Abstract
Traits related to primary and secondary sexual characteristics greatly impact females during puberty and day-to-day adult life. Therefore, we performed a GWAS analysis of 11,348 Japanese female volunteers and 22 gynecology-related phenotypic variables, and identified significant associations for bust-size, menstrual pain (dysmenorrhea) severity, and menstrual fever. Bust-size analysis identified significant association signals in CCDC170-ESR1 (rs6557160; P = 1.7 × 10−16) and KCNU1-ZNF703 (rs146992477; P = 6.2 × 10−9) and found that one-third of known European-ancestry associations were also present in Japanese. eQTL data points to CCDC170 and ZNF703 as those signals’ functional targets. For menstrual fever, we identified a novel association in OPRM1 (rs17181171; P = 2.0 × 10−8), for which top variants were eQTLs in multiple tissues. A known dysmenorrhea signal near NGF replicated in our data (rs12030576; P = 1.1 × 10−19) and was associated with RP4-663N10.1 expression, a putative lncRNA enhancer of NGF, while a novel dysmenorrhea signal in the IL1 locus (rs80111889; P = 1.9 × 10−16) contained SNPs previously associated with endometriosis, and GWAS SNPs were most significantly associated with IL1A expression. By combining regional imputation with colocalization analysis of GWAS/eQTL signals along with integrated annotation with epigenomic data, this study further refines the sets of candidate causal variants and target genes for these known and novel gynecology-related trait loci.
Highlights
Traits related to primary and secondary sexual characteristics greatly impact females during puberty and day-to-day adult life
Two secondary phenotypes related to dysmenorrhea possessed significant loci that overlapped those identified for dysmenorrhea pain severity: 1) if dysmenorrhea had an impact on daily life (QOL impact), and 2) pain medicine use during menstruation
None of the eighteen SNPs were identified as eQTLs in GTExPortal ver. 7 web-browser’s multi-tissue or single tissue data that was pre-filtered on FDR26, but we found that high linkage disequilibrium (LD) genome-wide association studies (GWAS) SNPs were strongly associated with coiled-coil domain containing 170 (CCDC170) expression in downloaded Metasoft random-effects meta-analysis (RE2) multi-tissue eQTL statistics[27,28] (Fig. 1b; top SNP rs5880935; PRE2 = 4.9 × 10−40)
Summary
Traits related to primary and secondary sexual characteristics greatly impact females during puberty and day-to-day adult life. Traits related to primary and secondary sexual characteristics exhibit variation in the human population Such traits in females, which can be broadly grouped as female or gynecology-related phenotypes, have a great impact during puberty as well as subsequent day-to-day adult life and may be influenced during development both by environmental and genetic factors. Several genome-wide association studies (GWAS) have analyzed a number of gynecology-related phenotypes and successfully identified genomic loci associated with age at menarche[7,8], age at menopause, dysmenorrhea[9,10], endometriosis[11,12,13,14], and breast size[15] These genetic variants are reported to be shared by other traits and diseases[16]. We performed a GWAS analysis of gynecology-related phenotypes and identified associations for menstruation associated phenotypes and breast size in the Japanese population
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