Japanese GWAS identifies variants for bust-size, dysmenorrhea, and menstrual fever that are eQTLs for relevant protein-coding or long non-coding RNAs

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.

Eliciting priors and relaxing the single causal variant assumption in colocalisation analyses

“…Out of these, we extracted the subset of 25 papers that were both applied papers (rather than methodological) and for which full text could be accessed (S1 Table). The studies covered a variety of trait pairs, generally integrating a disease GWAS with molecular quantitative trait loci (QTL) data, [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] but also comparing pairs of disease GWAS, [40] eQTL and pQTL [41,42] or eQTL and other molecular traits. [43,44] Only four studies considered the potential for multiple causal variants in a region, either discussing the implications on their results, or using conditioning in at least one trait, and 22 out of 25 studies used the software default priors across this diverse range of trait pairs.…”

Polymorphisms in the 3 ′ UTR Region of ESR2 and CYP19A1 Genes and Its Influence on Allele-Specific Gene Expression in Endometriosis

“…Disorders at the level of the ESR2 and CYP19A1 gene expressions, observed in endometriosis as related to the types and sites of lesions, associated with the disease, are confirmed by world literature reports [14][15][16][17][18][19][20]. Several different studies are conducted in order to evaluate the risk of endometriosis in association with different genes polymorphism: CYP17A1, CYP19A1, ESR1, ESR2, PGR, HSD17B1, and HSD17B2 [21][22][23][24][25][26].…”

Genotypes of Pain and Analgesia in a Randomized Trial of Irritable Bowel Syndrome

“…These SNPs mapped closely to L3MBTL4 which encodes the histone methyl-lysine binding protein and was genome-wide significant in a GWAS of pain severity in dysmenorrhea ( 13 ), a pain syndrome in women characterized by pain with menses.…”

“…Based on the findings in the exploratory GWAS, we analyzed the effect size [Standardized Mean Difference (SMD)] of hetero- and homozygous variants of the leading SNP of each of the two GWAS. Since a lead finding has been previously linked to pain in dysmenorrhea ( 13 ) and IBS symptom fluctuation has been linked to the menstrual cycle ( 10 , 14 ), we performed a mediation analysis of estradiol on the change in pain frequency linked to the lead SNP of the GWAS. We applied a full mediation model, tested using the PROCESS implementation ( 15 , 16 ) for IBM SPSS.…”