Five endometrial cancer risk loci identified through genome-wide association analysis

Abstract

We conducted a meta-analysis of three endometrial cancer GWAS and two replication phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five novel risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1 near SIVA1). A second independent 8q24.21 signal (rs17232730) was found. Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2=0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103-T endometrial cancer protective allele suppressed gene expression in vitro suggesting that regulation of KLF5 expression, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses

“…A number of the remaining risk loci prioritized by the meta-analysis harbor candidate genes that are potentially relevant candidates for etiology and/or treatment of endometriosis and endometrial cancer. For example, the missense variant rs2278868 located on chromosome 17q21.32 within exon 7 of the SKAP1 gene is in perfect linkage disequilibrium (r 2 = 1) with rs1452666, which we have previously reported as having borderline GWAS significant association with endometrial cancer in the combined GWAS and iCOGS datasets [9]. SNP variation in the SKAP1 region is associated with ovarian cancer, subtypes of which are clearly linked epidemiologically and genetically to endometriosis [25,45] and to endometrial cancer [46], although rs2278868 is in extremely low LD with the top ovarian cancer SNP rs9303542 (r 2 = 0.034) [33].…”

“…The cross-disease meta-analysis was performed using an inverse variance, fixed effects model in METAL [30] to search for genetic loci potentially contributing to the increased risk of both endometriosis and endometrial The results for the top SNPs (P ≤ 10 −5 ) from the endometriosis-endometrial cancer meta-analysis were then compared with results for the same SNPs from the fourth dataset included in this study, a separate, independent sample of 4402 endometrial cancer cases and 28,758 controls genotyped at 211,155 SNPs using a custom Illumina Infinium iSelect array by the Collaborative Oncological Gene-environment Study ("iCOGS") [33,34]. SNPs not included on the iCOGS array were imputed (including all SNPs within 1 Mb of the target SNP) using IMPUTE(v2) software [35] and the 1000 Genomes Project (2012 release) as the reference panel [9]. Imputation quality scores ranged from 0.34 to 1.00.…”

Improving power of association tests using multiple sets of imputed genotypes from distributed reference panels

“…Many novel disease-associated signals for a wide variety of diseases and traits have been successfully identified using imputation-based meta-analyses(Cheng & Thompson, 2016; Cooper et al, 2008; De Jager et al, 2009; Ge et al, 2016; Horikoshi et al, 2015; Houlston et al, 2008; Jin et al, 2016; Loos et al, 2008; Ruth et al, 2015; Zeggini et al, 2008; Zeggini et al, 2007). Genotype imputation is the process of inferring missing genotypes in study samples using a reference panel of high-density haplotypes(Li, Willer, Sanna, & Abecasis, 2009).…”

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

“…These power calculations take into account the asymmetric number of cases and controls, as is well reported in genetic association studies 82,88 .…”