Genome-wide causal mediation analysis identifies genetic loci associated with uterine fibroids mediated by age at menarche

• Published in: Human reproduction (Oxford) 2022-08, Vol.37 (9), p.2197-2212
• Main Authors: Tai, An-Shun, Lin, Ro-Ting, Lin, Yi-Chun, Wang, Chung-Hsing, Lin, Sheng-Hsuan, Imoto, Seiya
• Format: Article
• Language: English
• Subjects: Original
• ISSN: 0268-1161; 1460-2350
• DOI: 10.1093/humrep/deac136

Abstract STUDY QUESTION Could the direct contribution of genetic variants to the pathophysiology of uterine fibroids and the contribution mediated by age at menarche be different? SUMMARY ANSWER Age at menarche plays a mediation role in the genetic influence on uterine fibroids, and four causal genetic mechanisms underlying the age at menarche-mediated effects of common genetic loci on uterine fibroid development were identified. WHAT IS KNOWN ALREADY Uterine fibroids are common benign tumors developing from uterine smooth muscle. Genome-wide association studies (GWASs) have identified over 30 genetic loci associated with uterine fibroids in different ethnic populations. Several genetic variations in or nearby these identified loci were also associated with early age at menarche, one of the major risk factors of uterine fibroids. Although the results of GWASs reveal how genetic variations affect uterine fibroids, the genetic mechanism of uterine fibroids mediated by age at menarche remains elusive. STUDY DESIGN, SIZE, DURATION In this study, we conducted a genome-wide causal mediation analysis in two cohorts covering a total of 69 552 females of Han Chinese descent from the Taiwan Biobank (TWB). TWB is an ongoing community- and hospital-based cohort aiming to enroll 200 000 individuals from the general Taiwanese population between 30 and 70 years old. It has been enrolling Taiwanese study participants since 2012 and has extensive phenotypic data collected from 148 291 individuals as of May 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS We recruited individuals in two cohorts, with 13 899 females in TWB1 and 55 653 females in TWB2. The two sets of individuals are almost distinct, with only 730 individuals enrolled in both cohorts. Over 99% of the participants are Han Chinese. Approximately 21% of participants developed uterine fibroids. DNA samples from both cohorts were genotyped using two different customized chips (TWB1 and TWB2 arrays). After quality control and genotype imputation, 646 973 TWB1 single-nucleotide polymorphisms (SNPs) and 686 439 TWB2 SNPs were assessed in our analysis. There were 99 939 SNPs which overlapped between the TWB1 and TWB2 arrays, 547 034 TWB1 array-specific SNPs and 586 500 TWB2 array-specific SNPs. We performed GWASs for screening potential risk SNPs for age at menarche and for uterine fibroids. We subsequently identified causal mediation effects of risk SNPs on uterine fibroids mediated by age at menarche. MAIN RESULTS AND