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Many New Stroke Risk Loci Emerge From Multi-Ancestry Genome Meta-Analysis

NEW YORK (GenomeWeb) – Through a multi-ancestry genome-wide association study, an international team of researchers has uncovered 22 new risk loci for stroke, more than tripling the number of known loci.

Stroke — which is usually due to a brain infarction, but sometimes occurs because of an intracerebral hemorrhage — is the second leading cause of death worldwide. Previous studies had uncovered 10 stroke risk loci, and this new study now increased the number to 32.

To find stroke-linked loci, researchers led by Ludwig Maximilian University of Munich's Martin Dichgans, the University of Cambridge's Stephanie Debette, and others conducted a meta-analysis of GWAS that were performed among people of various ancestries. As they reported in Nature Genetics today, some of these variants were associated with particular stroke subtypes and stroke-related vascular traits. Further, the researchers found that the susceptibility loci were enriched in known targets of antithrombotic therapies, suggesting that stroke risk loci could aid in drug discovery. In addition, the study uncovered mechanisms not previously implicated in stroke pathophysiology

"The current transancestral meta-analysis more than triples the number of stroke risk loci and identifies novel loci for [any stroke], [any ischemic stroke], and all major subtypes of ischemic stroke," the researchers wrote in their paper.

The team tested some 8 million SNPs in up to 67,162 stroke cases and 454,450 controls from 29 different studies. One of their analyses focused on the 446,696 European samples, while the other included the European samples as well as 20,695 African, 45,564 East Asian, 9,144 South Asian, 698 mixed Asian, and 1,557 Latin American samples.

Within these, the researchers uncovered 22 novel loci associated with stroke with genome-wide significance. Eighteen of these were found in the transancestral meta-analysis, while four were found in the European-specific analysis.

As strokes can have different causes, the researchers broke down their analysis by stroke subtype. Eighteen loci reached genome-wide significance for any stroke, while 20 did for any ischemic stroke. Similarly, they uncovered six loci linked to large-artery atherosclerotic stroke, four to cardioembolic stroke, and two to stroke caused by small-vessel disease, all subtypes of ischemic stroke.

Some loci, like EDNRA and LINC01492, were only associated with a particular stroke subtype — in this case, large-artery atherosclerotic stroke — while others, like SH2B3, were linked to more than one subtype — here, both large-artery atherosclerotic stroke and stroke caused by small-vessel disease.

A number of the loci the researchers picked up were located near established vascular risk factor-associated loci. This led the team to comb through published GWAS, such as those by CHARGE and CARDIoGRAMplusC4D, that examined vascular risk factors like blood pressure, type 2 diabetes, coronary artery disease, and more. Seventeen of the 32 stroke lead variants overlapped with variants found by those studies, they reported.

They noted a particularly strong association between coronary artery disease and large-artery atherosclerotic stroke, which they attributed to shared pathophysiology, and a significant genetic overlap between triglyceride levels and any ischemic stroke.

The researchers also traced these variants back to the pathways they influence.  While they noted their involvement in pathways like the coagulation system and cardiac pathways, they also implicated pathways such as muscle-cell fate commitment and nitric oxide processes.

Through a combination of expression quantitative trait loci, methylation quantitative trait loci, and protein- expression quantitative trait loci analyses, the researchers found overlap between stroke risk loci and the most significant QTL in tissue relevant to stroke, like brain and vascular tissue. In conjunction with in silico functional analysis, the researchers used this to prioritize loci such as SH3PXD2A for follow up.

The researchers also uncovered overlap between stroke-linked genes and known drug targets. Of the 149 genes located within the 32 stroke risk loci, 11 percent, including FGA and PDE3A, are targets of approved drugs, including antithrombotic therapies. This suggests that the results could inform drug discovery efforts.