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

被引：101

作者：

Broce, Iris J. ^{[1
]}

Tan, Chin Hong ^{[1
,2
]}

Fan, Chun Chieh ^{[3
]}

Jansen, Iris ^{[4
]}

Savage, Jeanne E. ^{[4
]}

Witoelar, Aree ^{[5
]}

Wen, Natalie ^{[6
]}

Hess, Christopher P. ^{[1
]}

Dillon, William P. ^{[1
]}

Glastonbury, Christine M. ^{[1
]}

Glymour, Maria ^{[7
]}

Yokoyama, Jennifer S. ^{[8
]}

Elahi, Fanny M. ^{[8
]}

Rabinovici, Gil D. ^{[8
]}

Miller, Bruce L. ^{[8
]}

Mormino, Elizabeth C. ^{[9
]}

Sperling, Reisa A. ^{[10
,11
]}

Bennett, David A. ^{[12
]}

McEvoy, Linda K. ^{[13
]}

Brewer, James B. ^{[13
,14
,15
]}

Feldman, Howard H. ^{[14
]}

Hyman, Bradley T. ^{[10
]}

Pericak-Vance, Margaret ^{[16
]}

Haines, Jonathan L. ^{[17
,18
]}

Farrer, Lindsay A. ^{[19
,20
,21
,22
,23
]}

Mayeux, Richard ^{[24
,25
,26
]}

Schellenberg, Gerard D. ^{[27
]}

Yaffe, Kristine ^{[7
,8
,28
]}

Sugrue, Leo P. ^{[1
]}

Dale, Anders M. ^{[3
,13
,14
]}

Posthuma, Danielle ^{[4
]}

Andreassen, Ole A. ^{[5
]}

Karch, Celeste M. ^{[6
]}

Desikan, Rahul S. ^{[1
]}

机构：

[1] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, Neuroradiol Sect, L-352,505 Parnassus Ave, San Francisco, CA 94143 USA

[2] Nanyang Technol Univ, Div Psychol, Singapore, Singapore

[3] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA

[4] Vrije Univ, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

[5] Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway

[6] Washington Univ, Dept Psychiat, 425 S Euclid Ave,Campus Box 8134, St Louis, MO 63110 USA

[7] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[8] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[9] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Palo Alto, CA 94304 USA

[10] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA

[11] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, Boston, MA USA

[12] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

[13] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA

[14] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[15] Univ Calif La Jolla, Shiley Marcos Alzheimers Dis Res Ctr, San Diego, CA USA

[16] Univ Miami, John P Hussman Inst Human Gen, Miami, FL USA

[17] Case Western Univ, Dept Epidemiol & Biostat, Cleveland, OH USA

[18] Case Western Univ, Inst Computat Biol, Cleveland, OH USA

[19] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA

[20] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[21] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA

[22] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA

[23] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA

[24] Columbia Univ, Dept Neurol, New York, NY USA

[25] Columbia Univ, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA

[26] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA

[27] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA

[28] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA

来源：

ACTA NEUROPATHOLOGICA | 2019年 / 137卷 / 02期

基金：

美国国家卫生研究院;

关键词：

Lipids; Polygenic enrichment; Cardiovascular; Alzheimer's disease; Genetic pleiotropy; CHOLESTEROL-METABOLISM; COMMON VARIANTS; ASSOCIATION; EXPRESSION; IDENTIFICATION; SCHIZOPHRENIA; PLEIOTROPY; IMPLICATE; OVERLAP; TRAITS;

D O I：

10.1007/s00401-018-1928-6

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the epsilon 4 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 validatedtools 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=1.44x10(-9)), MINK1 (chromosome 17, meta-p=1.98x10(-7)) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene=DDB2, meta-p=7.01x10(-7) and closest gene=MYBPC3, meta-p=5.62x10(-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.

引用

页码：209 / 226

页数：18

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