title: Using Alzgene-like approaches to investigate susceptibility genes for vascular cognitive impairment.
abstract: Vascular cognitive impairment (VCI), including vascular dementia, is the second most common dementia after Alzheimer's disease. Despite its prevalence, the genetic etiology of sporadic VCI is largely unknown. We conducted a systematic review of all published genetic association studies of forms of sporadic VCI prior to 6 July 2012. An initial pool of 229 gene association studies yielded 104 papers (72 polymorphisms from 47 genes) that met inclusion criteria for analysis. Systematic meta-analysis was conducted on 6 polymorphisms (which had 3 or more published case-control cohorts from 69 papers) in the APOE, ACT, ACE, MTHFR, PON1, and PSEN-1 genes. Associations of increased risk for VCI were found for APOE ε4 (1.818 (95% CI = 1.611-2.053), p < 0.001; n = 3,554 cases, n = 12,277 controls) and MTHFR rs1801133 (1.323 (95% CI = 1.061-1.650) p = 0.013); n = 659 cases, n = 981 controls). There was marginal evidence of a protective effect for APOE ε2 (0.885 (95% CI = 0.783-0.999), p = 0.048; n = 3,320 cases, n = 10,786 controls). This systematic study of all published genetic association studies of sporadic VCI supports MTHFR and APOE as susceptibility genes for VCI. It also shows the utility of meta-analysis as a tool to identify potential candidate genes from numerous individual small-scale studies of diseases where sample recruitment may be limited for a variety of practical reasons.
authors.affiliation: Dementia Research Group, School of Clinical Sciences, University of Bristol, Frenchay Day Hospital, Bristol, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dwyer
authors.forename: Olivia Anna
authors.initials: OA
authors.lastname: Skrobot
authors.forename: James
authors.initials: J
authors.lastname: Dwyer
authors.forename: Marcus
authors.initials: M
authors.lastname: Munafo
authors.forename: Patrick Gavin
authors.initials: PG
authors.lastname: Kehoe
mesh_terms: D001057:Apolipoproteins E / Q000235:genetics*; D003072:Cognition Disorders / Q000150:complications / Q000235:genetics*; D030541:Databases, Genetic; D015140:Dementia, Vascular / Q000150:complications / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D011110:Polymorphism, Genetic
chemical_list: D001057:Apolipoproteins E; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)