A Trans-Ethnic Genome-Wide Association Study of Uterine Fibroids

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 an...

LUZP1 Controls Cell Division, Migration and Invasion Through Regulation of the Actin Cytoskeleton

“…Importantly, these features are not ascribed to elevated cell viability, since the lack of Luzp1 leads to a reduction in cell numbers and additionally, an increase in cell apoptosis. Our results coincide with the reported anti-proliferative effect of Luzp1 downregulation in colorectal cancer cells ( Poel et al, 2019 ) and the reported increase in proliferation due to Luzp1 upregulation in uterine fibroids ( Edwards et al, 2019 ). Considering the interaction between LUZP1 and LIMA1/EPLIN, our results mirror those showing increased metastatic potential upon loss or downregulation of the tumor suppressor EPLIN ( Jiang et al, 2008 ; Sanders et al, 2010 ; Zhang et al, 2011 ; Liu et al, 2012 ; Collins et al, 2018 ; Goncalves et al, 2020 ).…”

“…Although the exact contribution of LUZP1 in the pathogenesis of the 1p36 syndrome is unknown, it has been proposed to contribute to the development of the cardiovascular malformations ( Zaveri et al, 2014 ; Jordan et al, 2015 ). In addition, a recent study reported that increased LUZP1 expression in the uterus was associated with higher fibroid risk in humans ( Edwards et al, 2019 ). Furthermore, Poel and colleagues claimed that LUZP1 downregulation might mediate chemotherapy sensitivity mechanisms in colorectal cancer cells, potentially through cell cycle arrest ( Poel et al, 2019 ).…”

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

“…Although six uterine leiomyoma GWAS have been reported [14][15][16][17][18][19] , recent studies were conducted in European or African American populations. Our group previously reported a GWAS of uterine leiomyoma 18 , but more than 17,000 cases and 75,000 controls were analysed in this study.…”

“…There have been six published genome-wide association studies (GWAS) of uterine leiomyoma, and some common single nucleotide polymorphisms (SNPs) associated with leiomyoma risks at 1p36.12 (CDC42/ WNT4) [14][15][16][17] , 1q24.3 (DNM3) 16 , 2p25.1 (GREB1) 14,15,17 , 2p23.2 (BABAM2) 17 , 3p24.1 (NEK10) 14 , 3q26.2 (TERC/ LRRC34) 15,17 , 3q29 15 , 4q12 (SCFD2/LNX1/PDGFRA) 14,15,17 , 4q13.3 (SULT1B1/SULT1E1) 14,15,17 , 4q22.3(PD-LIM5) 17 , 5p15.33 (TERT) 14,15,17 , 5q35.2 (ZNF346) 15,17 , 6p21.31(GRM4/HMGA1) 17 , 6q25.2 (SYNE1/ESR1) [14][15][16][17] , 9p24.33 (KANK1/DMRT1/ANKRD15/LOC105375949) [14][15][16][17] , 10p11.22(ZEB1/ARHGAP12) 17 , 10q24.33 (OBFC1) [14][15][16][17][18] , 11p15.5 (SCGB1C1/BET1L/SIRT3/RIC8A) [14][15][16][17][18] , 11p14.1(FSHB) 17 , 11p13 (WT1/PDHX/...…”

Magnetic resonance-guided high-intensity ultrasound (MR-HIFU) in the treatment of symptomatic uterine fibroids — five-year experience

“…However, hormones are not the only factors influencing those pathophysiological pathways [9,10]. UF development is also largely dependent on genetic factors [11,12], with the disruption of DNA repair mechanisms also playing a role [13]. UFs are markedly more common in dark-skinned women, e.g., African Americans, compared to white women [5,14].…”