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Table 10 Literature evidence of the association with PD for the 50 genes prioritized with the consensus strategy

From: Efficient and biologically relevant consensus strategy for Parkinson’s disease gene prioritization

Official Gene symbol Direct Evidence Indirect Evidence Description
SLC18A2 1 0 Several studies reported the association between SLC18A2 and PD [117121]. In humans, the involvement of SLC18A2 in PD pathogenesis is supported by positron emission tomography studies showing significantly lower SLC18A2 densities in the putamen, caudate, and SN of PD patients [122125]. Its potential as PD biomarker [118] or even as a PD pharmacological target [126] have also been suggested. A method of diagnosing PD comprising a set of differentially expressed genes including SLC18A2 was patented [127].
AGTR1 1 0 AGTR1 have been significantly and consistently downregulated in several PD microarray studies [46, 47, 53, 128, 129]. Additionally, the protective effects on dopaminergic neurons of AGTR1 inhibitors have been well documented [130136] highlighting the role of AGTR1 as a potential pharmacological target in PD.
GBE1 1 0 GBE1 has been found to be downregulated in gene expression profiling studies of human substantia nigra pars compacta from PD patients employing high density microarrays [121, 137]. A method of diagnosing PD comprising a set of differentially expressed genes including GBE1 was patented [127].
PDCD2 1 0 The isoform 1 of PDCD2 was found to be ubiquitinated by parkin and increased in the substantia nigra of patients with both autosomal recessive and sporadic PD [138].
ALDH1A1 1 0 ALDH1A1 has been found to be significantly and consistently downregulated in several PD microarray studies [46, 47, 53, 121, 128, 129, 137, 139] highlighting DA metabolism dysfunction resulting in oxidative stress and most probably leading to neuronal cell death. Two methods of diagnosing PD comprising a set of differentially expressed genes including ALDH1A1 were patented [127, 140].
CCNH 0 1 So far, cyclin H (CCNH) has not been directly linked to the pathogenesis of PD. However, the cyclin-dependent kinase 5 (CDK5) was found to act as a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease [141], pointing the potential role of CCNH as a novel and unexplored PD biomarker.
NRXN3 0 0 No association between NRXN3 and PD was found.
SLC6A3 1 0 A combined analysis of published case–control genetic associations between SLC6A3 and PD involving several ethnicities provided evidences of the role of SLC6A3 as a modest but significant risk factor for PD [142].
DLK1 0 1 No direct associations between DLK1 and PD have been reported. However, through a combined gene expression microarray study in NURR1(−/−) mice DLK1 was identified as novel NURR1 target gene in meso-diencephalic DA neurons [143]. NURR1 (also known as NR4A2) encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily [144]. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction including PD [145163].
GPR161 0 0 No association between GPR161 and PD was found.
SCN3B 0 0 No association between SCN3B and PD was found.
TH 1 0 TH has been largely associated with PD [164167].
PCDH8 0 1 No direct association between PCDH8 and PD was found unless a network-based systems biology study utilizing several PD-related microarray gene expression datasets and biomolecular networks [168].
ORC5 0 0 No association between ORC5 and PD was found.
HECA 0 0 No association between HECA and PD was found.
SLIT1 0 1 No direct association between SLIT1 and PD was found. However, the axonal growth inhibition of fetal and embryonic stem cell-derived dopaminergic neurons reported for SLIT1 [169] suggest an indirect association with PD.
BMI1 0 1 Although BMI1 has not been directly associated with PD a previous study demonstrated that it is required in neurons to suppress apoptosis and the induction of a premature aging-like program characterized by reduced antioxidant defenses [170]. These findings provide a molecular mechanism explaining how BMI1 regulates free radical concentrations and reveal the biological impact of BMI1 deficiency on neuronal survival and aging. The activity of BMI1 against mitochondrial ROS may be also relevant to age-associated neurodegenerative diseases where cell death is apparently mediated by oxidative damage, such as in Parkinson disease [171].
QPCT 0 0 No association between QPCT and PD was found.
DLD 0 1 No direct association between DLD and PD was found. However, mice that are deficient in DLD [172] exhibited an increased vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [173], which have been proposed for use in models of PD [174]. DLD is a critical subunit of key mitochondrial enzyme complexes such as the ketoglutarate dehydrogenase complex (KGDHC) and the pyruvate dehydrogenase complex (PDHC) [175]. Altered energy metabolism, including reductions in KGDHC and PDHC are characteristic of many neurodegenerative disorders including PD [176, 177].
HIST1H2BD 1 0 HIST1H2BD was found to be significantly and differentially expressed in 20 out of the 21 brain regions studied in a multiregional gene expression analysis in postmortem brain coming from 23 control and 22 PD cases [178]. A method of diagnosing PD comprising a set of differentially expressed genes including HIST1H2BD was patented [179].
PBX1 0 1 No direct association between PBX1 and PD was found. However, the expression of PBX1 in dopaminergic neurons make it an important player in defining the axonal guidance of the midbrain dopaminergic neurons, with possible implications for the normal physiology of the nigro-striatal system as well as processes related to the degeneration of neurons during the course of PD [180].
SRP72 0 0 No association between SRP72 and PD was found.
DRD2 1 0 DRD2 has been largely associated with PD [181194].
EN1 1 0 Several studies have reported significant associations between EN1 and PD [195197].
TRIM36 1 0 TRIM36 has been found to be downregulated in a gene expression profiling study of human substantia nigra pars compacta from PD patients employing high density microarrays [137]. A method of diagnosing PD comprising a set of differentially expressed genes including TRIM36 was patented [127].
INSM1 0 1 Although INSM1 has not been directly associated with PD a previous study demonstrated that it is involved on the interrelation of odor and motor changes probably caused by a Mn-induced dopaminergic dysregulation affecting both functions [198]. In this study was found that the rs2871776 G allele, which was associated with the worst effect of Mn on motor coordination, was linked to alteration of a binding site for the transcription factor INSM1. This gene plays an important role in the developing CNS, and especially of olfactory progenitors, as shown in mouse [199] and human [200] embryos. Olfactory impairment is a highly recurrent non-motor dysfunction in PD and is considered an early predictive sign of neurodegeneration [201203].
MDH2 0 0 No association between MDH2 and PD was found.
CIRBP 0 0 No association between CIRBP and PD was found.
FABP7 1 0 A recent study reported that FABP7 levels were elevated in serum of 35 % of the patients with PD and only in 2 % of the healthy controls, suggesting the role of FABP7 as a potential biomarker for PD [204]. FABP7 was also identified as a promising candidate in a previous quantitative trait loci (QTL) study conducted to identify genes that mediate PPI in mice [205]. This finding was confirmed in a further experiment where FABP7-deficient mice showed decreased PPI. PPI deficiencies is considered a characteristic indicator of schizophrenia [82], but is also deficient in PD patients [206, 207].
PTPRN2 1 0 PTPRN2 has been found to be downregulated in a gene expression profiling study of human substantia nigra pars compacta from PD patients employing high density microarrays [137]. A method of diagnosing PD comprising a set of differentially expressed genes including PTPRN2 was patented [127].
PSMG1 0 0 No association between PSMG1 and PD was found.
VWA5A 1 0 VWA5A was associated with PD through a genome-wide genotyping study in PD and neurologically normal controls [208].
ITPR1 1 0 Kitamura et al. [209] reported since 1989 that ITPR1 binding sites were reduced by about 50 % in several brain regions of PD patients (caudate nucleus, putamen, and pallidum) as compared to findings in the age-matched controls, suggesting a probable implication of ITPR1 in PD.
BAI3 0 0 No association between BAI3 and PD was found.
CPT1B 0 0 No association between CPT1B and PD was found.
CACNB3 1 0 The calcium channel subunit b3 (CACNB3), the ATPase type 13A2 (PARK9), and several subunits of Ca2+ transporting ATPases (ATP2A3, ATP2B2, and ATP2C1) were downregulated in PD further substantiating the involvement of a deficit in organelle function and of Ca2+ sequestering.
ACP2 0 0 No association between ACP2 and PD was found.
CHORDC1 1 0 CHORDC1 was found to be significantly and differentially expressed in 19 out of the 21 brain regions studied in a multiregional gene expression analysis in postmortem brain coming from 23 control and 22 PD cases [178]. A method of diagnosing PD comprising a set of differentially expressed genes including CHORDC1 was patented [179].
SHOC2 0 0 No association between SHOC2 and PD was found.
VBP1 0 0 No association between VBP1 and PD was found.
PPM1B 0 0 No association between PPM1B and PD was found.
YME1L1 0 0 No association between YME1L1 and PD was found.
NDUFA9 1 0 NDUFA9 is included in the KEGG Parkinson’s Disease Pathway (http://www.genome.jp/dbget-bin/www_bget?pathway+hsa05012).
TRAPPC2L 0 0 No association between TRAPPC2L and PD was found.
HIST1H2AC 0 0 No association between HIST1H2AC and PD was found.
RGS4 1 0 RGS4 was found to be significantly and differentially expressed in several brain areas of postmortem samples coming from PD patients in comparison to control samples [53]. On the other hand, experiments in mice with reserpine-induced acute DA depletion suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in PD [210]. Lerner and Kreitzer [211] also identified RGS4 as a key link between DA 2/adenosine 2A signaling and endocannabinoid mobilization pathways. In addition, in contrast to wild-type mice, RGS4 deficient mice exhibited normal endocannabinoid-dependent long-term depression after DA depletion and were significantly less impaired in the 6-OHDA model of PD. Taken together, these results suggest that inhibition of RGS4 may be an effective nondopaminergic strategy for treating Parkinson’s disease. Finally, RGS4 was recently found to be involved in the generation of abnormal involuntary movements in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD [212].
CRYZL1 0 0 No association between CRYZL1 and PD was found.
RCN2 0 0 No association between RCN2 and PD was found.
SNRNP70 1 0 SNRNP70 was associated with woman affected by PD in an association study of four common polymorphisms in the DJ1 gene and PD involving 416 PD probands and their unaffected siblings matched by gender and closest age [213].
VPS4B 0 0 No association between VPS4B and PD was found.
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