Multi-ancestry meta-analysis identifies 5 novel loci for ischemic stroke and reveals heterogeneity of effects between sexes and ancestries

• Authors: Ida Surakka, University of Michigan Medical School; Kuan-Han Wu, University of Michigan Medical School; Whitney Hornsby, University of Michigan Medical School; Brooke N. Wolford, University of Michigan Medical School; Fred Shen, University of Michigan Medical School; Wei Zhou, Emory University; Jennifer E. Huffman, VA Boston Healthcare System; Anita Pandit, University of Michigan School of Public Health; Yao Hu, Fred Hutchinson Cancer Research Center; Ben Brumpton, Norges Teknisk-Naturvitenskapelige Universitet; Anne Heidi Skogholt, Norges Teknisk-Naturvitenskapelige Universitet; Maiken E. Gabrielsen, Norges Teknisk-Naturvitenskapelige Universitet; Robin G. Walters, Clinical Trial Service Unit and Epidemiological Studies Unit; Kristian Hveem, Norges Teknisk-Naturvitenskapelige Universitet; Charles Kooperberg, Fred Hutchinson Cancer Research Center; Sebastian Zöllner, University of Michigan School of Public Health; Peter Wilson, Emory University; Nadia R. Sutton, University of Michigan Medical School; Mark J. Daly, Massachusetts General Hospital; Benjamin M. Neale, Massachusetts General Hospital; Cristen J. Willer, University of Michigan Medical School
• Journal Title: Cell Genomics
• Volume: Volume 3, Number 8
• Publisher: Elsevier | 2023-08-09, Pages 100345-100345
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.xgen.2023.100345
• Subjects: Biology, Genetics; Gender Studies
• Keywords: GBMI; GWAS; heterogeneity; ischemic stroke; meta-analysis

Abstract

Stroke is the second leading cause of death and disability worldwide. Stroke prevalence varies by sex and ancestry, possibly due to genetic heterogeneity between subgroups. We performed a genome-wide meta-analysis of 16 biobanks across multiple ancestries to study the genetics of ischemic stroke (60,176 cases, 1,310,725 controls) as part of the Global Biobank Meta-analysis Initiative (GBMI) and further combined the results with previously published MegaStroke. Five novel loci for ischemic stroke (LAMC1, CALCRL, PLSCR1, CDKN1A, and SWAP70) were identified after replication in four additional datasets. One previously reported locus showed significant ancestry heterogeneity (ABO), and one showed significant sex heterogeneity (ALDH2). The ALDH2 association was male specific (males p = 1.67e−24, females p = 0.126) and was additionally observed only in the East Asian ancestry (male) samples. These findings emphasize the need for more diverse datasets with large sample sizes to further understand the genetic predisposition of stroke in different ancestry and sex groups.