Genome-Wide Association Studies of MRI-Defined Brain Infarcts

Abstract

Background and Purpose-Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed crosssectional genome-wide association analysis of MRI infarct using age-and sex-adjusted logistic regression models. 2 Although the majority of these MRI infarcts do not produce acute clinical symptoms leading to a diagnosis of stroke, they cannot be considered benign, silent, or asymptomatic, because they are associated with an increased risk for cognitive deficits, motor impairments, and future stroke. 2 The pathogenesis of these covert brain infarcts remains poorly understood.Whereas several monogenic disorders are known to cause brain infarcts, the genes underlying brain infarcts in the general population remain undetermined. 3 A genetic component is suggested by increased risk of covert MRI infarcts among individuals whose parents or siblings have experienced clinically overt infarcts. 4,5 Previous candidate gene studies of covert MRI infarcts have yielded inconsistent findings. Genome-wide association studies (GWAS) of MRI infarcts are lacking and would permit an unbiased search for genetic variants associated with this phenotype, without relying on a priori hypotheses about underlying pathophysiology. 6 To study genetics of these infarcts, we adapted an analytic approach used in a previous study 7 of stroke from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and combined GWAS from 6 prospective population-based cohort studies: the Aging GeneEnvironment Susceptibility-Reykjavik Study (AGESReykjavik); the Atherosclerosis Risk in Communities (ARIC) Study; the Austrian Stroke Prevention Study (ASPS); the Cardiovascular Health Study (CHS); the Framingham Heart Study (FHS); and the Rotterdam Study. We present results from this meta-analysis that included 9401 stroke-free white participants. Materials and Methods ConsortiumThe CHARGE consortium includes large prospective communitybased cohort studies having genome-wide variation data coupled with extensive data on multiple phenotypes. 8 All participating studies agreed on phenotype harmonization, covariate selection, prespecified analytic plans for within-study analyses, and meta-analysis of results. Each study secured approval from Institutional Review Boards, and all participants provided written informed consent for study participation, MRI scanning, and use of DNA for genetic research. SettingDetails of cohort selection, risk factor assessment, and outcome determination in the 6 studies have been reported previously (supplemental Appendix, section 1, available o...

APOE genotype and MRI markers of cerebrovascular disease

“…10-13 They are highly prevalent in older community-dwelling persons, [14][15][16] and can be assessed noninvasively and quantitatively in large population-based samples. Dissecting the relationship between APOE and MRI…”

“…7 MRI markers of CVD-white matter hyperintensities (WMH), brain infarcts (BI), and cerebral microbleeds (CMB)-are powerful predictors of stroke and dementia. [10][11][12][13] They are highly prevalent in older community-dwelling persons, [14][15][16] and can be assessed noninvasively and quantitatively in large population-based samples. Dissecting the relationship between APOE and MRI markers of CVD could provide important clues to the mechanisms underlying the association between APOE and risk of dementia.…”

Emerging Spectra of Silent Brain Infarction

“…В соответствии с рассмотренным ранее значением гомоцистеина и эндотелия мелких сосудов, специфи-ческие полиморфизмы генов метилентетрагидрофолат редуктазы [45,46] и эндотелиальной синтазы окиси азота [47] были идентифицированы в качестве неза-висимых факторов риска развития БИГМ. Некоторые однонуклеотидные полиморфизмы гена протеинкина-зы Cη [48], гена, содержащего домен MACRO 2 и гена фибронектин лейцин-обогащенного трансмембран- ЭПИДЕМИОЛОГИЯ И КЛИНИКА ного белка 3 [49] также были продемонстрированы. Наконец, мутация гена Notch3 на Chr19q12 привели к избыточному накоплению Notch3 белка в клетках гладкой мускулатуры, вызвав развитие артериопатии мелких сосудов [50].…”

Identifying the Genetic Contribution to Ischemic Stroke

“…Using family-based association analysis that combines the principles of traditional linkage studies and case-control association studies, Meschia et al 4 found a clustering of single-nucleotide polymorphisms on chromosomes 3p and 6p that were highly associated with the risk of ischemic stroke, though not significant at the genome-wide level. Thus, like the recent candidate-gene 5 and genome-wide association 6,7 studies, the SWISS elaborate genome-wide linkage approach identified yet another 2 novel candidate loci. As the authors state, this finding supports the idea that there is no common, high risk-conferring polymorphism for multifactorial ischemic stroke.…”