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

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.

SUBMITTER: Adedokun B

PROVIDER: S-EPMC8263739 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Adedokun Babatunde B Du Zhaohui Z Gao Guimin G Ahearn Thomas U TU Lunetta Kathryn L KL Zirpoli Gary G Figueroa Jonine J John Esther M EM Bernstein Leslie L Zheng Wei W Hu Jennifer J JJ Ziegler Regina G RG Nyante Sarah S Bandera Elisa V EV Ingles Sue A SA Press Michael F MF Deming-Halverson Sandra L SL Rodriguez-Gil Jorge L JL Yao Song S Ogundiran Temidayo O TO Ojengbede Oladosu O Blot William W Troester Melissa A MA Nathanson Katherine L KL Hennis Anselm A Nemesure Barbara B Ambs Stefan S Fiorica Peter N PN Sucheston-Campbell Lara E LE Bensen Jeannette T JT Kushi Lawrence H LH Torres-Mejia Gabriela G Hu Donglei D Fejerman Laura L Bolla Manjeet K MK Dennis Joe J Dunning Alison M AM Easton Douglas F DF Michailidou Kyriaki K Pharoah Paul D P PDP Wang Qin Q Sandler Dale P DP Taylor Jack A JA O'Brien Katie M KM Kitahara Cari M CM Falusi Adeyinka G AG Babalola Chinedum C Yarney Joel J Awuah Baffour B Addai-Wiafe Beatrice B Chanock Stephen J SJ Olshan Andrew F AF Ambrosone Christine B CB Conti David V DV Ziv Elad E Olopade Olufunmilayo I OI Garcia-Closas Montserrat M Palmer Julie R JR Haiman Christopher A CA Huo Dezheng D

Nature communications 20210707 1

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 t ...[more]

PMID: 34234117

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Project description:While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer's Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10-101), in ROBO1 (rs11919682, p = 1.63 × 10-8), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10-9). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10-9), CD2AP (rs7738720, p = 1.14 × 10-9), and ABCA7 (rs73505251, p = 3.26 × 10-10), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.

Dataset Information

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

Publications

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

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