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Genetic overlap between multiple sclerosis and several cardiovascular disease risk factors.

ABSTRACT: BACKGROUND:Epidemiological findings suggest a relationship between multiple sclerosis (MS) and cardiovascular disease (CVD) risk factors, although the nature of this relationship is not well understood. OBJECTIVE:We used genome-wide association study (GWAS) data to identify shared genetic factors (pleiotropy) between MS and CVD risk factors. METHODS:Using summary statistics from a large, recent GWAS (total n?>?250,000 individuals), we investigated overlap in single nucleotide polymorphisms (SNPs) associated with MS and a number of CVD risk factors including triglycerides (TG), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, body mass index, waist-to-hip ratio, type 2 diabetes, systolic blood pressure, and C-reactive protein level. RESULTS AND CONCLUSION:Using conditional enrichment plots, we found 30-fold enrichment of MS SNPs for different levels of association with LDL and TG SNPs, with a corresponding reduction in conditional false discovery rate (FDR). We identified 133 pleiotropic loci outside the extended major histocompatibility complex with conditional FDR?

SUBMITTER: Wang Y

PROVIDER: S-EPMC5001937 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Genetic overlap between multiple sclerosis and several cardiovascular disease risk factors.

Wang Yunpeng Y Bos Steffan D SD Harbo Hanne F HF Thompson Wesley K WK Schork Andrew J AJ Bettella Francesco F Witoelar Aree A Lie Benedicte A BA Li Wen W McEvoy Linda K LK Djurovic Srdjan S Desikan Rahul S RS Dale Anders M AM Andreassen Ole A OA

Multiple sclerosis (Houndmills, Basingstoke, England) 20160226 14

<h4>Background</h4>Epidemiological findings suggest a relationship between multiple sclerosis (MS) and cardiovascular disease (CVD) risk factors, although the nature of this relationship is not well understood.<h4>Objective</h4>We used genome-wide association study (GWAS) data to identify shared genetic factors (pleiotropy) between MS and CVD risk factors.<h4>Methods</h4>Using summary statistics from a large, recent GWAS (total n > 250,000 individuals), we investigated overlap in single nucleoti ...[more]

PMID: 26920376

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Project description:Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

Dataset Information

Genetic overlap between multiple sclerosis and several cardiovascular disease risk factors.

Publications

Genetic overlap between multiple sclerosis and several cardiovascular disease risk factors.

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