Multi-ancestry meta-analysis identifies 2 novel loci associated with ischemic stroke and reveals heterogeneity of effects between sexes and ancestries

Cerebrovascular accident (stroke) is the second leading cause of death and disability worldwide. Stroke prevalence varies by sex and ancestry, which could be due to genetic heterogeneity between subgroups. We performed a genome-wide meta-analysis of 16 biobanks across multiple ancestries to study the genetic contributions underlying ischemic stroke (60,176 cases, 1,310,725 controls) as part of the Global Biobank Meta-analysis Initiative (GBMI). Two novel loci associated ischemic stroke with plausible candidate genes, FGF5 and CENPQ/MUT , were identified after replication in four additional datasets. One locus showed significant ancestry heterogeneity ( PDE3A ) and two loci showed significant sex-heterogeneity ( SH3PXD2A and ALDH2 ). The ALDH2 locus had a male-specific association for stroke in GBMI (P-value males = 1.67e-24, P-value females = 0.126). To test whether we would see a difference in the predictive power of sex-specific polygenic risk scores (PRSs), we compared the C-indexes for sex-specific and sex-combined PRSs in HUNT dataset. A sex-combined PRS was more successful at predicting stroke cases than a sex-specific PRS, most likely due to more stable effect estimates from the sex-combined summary-statistics. These approaches can be applied to further unravel the genetic underpinnings of stroke and other complex diseases. ### Competing Interest Statement NRS is an advisor for Abbott, Philips, and Shockwave and have received honoraria for speaking from Zoll Cordis. The spouse of CJW works at Regeneron pharmaceuticals. ### Funding Statement Provided as a separate PDF. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Participation in the HUNT Study is based on informed consent and the study has been approved by the Data Inspectorate and the Regional Ethics Committee for Medical Research in Norway (REK: 2014/144) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors