Genetic Architecture of White Matter Hyperintensities Differs in Hypertensive and Nonhypertensive Ischemic Stroke
Year: 2014
Type: article
Study design: Observational Study
Abstract: BACKGROUND AND PURPOSE: Epidemiological studies suggest that white matter hyperintensities (WMH) are extremely heritable, but the underlying genetic variants are largely unknown. Pathophysiological heterogeneity is known to reduce the power of genome-wide association studies (GWAS). Hypertensive and nonhypertensive individuals with WMH might have different underlying pathologies. We used GWAS data to calculate the variance in WMH volume (WMHV) explained by common single nucleotide polymorphisms (SNPs) as a measure of heritability (SNP heritability [HSNP]) and tested the hypothesis that WMH heritability differs between hypertensive and nonhypertensive individuals. METHODS: WMHV was measured on MRI in the stroke-free cerebral hemisphere of 2336 ischemic stroke cases with GWAS data. After adjustment for age and intracranial volume, we determined which cardiovascular risk factors were independent predictors of WMHV. Using the genome-wide complex trait analysis tool to estimate HSNP for WMHV overall and within subgroups stratified by risk factors found to be significant in multivariate analyses. RESULTS: A significant proportion of the variance of WMHV was attributable to common SNPs after adjustment for significant risk factors (HSNP=0.23; P=0.0026). HSNP estimates were higher among hypertensive individuals (HSNP=0.45; P=7.99×10(-5)); this increase was greater than expected by chance (P=0.012). In contrast, estimates were lower, and nonsignificant, in nonhypertensive individuals (HSNP=0.13; P=0.13). CONCLUSIONS: A quarter of variance is attributable to common SNPs, but this estimate was greater in hypertensive individuals. These findings suggest that the genetic architecture of WMH in ischemic stroke differs between hypertensives and nonhypertensives. Future WMHV GWAS studies may gain power by accounting for this interaction.
Source: Stroke
Authors: Poneh Adib-Samii, William Devan, Matthew Traylor, Silvia Lanfranconi, Cathy R. Zhang, Lisa Cloonan, Guido J. Falcone, Farid Radmanesh, Kaitlin Fitzpatrick, Allison Kanakis, Peter M. Rothwell, Cathie Sudlow, Giorgio B. Boncoraglio, James F. Meschia, Chris Levi, Martin Dichgans, Steve Bevan, Jonathan Rosand, Natalia S. Rost, Hugh S. Markus
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: A genome wide association study in ischaemic stroke., NIHR Senior Investigator Award, Siblings With Ischemic Stroke Study (SWISS), Statins augment small vessel function and improve stroke outcomes, Improving prevention of stroke by better understanding of existing risk factors and treatments., G573982542, Genetic variation in white matter hyperintensity and risk of ischemic stroke, ISGS: The Ischemic Stroke Genetics Study, The NINDS International Stroke Genetics Consortium Study
OpenAlex ID: W2132618560