Fig. 1
Genetic associations at the TACR3 region: A Associations with VMS in UK Biobank. GWAS signals for age at menarche and the TACR3 LOF allele (rs144292455 C > T) were not associated with VMS at P < 5 × 10–8 and show little correlation with the VMS signal (LD r2 < 0.2); B Associations with age at menarche in published GWAS. GWAS signals for age at menarche and the TACR3 LOF allele (rs144292455 C > T) were strongly associated with age at menarche. The VMS lead variant shows association at P < 5 × 10–8 with age at menarche in this univariate analysis though was not identified as an independent signal in published age at menarche GWAS. C Univariate and conditional association analyses in UK Biobank. The VMS lead variant was associated with age at menarche at P < 5 × 10–8 in univariate analyses (“Single”) but this association attenuated in analysis adjusting for the genotypes of the age at menarche GWAS signals (“Conditional”). The TACR3 LOF allele (rs144292455 C > T) was strongly associated with later age at menarche but not VMS. Notes: Variants shown are within ± 400 kb of rs34867104, the lead variant for VMS, and LD r2 shown is with rs34867104. Labelled variants are four variants associated with age at menarche within this region (triangles) [16], VMS (purple diamond) and also the LOF variant rs144292455 (triangle). For clarity, other variants with P > 1 × 10–5 are not shown. Association statistics for rs144292455 were calculated in directly genotyped data in UK Biobank whereas all other statistics are from GWAS of imputed data. Association statistics for age at menarche GWAS are from published ReproGen meta-analyses excluding 23andMe [16]. Results presented in Fig. 1C are from analysis of directly genotyped data performed in 379,768 unrelated individuals adjusting for genetic principal components (Supplementary Table 5)