(4)

              Multiple Sclerosis

              HLADRB1(8)

              APOE(5)

              CTLA4(4)

              PTPRC(4)

              MBP(3)

              HLA-DQB1(3)

              IFNG(2)

              CRYAB(2)

              Amyotrophic Lateral Sclerosis

              SOD1(6)

              PON1(2)

              PON2(2)

              VEGFA(2)

              SMN1(1)

              MAPT(1)

              MT-ND5(1)

              PON3(1)

              Brain Ischemia

              FGB(5)

              PDE4D(3)

              NOS3(3)

              ACE(2)

              PON1(2)

              MTHFR(2)

              ITGB3(2)

              TLR4(1)

              Cerebrovascular Accident

              NOS3(5)

              APOE(5)

              FGB(5)

              PON1(4)

              SERPINE1(3)

              ALOX5AP(3)

              ACE(2)

              KL(2)

              Carotid Artery Diseases

              NOS3(4)

              PON1(3)

              MTHFR(3)

              CCL2(2)

              IL6(2)

              APOE(2)

              CD14(2)

              ACE(1)

              Dementia

              APOE(4)

              MAPT(3)

              MT-ND1(1)

              PRNP(1)

              PSEN1(1)

              TNF(1)

              CDC2(1)

              IGF1R(1)

              DISEASE CLASS - NUTR. AND METABOLIC DISEASES

                      

              Diabetes Mellitus, Type 2

              ACE(25)

              PPARG(18)

              ADIPOQ(17)

              TCF7L2(15)

              CAPN10(14)

              HNF4A(13)

              FABP2(12)

              NOS3(10)

              Obesity

              ADRB3(17)

              LEPR(12)

              MC4R(11)

              PPARG(11)

              UCP2(11)

              ADRB2(10)

              UCP1(8)

              ADIPOQ(8)

              Insulin Resistance

              ADIPOQ(11)

              FABP2(10)

              INSR(7)

              IRS1(7)

              ENPP1(7)

              ADRB3(6)

              NOS3(6)

              ACE(5)

              Diabetes Mellitus

              PPARG(6)

              ACE(3)

              INS(3)

              NOS3(3)

              PON1(2)

              UBL5(2)

              IRS1(2)

              TCF7L2(2)

              Hyperlipidemias

              APOA5(5)

              FABP2(4)

              LPL(3)

              APOE(3)

              ACE(2)

              APOA1(2)

              PPARA(2)

              PPARG(2)

              Hypertriglyceridemia

              APOC3(5)

              APOA5(4)

              LPL(3)

              APOE(3)

              ADRB2(2)

              APOA4(2)

              GP1BA(1)

              LTA(1)

              Glucose Intolerance

              LEPR(3)

              ADIPOQ(3)

              IGF1(2)

              KCNJ11(2)

              PTPN1(2)

              PPARG(2)

              HNF4A(2)

              NEUROG3(1)

              Hypercholesterolemia

              APOA1(3)

              APOB(3)

              F12(3)

              ACE(2)

              LDLR(2)

              LPL(2)

              PCSK9(2)

              ABCG8(2)

              Metabolic Syndrome

              APOC3(3)

              UBL5(2)

              NOS3(2)

              ACE(1)

              PPARD(1)

              NPY5R(1)

              ACE2(1)

              RGS2(1)

              DISEASE CLASS - EYE DISEASES

                      

              Macular Degeneration

              CFH(19)

              APOE(4)

              PON1(2)

              C2(1)

              CFB(1)

              ABCA1(1)

              HTRA1(1)

              MELAS(1)

              Diabetic Retinopathy

              VEGFA(7)

              AKR1B1(4)

              PON1(3)

              RAGE(3)

              AGER(3)

              ACE(2)

              ITGA2(2)

              ICAM1(2)

              Glaucoma

              CYP1B1(3)

              OPTN(2)

              OPA1(2)

              OPTC(1)

              EDNRA(1)

              MYOC(1)

                

              Ocular Hypertension

              OPTN(2)

              CYP1B1(1)

              OLFM2(1)

              OPA1(1)

                  

              Cataract

              GALT(1)

              AIPL1(1)

              IFNGR1(1)

              GCNT2(1)

                  

              Retinal Degeneration

              NDP(1)

              GUCA1A(1)

              AIPL1(1)

              COL2A1(1)

              RHO(1)

              GUCA1B(1)

              ABCA4(1)

               

              Myopia

              HLADPB1(1)

              LUM(1)

              COL2A1(1)

              NYX(1)

              MYOC(1)

                 
              Table 8

              Selected Mouse Disease Related Phenotypes

              PhenoCode

              PhenoType

                     
               

              DISEASE CLASS CARDIOVASCULAR

              Gene 1

              Gene 2

              Gene 3

              Gene 4

              Gene 5

              Gene 6

              Gene 10

              MP:0005048

              thrombosis

              Abca5

              Actc1

              Adamts13

              Ahr

              Alox12

              Anxa2

              F2rl2

              MP:0005341

              decreased sus. to atherosclerosis

              APOA1

              Apoe

              Artles

              Ath17

              Ath29

              Ath37

              Icam1

              MP:0000231

              hypertension

              Abcc9

              Ace2

              Add2

              Agt

              Alb1-Ren

              Bpq5

              Chga

              MP:0004181

              abnormal carotid artery morphology

              Aldh1a2

              Chrd

              Crk

              Ednra

              Fgf8

              Foxm1

              Shc1

              MP:0004111

              abnormal coronary artery morph.

              Adm

              Ahr

              Fgf8

              Gja1

              Hspg2

              Itga4

              Vegfa

              MP:0005338

              atherosclerotic lesions

              Aorls1

              Aorls2

              Apoe

              Ath29

              Ath6

              Ath8

              Fabp4-Aebp1

              MP:0000343

              altered resp. to myocardial infarction

              Agtr2

              Aifm1

              Ak1

              Bnip3

              CMV-Abcc9

              Ccr1

              Ckm-Prkaa2

              MP:0006058

              decreased cerebral infarction size

              ACTB-Ngb

              EGFP

              Adora2a

              Cx3cl1

              F11

              F12

              Plat

              MP:0003037

              increased infarction size

              Aifm1

              Fgf2

              Hmox1

              Kit

              Mapk1

              Myh6-tTA

              Thbd

              MP:0004875

              Inc. mean arterial blood pressure

              Ddah1

              Edn1

              Ednrb

              Kcnn3

              Ptger1

              Tagln-tTA

               

              MP:0005339

              Inc. susceptibility to atherosclerosis

              Apoa1

              Apoe

              Artles

              Ascla1

              Ascla2

              Ascla3

              Ath18

               

              DISEASE CLASS - DIGESTIVE SYSTEM DISEASES

              Gene 1

              Gene 2

              Gene 3

              Gene 4

              Gene 5

              Gene 6

              Gene 10

              MP:0003119

              abnormal digestive system dev.

              Cdkn1c

              Cyp26a1

              Foxp4

              Mapk7

              Mcm4

              Nckap1

              Tbx6

              MP:0000462

              abnormal digestive system morph.

              Apc

              Bmp5

              Cdcs1

              Cdkn1c

              Cftr

              Ctnnbip1

              Gast

              MP:0001663

              abnormal digestive system phys.

              Apoe

              Cd44

              Cftr

              Clec7a

              Col2a1

              Fut2

              Gpx1

              MP:0000474

              abnormal foregut morphology

              Apc

              Foxa2

              Gata4

              Gdf1

              Hgs

              Ldb1

              Otx2

              MP:0000488

              abnormal intestinal epithelium morph

              Atr

              B4galt1

              B9d2

              Bdkrb2

              Cbfa2t2

              Col1a1

              Elf3

              MP:0003449

              abnormal intestinal goblet cells

              Areg

              Cbfa2t2

              Cftr

              Clca3

              Ctnnb1

              E2f4

              Il13

              MP:0006001

              abnormal intestinal transit time

              Drd2

              Gfra2

              Gucy1b3

              Hmox2

              Mrvi1

              Smtn

               

              MP:0000470

              abnormal stomach morphology

              Ahr

              Aire

              Barx1

              Celsr3

              Cfc1

              Col1a1

              Gdf11

               

              DISEASE CLASS - DIS. OF ENVIRONMENTAL ORIGIN

              Gene 1

              Gene 2

              Gene 3

              Gene 4

              Gene 5

              Gene 6

              Gene 10

              MP:0001425

              abnormal alcohol consumption

              Aaq1

              Alcp1

              Alcp19

              Alcp2

              Ap7q

              Ap8q

              Ppp1r1b

              MP:0005443

              abnormal ethanol metabolism

              Adh1

              Adh7

              Afteq1

              Afteq2

              Alcw3

              Htas2

               

              MP:0002552

              abnormal response to addictive sub.

              Adora2a

              Adra1d

              Alcw1

              Alcw2

              Alcw3

              Alcw4

              Chrna4

              MP:0001987

              alcohol preference

              Alcp1

              Alcp25

              Alcp3

              Alcp4

              Alprf

              Ap1q

              Ap5q

              MP:0001988

              cocaine preference

              Grm2

              Homer1

              Homer2

              Per2

              Slc6a3

              Slc6a4

               

              MP:0003546

              decreased alcohol consumption

              Camk2a

              Gnas

              Gria3

              Prkce

              tmgc55

                

              MP:0004048

              resistance to addictive substance

              Adora2a

              Adra1b

              Apba1

              Aqp4

              Btbd14b

              Chrna4

              Slc6a3

               

              DISEASE CLASS - IMMUNE SYSTEM DISEASES

              Gene 1

              Gene 2

              Gene 3

              Gene 4

              Gene 5

              Gene 6

              Gene 10

              MP:0001844

              autoimmune response

              Tcra

              Tcrb

              ACTB

              Aire

              Cd1d1

              Fas

              Ikzf3

              MP:0005016

              decreased lymphocyte cell number

              Atm

              Bcl2

              Bcl6b

              Birc2

              C3ar1

              Ccr9

              Ctsd

              MP:0008088

              abnormal T-helper 1 cell diff.

              Cbfb

              Ifngr2

              Il2

              Il4

              Irf4

              Mapk8

              Sit1

              MP:0002499

              chronic inflammation

              Ccr7

              Gstz1

              Hmox1

              Il10

              Il1rn

              Jak3

              Plcg2

              MP:0004804

              dec. sus. to autoimmune diabetes

              HLA-DQA1

              HLA-DQB1

              Art2a

              B2m

              Cd4

              Cd4DsRed

              Cdk4

              MP:0002411

              decreased sus. to bacterial infection

              Anth

              Anth2

              B2m

              C4b

              Casp1

              Cd97

              Dcn

              MP:0005597

              dec. sus. to type I hypers-reaction

              Alox5

              Alox5ap

              Cysltr1

              Cysltr2

              Fcer1a

              Fcer1g

              Orai1

              MP:0003725

              increased autoantibody level

              Tcra

              Tcrb

              Acla1

              Acla2

              Aire

              Cd276

              Cia38

              MP:0005014

              increased B cell number

              BCL2

              Bak1

              Bax

              Bcl11b

              Bcl2l11

              Bst1

              Cdkn2c

              MP:0005013

              increased lymphocyte cell number

              Axl

              B4galt1

              Bak1

              Casp8

              Cd19

              Ewsr1

              Galnt1

              MP:0004803

              Inc. sus. to autoimmune diabetes

              Ins1-Cat

              Tyr

              B2m

              Cd274

              Cd28

              Cd38

              Cdk2

              MP:0005350

              Inc. sus. to autoimmune disorder

              Tcra

              Tcrb

              Ads1

              Ads2

              Ads3

              Ads4

              Bak1

              MP:0002412

              increased sus. to bacterial infection

              Adamts13

              Adcyap1r1

              Adh5

              Atf2

              Bbaa21

              Bcl10

              C3

               

              DISEASE CLASS - MENTAL DISORDERS DISEASE CLASS - MENTAL DISORDERS

              Gene 1

              Gene 2

              Gene 3

              Gene 4

              Gene 5

              Gene 6

               

              MP:0001412

              excessive scratching

              Atp2b4

              Bdnf

              Ctsl

              EIF1AX

              Lck-Il31ra

              Mapt

              Gene 10

              MP:0001362

              abnormal anxiety-related response

              App

              Araf

              Axtofd1

              Axtofd3

              Axtofd4

              Axtofd5

               

              MP:0001458

              abnormal object recognition memory

              Gabbr1

              Gal

              Grin1

              Prnp

              Prnp-App

              Psen1

              Crhr1

              MP:0001360

              abnormal social investigation

              Avpr1a

              Avpr1b

              Cadps2

              En2

              Gnao1

              Grin1

               

              MP:0002557

              abnormal social/conspecific int.

              Ar

              Cadps2

              Disc1

              En2

              Grin1

              Grin3b

              Maoa

              MP:0002065

              abnormal fear/anxiety-related beh.

              APPV717I

              App

              Atp1a2

              Crebbp

              Egr1

              Gnai1

              Oxt

              MP:0001364

              decreased anxiety-related response

              APP

              Adcy8

              Adcyap1

              Adcyap1r1

              Avpr1a

              B3galt2

              Nos3

              MP:0002573

              behavioral despair

              Adra2c

              B3gnt2

              Cacna1c

              Crhr2

              Desp1

              Desp2

              Camk2a

              MP:0001462

              abn. avoidance learning behavior

              Aal

              Aap

              Dcx

              Idua

              Ntrk2

               

              Nr3c1

               

              DISEASE CLASS - NUTR. AND METABOLIC DISEASES

              Gene 1

              Gene 2

              Gene 3

              Gene 4

              Gene 5

              Gene 6

               

              MP:0005560

              decreased circulating glucose level

              Ins1-Cat

              Tyr

              Acadm

              Adipoq

              Apcs-Lep

              Apoe

              Gene 10

              MP:0004185

              abnormal adipocyte glucose uptake

              Akt2

              Bglap1

              Cebpa

              Pik3r1

              Prkci

              Ptprv

              Cd36

              MP:0000188

              abnormal circulating glucose level

              Adipor1

              Cidea

              Ciita

              Ckm

              Crh

              Dbm3

               

              MP:0001560

              abnormal circulating insulin level

              Cacna1c

              Cebpa

              Foxa1

              Gal

              Gck

              IGFBP2

              Irs2

              MP:0003383

              abnormal gluconeogenesis

              Adipoq

              Adipor1

              Cebpa

              Cebpb

              Lpin1

              Mc2r

              Mgat4a

              MP:0005291

              abnormal glucose tolerance

              Adipoq

              Fstl3

              Irs4

              Lep

              Pcsk1

              Pnpla2

              Smarcb1

              MP:0003564

              abnormal insulin secretion

              Eif2ak3

              Gast

              Gck

              Gjd2

              Ins2

              Lep

               

              MP:0002727

              decreased circulating insulin level

              Adcyap1r1

              Adipor2

              Ahsg

              Akt2

              Apcs-Lep

              Apoa2

               

              MP:0002711

              decreased glucagon secretion

              Cacna1e

              Dbh

              Kcnj11

              Nkx2-2

              Pcsk2

               

              Bglap1

              MP:0003059

              decreased insulin secretion

              Abcc8

              Anxa7

              Bglap1

              Cacna1e

              Cartpt

              Chrm3

               

              MP:0001548

              hyperlipidemia

              APOC1

              Acox1

              Apc

              Apoe

              Cdkn1b

              Cpt1c

              Eif2s1

              MP:0005293

              impaired glucose tolerance

              APPswe

              PSEN1dE9

              Abcc8

              Acadvl

              Adcyap1r1

              Adipoq

              Lepr

              MP:0005292

              improved glucose tolerance

              Adipor2

              Ahsg

              Bcat2

              Cbl

              Crebbp

              Cxcl14

              Akt2

              MP:0004892

              increased adiponectin level

              Actb

              Adipor2

              Cideb

              Crebbp

              Pde3b

              Pten

              Gcgr

              MP:0002575

              Inc. circulating ketone body level

              Acacb

              Adcyap1

              Gck

              AZIP

              Ins2

              Ins2-Nos2

              Scd1

              MP:0003645

              Inc. pancreatic beta cell number

              ACTB

              Akt2

              Arx

              Hnf4a

              Cdkn1b

              Foxo1

              Ins2-rtTA

              MP:0001759

              increased urine glucose level

              Aqp1

              Aqp7

              Cdk4

              Cdk4

              Cryaa-TAg

              Dnajc3a

              Ins1

              MP:0005331

              insulin resistance

              APOB

              Adipoq

              Adipor1

              Clcn5

              Adra1b

              Akt2

              Bglap1

               

              DISEASE CLASS - EYE DISEASES

              Gene 1

              Gene 2

              Gene 3

              Gene 4

              Gene 5

              Gene 6

              Gene 10

              MP:0001299

              abnormal eye distance/position

              Dst

              Edg2

              Hectd1

              Hesx1

              Itgb1

              Nrtn

               

              MP:0000776

              abnormal inferior colliculus

              Atg5

              En1

              Ext1

              Fgf17

              Fgf8

              Fgfr1

               

              MP:0003236

              abnormal lens capsule morphology

              Abi2

              Cdkn2a

              Cryaa

              Cryga

              Hsf1

              Hsf4

              Otx2

              MP:0002864

              abnormal ocular fundus morphology

              Crb1

              Gpr143

              Mitf

              Pitx3

              Rd9

              Rp1h

               

              MP:0002638

              abnormal pupillary reflex

              Cat4

              Cnga3

              Cry1

              Eccp

              Foxe3

              Iac

              tmgc25

              MP:0002699

              abnormal vitreous body

              Aldh1a1

              Aldh1a3

              Bmp4

              Cdkn2a

              Fzd4

              Gas1

               

              MP:0001314

              corneal opacity

              Alm

              Apo

              Areg

              Bmp4

              Cat4

              Col4a1

              Lim2

              MP:0001851

              eye inflammation

              Adam17

              Atf2

              Eda

              Fign

              ITGA2

              ITGA5

              Dsc1

              MP:0005542

              corneal vascularization

              Dstn

              Eda

              Fign

              Flt1

              Foxe3

              Ifnar1

              Plg

              MP:0003011

              delayed dark adaptation

              Rbp1

              Rdh11

              Rdh12

              Rdh5

              Rdh8

              Rlbp1

              Pgf

              MP:0005172

              reduced eye pigmentation

              Ap3b1

              Ap3d1

              Hps5

              Hps6

              Mitf

              Nf1

              Sema4a

              Human

              Table 4 shows examples of selected genes in each row that have been positively associated with specific disease phenotype keywords. Each human gene symbol is followed by a specific MeSH disease term and the number of times that gene has been positively associated with the term, in declining order. A major feature of Table 4 is that individual genes have been positively associated with sometimes overlapping disease phenotypes over a broad range from more frequently to less frequently. Table 4 is a small representative subset, truncated in the number of genes (rows) and the number of MeSH terms (columns). The complete list of 1,584 human genes with additional information can be found in Table S1a [20]. An interactive version of the same list can be found in Table S1b[21].

              Quite often the resulting list of phenotypes associated with a specific gene may include the major disease phenotype followed by specific sub-phenotypes of the disease that contribute distinct aspects to the overall clinical disease phenotype. For example, IL13 has been associated with asthma at least 11 times as well as to the asthma sub-phenotype immediate hypersensitivity 4 times. Similarly, the gene CFH has been associated with macular degeneration at least 19 times, as well as to the endo-phenotype of macular degeneration, choroidal neovascularization 3 times. Although replication in genetic association studies has been widely debated[22], consistent replication by independent groups, although sometimes with both modest risk and significance values[23], suggests a fundamental measure of scientific validity. This is true for both candidate gene as well as GWAS studies.

              In other cases, individual genes have been associated with independent but related disorders that may share fundamental biological pathways in disease etiology, such as HLA-DQB1, CTLA4, and PTPN22 as in the case of autoimmune disorders. This gene overlap emphasizes the fundamental, often step-wise biochemical role each gene plays in shared disease etiology [2427]. That is, HLA-DQB1 in antigen presentation, CTLA4 in regulation of the expansion of T cell subsets, and PTPN22 in T cell receptor signaling, all contributing to immunological aberrations and progression to clinical disease, as in rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. In other cases, the same gene has been associated with quite different clinical phenotypes, suggesting sharing of complex biological mechanisms at a more underlying level. For example, the gene CFTR, widely recognized as the cause of cystic fibrosis, has been consistently associated with pancreatitis, may be implicated in chronic rhinitis [28], and may play a protective role in gastrointestinal disorders [29].

              Mouse

              Tables 5 and S2 are the mouse equivalents of the human GENE-to-Disease/Phenotype lists (tables 4 and S1 for human). These were developed from the mouse phenotype table of genes with mouse phenotype ontological codes ftp://​ftp.​informatics.​jax.​org/​pub/​reports/​index.​html#pheno, downloaded on 4-4-08. To build tables 5 and S2, the matching phenotypic terms were exchanged for each Mammalian Phenotype code (MP:#). This resulted in the mouse GENE-to-Disease/Phenotype tables (tables 5 and S2) similar in structure to human GENE-to-Disease/Phenotype tables (tables 4 and S1). Unlike the human tables, the mouse GENE-to-Disease/Phenotype tables come from individual mouse experimental knockout or other genetic studies. They are not based on population based epidemiological studies. They also do not have the quantitative aspect of the human tables with publication frequency counts tagged to each record. In addition, although they include a wide variety of physiological, neurological, and behavioral phenotypes, they do emphasize developmental studies and observational morphological phenotypes common in mouse knockout studies. Table 5 is a small representative subset, truncated in the number of genes (rows) and the number of Phenotype terms (columns). The complete list of 5011 mouse genes with annotated phenotypes and additional information can be found in Table S2a[30]. An interactive version of the same list can be found in Table S2b[31].

              Direct comparison of human and mouse genes disease/phenotypes

              We can now compare these tables directly, thereby allowing gene-by-gene comparison of human disease phenotypes and mouse genetic phenotypes. Tables 6 and S3 are comparisons of the genes that overlap between the human and mouse gene lists (Table S1 and Table S2) showing mouse gene symbols and their human orthologs. Table 6 is a small subset of selected gene-phenotype cross species comparisons. Even though in some cases the human studies have not been replicated, there is often a striking concordance between human disease phenotypes and mouse genetically determined phenotypes. For example, the human gene inhibin alpha (INHA) has been associated with premature ovarian failure[32], and shows mouse phenotypes of abnormal ovarian follicle morphology, female infertility, and ovarian hemorrhage[33], among other phenotypes relevant to human disease. Similarly, in humans the engrailed homeobox 2 gene (EN2) has been associated with autistic disorder[34] while the comparison to mouse En2 has genetic mutations involved in abnormal social integration, spatial learning, and social/consecutive interaction, among others[35]. Importantly, the few mouse studies highlighted above, and many found in the main table S3, were published after the corresponding human genetic population based epidemiological studies. Given concerns of false positives and publication bias in human genetic association studies, direct comparisons to related mouse phenotypes may provide supporting evidence that a given gene may be relevant to a specific human disease phenotype. Table S3[36] is a full listing of the 1104 shared genes between the human disease and mouse phenotype summaries.

              Summaries of phenotypes and genes in human and mouse

              The second type of main summary tables are DISEASE/PHENOTYPE-to-Gene lists. Disease/Phenotype gene summaries are essentially transposed versions of the GENE-to-Disease/Phenotype summaries (Tables S1 & S2) that allow different types of comparisons. These are non-redundant lists of phenotype keywords, MeSH disease terms in the case of human and Mammalian Phenotype Terms (MP) in the case of mouse, followed by the genes associated or annotated to those disease phenotype keywords.

              Human

              Table 7 shows examples of selected human disease phenotypes in each row positively associated with specific human genes for 8 major MeSH disease classes including cardiovascular, digestive system diseases, diseases of environmental origin, immune system diseases, mental disorders, nervous system diseases, nutritional and metabolic diseases, and eye diseases. Each Mesh phenotype term is followed by the number of times that a specific disease term has been positively associated with a particular gene in each row, in decreasing order. Table 7 is a small representative set, truncated in the number of disease phenotypes (rows) and the number of genes (columns). The complete list of 1,318 MeSH disease phenotype terms with additional information can be found in Table S4a[37]. An interactive version of the complete list can be found in Table S4b[38].

              Mouse

              Tables 8 and S5 constitute the mouse DISEASE/PHENOTYPE-to-Gene summaries. Table 8 consists of selected mouse phenotypes which fall into similar general classes of the human table 7 followed by 6 representative genes that have been assigned to the appropriate phenotypic term due to a specific mouse genetic model. Unlike the human Disease/Phenotype-to-gene tables 7 and S4, the mouse tables 8 and S5 do not have quantitative information. Table 8 is also a small representative set, truncated in the number of disease phenotypes (rows) and the number of genes (columns). The complete list of 5,142 mouse phenotype terms with their corresponding Mammalian PhenoCode designations can be found in Table S5a[39]. An interactive version of the complete list can be found in Table S5b[40].

              Using disease and gene lists

              The purpose of this project is not simply to generate lists and information. It is to provide a distillation of disease and phenotype information that can be used in dissecting the complexities of human disease and mouse biology. Now that we have generated GENE-to-disease/phenotype summaries and DISEASE/PHENOTYPE-to-gene summaries for both mouse and human, they can be used for systematic analysis, comparison, and integrating of orthologous data with the goal of providing higher order interpretations of human disease and mouse genetically determined phenotypes.

              Human disease and mouse phenotype based gene sets

              Gene sets have been defined simply as groups of genes that share common biological function, chromosomal location, or regulation[41]. Gene sets are used in high-throughput systematic analysis of microarray data using a priori knowledge. Unlike previously defined gene sets based on biological pathways or differentially expressed genes[41], GAD disease gene sets are unique in that they are composed of genes that have been previously shown to be both polymorphic and have been determined to be genetically positively associated with a specific disease phenotype in a human population based genetic association study. Similarly, Table S5a[39] the mouse DISEASE/PHENOTYPE-to-Gene list is used as a source for gene sets for mouse phenotypes (MP gene sets) comprised of unique gene based mouse genetic models. These gene set files are currently the largest set of gene set files publicly available and the only gene sets files where each gene is based on direct human or mouse genetic studies.

              Comparison of individual GAD disease gene sets

              One aspect of common complex disease is that the development of disease and disease phenotypes quite often present along a broad spectrum of symptoms and share clinical characteristics, endo-phenotypes, or quantitative traits with closely related disorders [25]. This is evident in gene sharing, as mentioned above, and equally in the overlap of biological pathways between related disorders. Using GAD disease gene sets, Venn diagram comparisons among related disorders shows modest gene sharing. However, when gene sets are then placed into biological pathways and compared by Venn analysis, there is a marked increase in the overlap in pathways between related disorders. This was not found in gene sets from unrelated disorders. For example, major autoimmune disorders quite often share endophenotypes of lymphoproliferation, autoantibody production, and alterations in apoptosis, as well as other immune cellular and biochemical aberrations. As shown in Figure 1a, genes that have been positively associated with type 1 diabetes, rheumatoid arthritis, and Crohn's disease show a modest overlap. However, when individual gene sets are fitted into biological pathways, then compared for overlap of pathway membership, there is a striking increase in the overlap at the pathway level. This is true in a comparison of gene and pathways for type 2 diabetes, insulin resistance, and obesity as well (Figure 1b). This pattern of major pathway overlap does not seem to occur between unrelated disorders, such as insulin resistance, rheumatoid arthritis and bipolar disorder (Figure 1c). This disease related sharing at the pathway level suggests common regulatory mechanisms between these disorders and that the original positive associations are not necessarily due to random chance alone.
              http://static-content.springer.com/image/art%3A10.1186%2F1755-8794-3-1/MediaObjects/12920_2009_Article_136_Fig1_HTML.jpg
              Figure 1

              Venn Diagram analysis of individual GAD disease gene sets (circles) versus pathways (rectangles) produced from the corresponding gene set. All Venn Diagrams were produced with Venny http://​bioinfogp.​cnb.​csic.​es/​tools/​venny/​index.​html.

              Group analysis of GAD disease gene sets between major classes of disease/phenotypes

              Dendrogram analysis of human disease gene sets
              As archival information grows, analysis of complex molecular and genetic datasets using clustering or network approaches has become increasingly more useful [13, 4245]. Therefore, in addition to comparisons between individual diseases using human and mouse gene sets, we analyzed large gene groups using dendrogram and clustering approaches based on gene sharing between gene sets. Figure 2 shows a broad based dendrogram comparison based on gene sharing between 480 GAD disease gene sets, using gene sets each containing at least 3 genes. A striking feature of this analysis is that at a coarse level, major disease groups cluster together in space demonstrating shared genes between major clinically important disease groups. Disease domains are represented by groups such as cardiovascular disorders, metabolic disorders, cancer, immune and inflammatory disorders, vision, and chemical dependency. At finer detail within a specific broader group, it becomes clear that individual diseases with overlapping phenotypes are found close in space, such as asthma, allergic rhinitis, and atopic dermatitis. This overlap due to gene sharing recapitulates an overlap in clinical characteristics between these related disorders. Similarly, phenotypes within the metabolic group related to diabetes are closely aligned in space including; insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. This close apposition of related disease phenotypes and sub-phenotypes at both a coarse and fine level is a consistent feature of the overall display. The human gene sets used in creating this tree diagram can be found in Table S6[46]. It is important to emphasize that this display and the distance relationships between diseases are calculated through an unbiased gene-sharing algorithm independent of disease phenotype labels and not as a result of an imposed logical hierarchy or an ontological annotation system. This grouping of major disease phenotypes based solely on gene sharing provides supporting evidence that the underlying disease based gene sets may have a fundamental relevance to disease and may not be reported in the literature by chance alone.
              http://static-content.springer.com/image/art%3A10.1186%2F1755-8794-3-1/MediaObjects/12920_2009_Article_136_Fig2_HTML.jpg
              Figure 2

              Human dendrogram comparison of 480 GAD disease gene sets based on gene sharing. The input GAD gene set file for this figure can be found in Table S6[46].

              Dendrogram analysis of mouse phenotypic gene sets
              Figure 3 is a similar dendrogram to the human tree using 1056 mouse phenotypic gene sets, using gene sets each containing at least 10 genes. This was produced using the same gene sharing algorithm as for the human gene sets in Figure 2. As with the human dendrogram, the mouse tree displays informative groupings at both a coarse and fine level. This tree groups into major groupings nominally assigned as brain development and brain function, embryonic development, cardiovascular, reproduction, inflammation, renal function, bone development, metabolism, and skin/hair development. The identification of major groupings emphasizing developmental processes reflects the emphasis of gene knockouts and developmental models resulting in observable morphological traits and less so with regard to end stage clinical diseases as in the human dendrogram. Like the human dendrogram (Figure 2) discrete major functional groupings in the mouse dendrogram suggests that individual experimental observations are not random. Fundamental complex processes such as metabolism, cardiovascular phenomena, and developmental processes are integrated by extensive sharing of related pliotropic genes. Moreover, like the human tree, fine structure in the mouse tree shows related mouse phenotypes are closely positioned in space. For example, in the metabolism major grouping, the individual phenotypes of body mass, adipose phenotypes, and weight gain are closely positioned. Similarly, in the brain function group, the behavioral phenotypes of anxiety, exploration, and responses to novel objects are found next to one another. This pattern is a fundamental feature of this tree. Like the human tree, the mouse dendrogram shown here is based solely on a gene sharing algorithm using genes assigned to individual phenotypes. It is not based on an imposed predetermined hierarchy or ontology. Importantly, unlike the human tree, the information contained in the mouse tree is derived from individual independent mouse genetic studies and phenotypic observations and not from large case controlled population based epidemiological studies. Controversial issues such as publication bias or study size which confound human genetic association studies are not as relevant here in the context of studies of experimentally determined individual mouse gene knockouts and related studies. The mouse gene sets used in creating this tree diagram can be found in Table S7[47].
              http://static-content.springer.com/image/art%3A10.1186%2F1755-8794-3-1/MediaObjects/12920_2009_Article_136_Fig3_HTML.jpg
              Figure 3

              Mouse dendrogram comparison of 1056 mouse phenotype (MP) gene sets based on gene sharing. The input MP gene set file for this figure can be found in Table S7[47].

              Hierarchical clustering of human and mouse gene sets

              Hierarchical clustering has become a common tool in the analysis of large molecular data sets[48] allowing identification of similar patterns in a scalable fashion from the whole experiment down to a level of fine structure. To provide further evidence of disease relevance and biological content contained in both the human and mouse gene sets hierarchical clustering was performed on both human and mouse. Four hundred and eighty human gene sets were clustered producing 46 major disease clusters. In the mouse, clustering was performed on 2067 mouse phenotype gene sets, using gene sets containing at least 3 genes. This resulted in 165 major subgroups of functional phenotypic specificity. Hierarchical clustering is shown for human [Additional file 1 and Additional file 2] and for mouse [Additional file 3 and Additional file 4]. Like the human and mouse dendograms, this hierarchical clustering showed functional disease grouping at both a coarse group level and at a fine level within major phenotypic groupings. These clusters in both human and mouse falling into closely defined broad functional groups as well as closely related clinical, physiological, and developmental phenotypes demonstrates a general pattern of relevance to disease in their original underlying genetic associations. As in the dendrogram displays, this suggests that the genes nominally positively associated to these disorders, drawn from the medical literature, are not pervasively randomly assigned or due to a widespread pattern of random false positives associations.

              Discussion and Conclusion

              This report describes a summary of the positive genetic associations to disease phenotypes found in the Genetic Association Database as well as a summary of mouse genetically determined phenotypes from the MGI phenotypes database. The genes and disease lists described here were derived from a broad literature mining approach. We have shown disease relevance in three distinct ways; a) in comparing individual gene lists and pathways, b) comparing between species and, c) in broad based comparative analysis utilizing complex systems approaches. Moreover, we identify disease based genes sets for 1,317 human disease phenotypes as well as 5,142 mouse experimentally determined phenotypes. These resources are the largest gene set files currently publicly available and the only gene set files derived from population based human epidemiological genetic studies and mouse genetic models of disease.

              Each individual GAD disease gene set (i.e. a single disease term followed by a string of genes) or mouse phenotype gene set becomes a candidate for a number of uses and applications including:

              a) contributing to complex (additive, multiplicative, gene-environment) statistical models for any given disease phenotype [4953]; b) use in comparative analysis of disease between disease phenotypes; c) use in interrogating other related data types, such as microarray (see below), proteomic, or SNP data [5456]; and d) integration into annotation engines[57] or genome browsers[58] or other analytical software to add disease information in comparative genomic analysis. In a sense, each individual human or mouse disease/phenotype gene set becomes a unique hypothesis, testable in a variety of ways. Increasingly, combinations of genes may have important predictive value as combinatorial biomarkers in predicting disease risk as opposed to single candidate genes [59, 60].

              In addition, in an ongoing parallel set of experiments, using a Gene Set Analysis (GSA) approach using the web tool Disease/Phenotype web-PAGE, in the analysis of orthologous microarray data (De S, Zhang Y, Garner JR, Wang SA, Becker KG: Disease and phenotype gene set analysis of disease based gene expression, unpublished), both the human and mouse disease/phenotype gene sets defined above demonstrate striking disease specificity in PAGE[61] gene set analysis of previously published microarray based gene expression studies from numerous independent laboratories in both a species specific and cross species manner. This was true when studying gene expression studies of type 2 diabetes, obesity, myocardial infarction and sepsis, among others, providing further evidence of the disease and clinical relevance of both the human and mouse gene sets.

              This approach is limited in a number of ways. In particular, the GAD database compares the results of human population based epidemiological studies performed using different sample sizes, populations, statistical models, and at different times over approximately the last 16 years. In addition, the GAD database draws on association studies of broad quality with different degrees of detail provided. Although all human genetic association studies discussed here have been individually determined to be positively associated with a disease or phenotype in a peer reviewed journal, we make no assertion that any individual study is correct and we recognize the controversy in the genetics community regarding statistical and biological significance of genetic association studies. Moreover, although the GAD database contains information on polymorphism and variation, and each GAD record is fundamentally based on polymorphism, this report does not consider variation or polymorphism in the summaries shown. Likewise, mouse genetic models in many cases are weighted to gene knockouts which may not be necessarily be directly representative of multifactorial human common complex disease.

              However, even with these limitations, we believe valuable insights can be gained from broad based literature assessments of the genetic contribution in human common complex disease and in mouse phenotypic biology. More importantly, this suggests greater opportunities for systematic mining and analysis of published data and in cross comparison of archival molecular databases in both human and animal models of disease with regard to genetic variation, population comparisons, and integration with many different types of orthologous information.

              Abbreviations

              GAD: 

              Genetic Association Database

              MGI: 

              Mouse Genome Informatics

              MeSH: 

              Medical Subject Headings

              GWAS: 

              Genome Wide Association Study

              CDC: 

              Centers for Disease Control and Prevention

              HuGENet: 

              Human Genome Epidemiology Network

              Declarations

              Acknowledgements

              The authors would like to thank Dr. Ilya Goldberg for helpful discussions, and Drs. Goldberg, David Schlessinger, and Chris Cheadle and for critical reading of the manuscript.

              This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and Center for Information Technology.

              Authors’ Affiliations

              (1)
              Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health
              (2)
              Division of Computational Bioscience, Center for Information Technology, National Institutes of Health

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              © Zhang et al. 2010

              This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.