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New Stroke Risk Locus Detected Through GWAS Meta-Analysis

NEW YORK (GenomeWeb) – An international team of researchers has uncovered a novel stroke risk locus near the FOXF2 gene.

Through a meta-analysis of 18 genome-wide association studies, researchers from a trio of international stroke genetics research consortiums identified 21 loci linked to risk of stroke, and confirmed two of them in follow-up samples. While one was a known risk locus, the other — located between FOXQ1 and FOXF2 — hadn't before been tied to stroke risk, as the researchers reported in the Lancet Neurology. In animal studies, they found that the lack of the FOXF2 gene affected pericyte coverage in zebrafish and led to cerebral infarction and microhemorrhage in mice.

"Our research has identified a gene affecting … ischemic stroke, due to small vessel disease, and also suggests some genes may be associated with both ischemic and hemorrhagic stroke and may act through a novel pathway affecting pericytes, a type of cell in the wall of small arteries and capillaries," co-author Sudha Seshadri, a professor of neurology at Boston University School of Medicine, said in a statement. "Unraveling the mechanisms of small vessel disease is essential for the development of therapeutic and preventive strategies for this major cause of stroke."

In the discovery stage of their study, Seshadri and her colleagues compared GWAS data from 4,348 stroke patients and 80,613 controls to find 177 genetic variants in 21 independent loci associated with incident all stroke, ischemic stroke, cardioembolic stroke, or non-cardioembolic stroke. In a follow-up study drawing on 19,816 stroke patients and 50,988 controls, the researchers replicated the association between two loci — chr6p25.3 and chr4q25 — and incident all stroke or incident cardioembolic stroke, respectively, in a combined analysis

The chr4q25 locus, the researchers noted, is a known risk locus for cardioembolic ischemic stroke. But the chr6p25.3 locus, which falls between the FOXQ1 and FOXF2 genes hadn't previously been linked to stroke risk.

When the researchers looked at stroke subtypes, they found that the chr6p25.3 locus was linked with incident ischemic stroke, non-cardioembolic I ischemic stroke, and cardioembolic ischemic stroke in their discovery cohort and with small-vessel ischemic stroke in their follow-up cohort, though not with large vessel or with cardioembolic ischemic stroke in that group. They further noted an association between the chr6p25.3 locus and white matter hyperintensity.

This risk region, they added, included a number of enhancers as well as DNase hypersensitivity I regions. In combination with the region's Regulome DB score, this suggested to the researchers that the region has a role in regulating gene expression.

In a set of animal studies, Seshadri and her colleagues found that mice with inactivated FOXF2, one of the genes near this risk locus in humans, exhibited evidence of ischemic infarction as well as of microhemorrhage, while control mice did not. Mice lacking FOXF2 also had higher mortality rates. Further, the researchers noted that the zebrafish orthologs of FOXF2 are expressed in the cerebral endothelium in pericytes, and that knocking those orthologs out leads to decreased expression of pericyte markers, indicating a pericyte maturation defect as well as a smooth muscle defect in developing cerebral vasculature.

This suggests that FOXF2 could affect stroke risk due to defects in cerebral vascular mural cells and its influence on small vessel disease, the researchers wrote.

While mice with mutant FOXQ1, the other gene near this risk locus, only exhibited difference in hair differentiation and gastric mucin section, another gene in the cluster, FOXC1, is also expressed in the brain vasculature and is thought to affect vessel morphogenesis. Variants near this gene that have been previously linked to stroke risk are independent of this newly identified risk locus, the researchers added. This, they said, indicates that these two related genes have independent roles in cerebral small vessel disease.

Small vessel disease, Seshadri and her colleagues noted, is also linked to dementia risk as well as to gait problems and depression. "Hence, it is exciting that we are beginning to better understand the cause of this very important and poorly understood type of stroke," she said.