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Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease.

TitleDissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2019
AuthorsBroce IJ, Tan CHong, Fan CChieh, Jansen I, Savage JE, Witoelar A, Wen N, Hess CP, Dillon WP, Glastonbury CM, Glymour M, Yokoyama JS, Elahi FM, Rabinovici GD, Miller BL, Mormino EC, Sperling RA, Bennett DA, McEvoy LK, Brewer JB, Feldman HH, Hyman BT, Pericak-Vance M, Haines JL, Farrer LA, Mayeux R, Schellenberg GD, Yaffe K, Sugrue LP, Dale AM, Posthuma D, Andreassen OA, Karch CM, Desikan RS
JournalActa Neuropathol
Date Published2019 02

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), MINK1 (chromosome 17, meta-p = 1.98 × 10) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10 and closest gene = MYBPC3, meta-p = 5.62 × 10). 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.

Pubmed Link
Alternate JournalActa Neuropathol.
PubMed ID30413934
PubMed Central IDPMC6358498
Grant List225989 / / Norges Forskningsråd / International
K24 AG035007 / AG / NIA NIH HHS / United States
K01 AG049152 / AG / NIA NIH HHS / United States
MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
U01 AG032984 / AG / NIA NIH HHS / United States
237250/EU JPND / / Norges Forskningsråd / International
U24 AG056270 / AG / NIA NIH HHS / United States
K01 AG046374 / AG / NIA NIH HHS / United States
213837 / / Norges Forskningsråd / International
P30 AG010161 / AG / NIA NIH HHS / United States
223273 / / Norges Forskningsråd / International
RF1 AG015473 / AG / NIA NIH HHS / United States

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