Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women

Babatunde Adedokun,Qin Wang,Katie M O’Brien,Sarah J Nyante ,Melissa A Troester,Adeyinka G Falusi,Sue A Ingles,Regina G Ziegler,Kyriaki Michailidou,Guimin Gao,Jeannette T Bensen,Thomas U Ahearn,Gabriela Torres-Mejı́a ,Lara E Sucheston‐Campbell ,Andrew F Olshan,Stephen J Chanock,Manjeet K Bolla,Joe Dennis,Christine B Ambrosone,Douglas F Easton,Barbara Nemesure,Jennifer J Hu,Alison M Dunning,Julie R Palmer,Baffour Awuah,Beatrice Addai-Wiafe,Chinedum P Babalola ,Jonine D Figueroa ,Dale P Sandler,Cari M Kitahara,Anselm Hennis,Kathryn L Lunetta,Zhaohui Du,Lawrence H Kushi,Stefan Ambs,Song Yao,Sandra Deming-Halverson ,Olufunmilayo I Olopade,Elisa V Bandera,William J Blot ,Elad Ziv,Gbhs Study Team ,Katherine L Nathanson,Peter N Fiorica,Joel Yarney,Donglei Hu,Christopher A Haiman,Jorge L Rodriguez-Gil,Gary Zirpoli,David V Conti,Laura Fejerman,Temidayo O Ogundiran,Esther M John,Leslie Bernstein,Montserrat García-Closas ,Zheng Wang ,Jack A Taylor,Paul D.p Pharoah ,Michael F Press,Oladosu Ojengbede,Dezheng Huo

doi:10.1038/s41467-021-24327-x

Abstract

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.

Highlights

Our study describes breast cancer risk loci using a cross-ancestry Genome-wide association studies (GWAS) approach
We discovered six loci containing seven single nucleotide polymorphisms (SNPs) significantly associated with breast cancer at P < 5 × 10−8 on cross-ancestry meta-analysis, with odds ratios (OR) ranging from 0.95 to 1.05 (Tables 1, 2; Supplementary Figs. 1, 2)
Five SNPs were associated with overall breast cancer risk and two were associated with estrogen receptor (ER)-negative breast cancer

Summary

Introduction

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptornegative disease (1q41 and 7q11.23) at genome-wide significance. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants. Genome-wide association studies (GWAS) have been successful in identifying common low-penetrance genetic variation and approximately 200 risk loci have been identified[5,6,7]. The earliest GWAS conducted in African ancestry populations identified genetic variants at 5p15.33 (TERT-CLPTM1L) associated with estrogen receptor (ER) negative breast cancer[15]. 248,000 women, genetic risk variants at 1p13.3, 5q31.1, 15q24, and 15q26.3 for overall breast cancer, and at 1q41 and 7q11.23 for ER-negative disease. The consistency of the directions of the risk for these loci in African and European samples increases the likelihood of their being causal variants

Methods

Results

Conclusion