A trans-ethnic genome-wide association study of uterine fibroids
Date
2019
Journal Title
Journal ISSN
Volume Title
Publisher
Frontiers Media
Abstract
ENGLISH ABSTRACT: Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in
healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not
well understood. We conducted a two-stage case-control meta-analysis of genetic variants in
European and African ancestry women with and without fibroids classified by a previously
published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven
electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and
5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB,
5,772 cases and 61,457 controls) were included in the discovery genome-wide association study
(GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS (P < 1 ×
10−⁵) were targeted in an independent replication sample of African and European
ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477
controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and
site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804
cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci,
with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789;
P = 4.7 × 10−⁸), chromosome 16q12.1 (sentinel-SNP rs4785384; P = 1.5 × 10−⁹) and chromosome 20q13.1
(sentinel-SNP rs6094982; P = 2.6 × 10−⁸). Our statistically
significant findings further support previously reported loci including SNPs near WT1, TNRC6B,
SYNE1, BET1L, and CDC42/WNT4. We report evidence of ancestry-specific findings for sentinel-SNP
rs10917151 in the CDC42/WNT4 locus (P = 1.76 × 10−²⁴).
Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-
between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European
women (OR = 1.16). Genetically-predicted gene expression of several genes including LUZP1
in vagina (P = 4.6 × 10−⁸), OBFC1 in esophageal mucosa (P = 8.7 × 10−⁸), NUDT13 in
multiple tissues including subcutaneous adipose tissue (P = 3.3 × 10−⁶), and HEATR3 in
skeletal muscle tissue (P = 5.8 × 10−⁶) were associated with fibroids. The finding for
HEATR3 was supported by SNP-based summary Mendelian randomization analysis. Our study suggests
that fibroid risk variants act through regulatory mechanisms affecting gene expression and
are comprised of
alleles that are both ancestry-specific and shared across continental ancestries.
Description
CITATION: Edwards, T. L., et al. 2019. A trans-ethnic genome-wide association study of uterine fibroids. Frontiers in Genetics, 10:511, doi:10.3389/fgene.2019.00511.
The original publication is available at https://www.frontiersin.org
The original publication is available at https://www.frontiersin.org
Keywords
Uterine fibroids, Pelvis -- Cancer, Hysterectomy, Ethnic diversity -- Genomes
Citation
Edwards, T. L., et al. 2019. A trans-ethnic genome-wide association study of uterine fibroids. Frontiers in Genetics, 10:511, doi:10.3389/fgene.2019.00511