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Title: Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease
Authors: Posthuma, Danielle
Andreassen, Ole A.
Karch, Celeste M.
Desikan, Rahul S.
Broce, Iris J.
Tan, Chin Hong
Fan, Chun Chieh
Jansen, Iris
Savage, Jeanne E.
Witoelar, Aree
Wen, Natalie
Hess, Christopher P.
Dillon, William P.
Glastonbury, Christine M.
Glymour, Maria
Yokoyama, Jennifer S.
Elahi, Fanny M.
Rabinovici, Gil D.
Miller, Bruce L.
Mormino, Elizabeth C.
Sperling, Reisa A.
Bennett, David A.
McEvoy, Linda K.
Brewer, James B.
Feldman, Howard H.
Hyman, Bradley T.
Pericak-Vance, Margaret
Haines, Jonathan L.
Farrer, Lindsay A.
Mayeux, Richard
Schellenberg, Gerard D.
Yaffe, Kristine
Sugrue, Leo P.
Dale, Anders M.
Keywords: Polygenic Enrichment
Social sciences::Psychology
Issue Date: 2018
Source: Broce, I. J., Tan, C. H., Fan, C. C., Jansen, I., Savage, J. E., Witoelar, A., . . . Desikan, R. S. (2019). Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease. Acta Neuropathologica, 137(2), 209-226. doi:10.1007/s00401-018-1928-6
Series/Report no.: Acta Neuropathologica
Abstract: 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.
ISSN: 0001-6322
DOI: 10.1007/s00401-018-1928-6
Schools: School of Social Sciences 
Rights: © 2018 Springer-Verlag GmbH Germany, part of Springer Nature. All rights reserved. This paper was published in Acta Neuropathologica and is made available with permission of Springer-Verlag GmbH Germany, part of Springer Nature.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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