Genetic architecture of lacunar stroke

Traylor, Matthew and Bevan, Stephen and Baron, Jean-Claude and Hassan, Ahamad and Lewis, Cathryn M. and Markus, Hugh S. (2015) Genetic architecture of lacunar stroke. Stroke; a journal of cerebral circulation, 46 (9). pp. 2407-2412. ISSN 0039-2499

Full content URL: http://stroke.ahajournals.org/content/46/9/2407

Documents
Genetic architecture of lacunar stroke
[img]
[Download]
[img]
Preview
PDF
STROKEAHA.115.009485.full.pdf - Whole Document
Available under License Creative Commons Attribution Non-commercial.

827kB
Item Type:Article
Item Status:Live Archive

Abstract

BACKGROUND AND PURPOSE

Lacunar strokes comprise ≈20% of all strokes. Despite this frequency, their pathogenesis is poorly understood. Previous genome-wide association studies in lacunar stroke have been disappointing, which may be because of phenotypic heterogeneity. Pathological and radiological studies suggest that there may be different pathologies underlying lacunar strokes. This has led to the suggestion of 2 subtypes: isolated lacunar infarcts and multiple lacunar infarcts and leukoaraiosis.

METHODS

We performed genome-wide analyses in a magnetic resonance imaging-verified cohort of 1012 younger onset lacunar stroke cases and 964 controls. Using these data, we first estimated the heritability of lacunar stroke and its 2 hypothesized subtypes, and secondly, we determined whether this is enriched for regulatory regions in the genome, as defined by data from Encyclopedia of DNA Elements (ENCODE) and other sources. Finally, we determine the evidence for a polygenic contribution from rare variation to lacunar stroke and its subtypes.

RESULTS

Our results indicate a substantial heritable component to magnetic resonance imaging-verified lacunar stroke (20%-25%) and its 2 subtypes (isolated lacunar infarct, 15%-18%; multiple lacunar infarcts/leukoaraiosis, 23%-28%). This heritable component is significantly enriched for sites affecting expression of genes. In addition, we show that the risk of the 2 subtypes of lacunar stroke in isolation, but not in combination, is associated with rare variation in the genome.

CONCLUSIONS

Lacunar stroke, when defined on magnetic resonance imaging, is a highly heritable complex disease. Much of this heritability arises from regions of the genome affecting gene regulation. Rare variation affects 2 subtypes of lacunar in isolation, suggesting that they may have distinct genetic susceptibility factors.

Keywords:Stroke, Genetics, JCOpen
Subjects:C Biological Sciences > C420 Human Genetics
Divisions:College of Science > School of Life Sciences
ID Code:19435
Deposited On:04 Nov 2015 14:49

Repository Staff Only: item control page