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

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

doi:10.1007/s00401-018-1928-6

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

Acta Neuropathol. 2019 Feb;137(2):209-226. doi: 10.1007/s00401-018-1928-6. Epub 2018 Nov 9.

Authors

Iris J Broce¹, Chin Hong Tan^{2

3}, Chun Chieh Fan⁴, Iris Jansen⁵, Jeanne E Savage⁵, Aree Witoelar⁶, Natalie Wen⁷, Christopher P Hess², William P Dillon², Christine M Glastonbury², Maria Glymour⁸, Jennifer S Yokoyama⁹, Fanny M Elahi⁹, Gil D Rabinovici⁹, Bruce L Miller⁹, Elizabeth C Mormino¹⁰, Reisa A Sperling^{11

12}, David A Bennett¹³, Linda K McEvoy¹⁴, James B Brewer^{14

15

16}, Howard H Feldman¹⁵, Bradley T Hyman¹¹, Margaret Pericak-Vance¹⁷, Jonathan L Haines^{18

19}, Lindsay A Farrer^{20

21

22

23

24}, Richard Mayeux^{25

26

27}, Gerard D Schellenberg²⁸, Kristine Yaffe^{8

9

29}, Leo P Sugrue², Anders M Dale^{4

14

15}, Danielle Posthuma⁵, Ole A Andreassen⁶, Celeste M Karch³⁰, Rahul S Desikan³¹

Affiliations

¹ Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA. [email protected].
² Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA.
³ Division of Psychology, Nanyang Technological University, Singapore, Singapore.
⁴ Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA, USA.
⁵ Department of Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
⁶ Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁷ Department of Psychiatry, Washington University in St Louis, 425 S Euclid Ave, Campus Box 8134, St Louis, MO, 63110, USA.
⁸ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
⁹ Department of Neurology, University of California, San Francisco, CA, USA.
¹⁰ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA, USA.
¹¹ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹² Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹³ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
¹⁴ Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
¹⁵ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
¹⁶ Shiley-Marcos Alzheimer's Disease Research Center, University of California, La Jolla, San Diego, CA, USA.
¹⁷ John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
¹⁸ Department of Epidemiology and Biostatistics, Case Western University, Cleveland, OH, USA.
¹⁹ Institute for Computational Biology, Case Western University, Cleveland, OH, USA.
²⁰ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
²¹ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
²² Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA.
²³ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
²⁴ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
²⁵ Department of Neurology, Columbia University, New York, NY, USA.
²⁶ Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
²⁷ Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA.
²⁸ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁹ Department of Psychiatry, University of California, San Francisco, CA, USA.
³⁰ Department of Psychiatry, Washington University in St Louis, 425 S Euclid Ave, Campus Box 8134, St Louis, MO, 63110, USA. [email protected].
³¹ Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA. [email protected].

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.

Keywords: Alzheimer’s disease; Cardiovascular; Genetic pleiotropy; Lipids; Polygenic enrichment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Alleles
Alzheimer Disease / genetics*
Apolipoproteins E / genetics
Cardiovascular Diseases / genetics*
Cohort Studies
Diabetes Mellitus, Type 2 / genetics*
Female
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
Humans
Male
Middle Aged
Risk Factors

Substances

Apolipoproteins E

Abstract

Publication types

MeSH terms

Substances

Grants and funding