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09.11.2018 | Original Paper

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

verfasst von: Iris J. Broce, Chin Hong Tan, Chun Chieh Fan, Iris Jansen, Jeanne E. Savage, Aree Witoelar, Natalie Wen, Christopher P. Hess, William P. Dillon, Christine M. Glastonbury, Maria Glymour, Jennifer S. Yokoyama, Fanny M. Elahi, Gil D. Rabinovici, Bruce L. Miller, Elizabeth C. Mormino, Reisa A. Sperling, David A. Bennett, Linda K. McEvoy, James B. Brewer, Howard H. Feldman, Bradley T. Hyman, Margaret Pericak-Vance, Jonathan L. Haines, Lindsay A. Farrer, Richard Mayeux, Gerard D. Schellenberg, Kristine Yaffe, Leo P. Sugrue, Anders M. Dale, Danielle Posthuma, Ole A. Andreassen, Celeste M. Karch, Rahul S. Desikan

Erschienen in: Acta Neuropathologica | Ausgabe 2/2019

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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.

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Titel: Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease
verfasst von: Iris J. Broce
Chin Hong Tan
Chun Chieh Fan
Iris Jansen
Jeanne E. Savage
Aree Witoelar
Natalie Wen
Christopher P. Hess
William P. Dillon
Christine M. Glastonbury
Maria Glymour
Jennifer S. Yokoyama
Fanny M. Elahi
Gil D. Rabinovici
Bruce L. Miller
Elizabeth C. Mormino
Reisa A. Sperling
David A. Bennett
Linda K. McEvoy
James B. Brewer
Howard H. Feldman
Bradley T. Hyman
Margaret Pericak-Vance
Jonathan L. Haines
Lindsay A. Farrer
Richard Mayeux
Gerard D. Schellenberg
Kristine Yaffe
Leo P. Sugrue
Anders M. Dale
Danielle Posthuma
Ole A. Andreassen
Celeste M. Karch
Rahul S. Desikan
Publikationsdatum: 09.11.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 2/2019
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1928-6

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

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