Genetic Determinants of White Matter Hyperintensities on Brain Scans

Abstract

Background and Purpose-White matter hyperintensities (WMH) are highly heritable and associated with small artery ischemic stroke, so they may be a useful trait for studying the genetics of small vessel disease. Many studies have attempted to find associations between polymorphisms in various candidate genes and WMH. We aimed to evaluate the evidence for these associations by performing a systematic review and series of meta-analyses. Methods-We used a comprehensive search strategy to identify studies of the association between any genetic polymorphism and WMH. For all polymorphisms in genes studied in Ͼ2000 subjects we performed meta-analyses, calculating pooled odds ratios or standardized mean differences. Results-We identified 46 studies of polymorphisms in 19 genes in Ϸ19 000 subjects. Most genes were involved in lipid metabolism, control of vascular tone, or blood pressure regulation. Polymorphisms in the apolipoprotein E, angiotensinconverting enzyme, methylenetetrahydrofolate reductase, and angiotensinogen genes had been studied in Ͼ2000 subjects and were evaluated by meta-analysis. There was no evidence for an association between apolipoprotein E (4ϩ/Ϫ), methylenetetrahydrofolate reductase (677 cytosine/thymine polymorphism [C/T]), or angiotensinogen (Met235Thr) and WMH. For the angiotensin-converting enzyme insertion/deletion polymorphism (I/D) there appeared to be a significant association (OR, 1.95; 95% CI, 1.09 -3.48), but this may be partly attributable to the small study (mainly publication) and other biases. Conclusion-No genetic polymorphism has yet shown convincing evidence for an association with WMH. Much larger studies will be needed to detect and confirm genetic associations with this promising trait in the era of genome-wide association studies.

APOE/TOMM40 Genetic Loci, White Matter Hyperintensities, and Cerebral Microbleeds

“…Our findings align with previous meta‐analyses in observing no significant APOE /WMH association 5, 6. In terms of CMB, this report does not align with recent meta‐analyses that concluded significant deleterious effects of APOE ε4 6, 7.…”

“…It is possible that the sample size examined here is not sufficiently powered to detect any possibly modest effects of APOE or TOMM40 genotypes on WMH/CMB 5. It is possible that the LBC1936 sample is generally healthier when compared with other samples, exacerbated by a selection bias where healthier participants were more likely to attend brain MRI assessment 24.…”

“…Paternoster et al . 5 did not stratify analyses by whether participants were generally healthy or not (total n  = 8546), whereas Schilling et al . 6 did (‘healthy’ n  = 8405).…”

Blood and CSF biomarkers in brain subcortical ischemic vascular disease: Involved pathways and clinical applicability

“…104 Free genome-wide approaches have become available in the past few years. This approach enhances power to detect genetic associations in common diseases when combining results of different cohorts in meta-analysis.…”

Shared Genetic Effects among Measures of Cognitive Function and Leukoaraiosis

“…Candidate gene studies for leukoaraiosis have primarily concentrated on genes in pathways known to be involved in hypertension, vasculature, and endothelial damage. Although initial findings have been encouraging, no specific genetic factors have been unequivocally shown to be associated with this trait (Paternoster et al, 2009). Genome-wide association studies (GWAS) for this trait have also been limited, but are currently being conducted in several ethnic groups.…”