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

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. iris.broce@ucsf.edu.
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. karchc@wustl.edu.
³¹ Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA. rahul.desikan@ucsf.edu.

PMID: 30413934
PMCID: PMC6358498
DOI: 10.1007/s00401-018-1928-6

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

Iris J Broce et al. Acta Neuropathol. 2019 Feb.

. 2019 Feb;137(2):209-226.

doi: 10.1007/s00401-018-1928-6. Epub 2018 Nov 9.

Authors

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. iris.broce@ucsf.edu.
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. karchc@wustl.edu.
³¹ Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA. rahul.desikan@ucsf.edu.

PMID: 30413934
PMCID: PMC6358498
DOI: 10.1007/s00401-018-1928-6

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest JBB served on advisory boards for Elan, Bristol-Myers Squibb, Avanir, Novartis, Genentech, and Eli Lilly and holds stock options in CorTechs Labs, Inc. and Human Longevity, Inc. AMD is a founder of and holds equity in CorTechs Labs, Inc., and serves on its Scientific Advisory Board. He is also a member of the Scientific Advisory Board of Human Longevity, Inc. (HLI), and receives research funding from General Electric Healthcare (GEHC). The terms of these arrangements have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies.

Figures

**Fig. 1**
Fold enrichment plots of nominal − log₁₀ p values (corrected for inflation and excluding *APOE, MAPT*, and *HLA* regions) in Alzheimer’s disease (AD) below the standard GWAS threshold of p < 5 × 10⁻⁸ as a function of significance of association with body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) at the level of p ≤ 1, p ≤ 0.1, p ≤ 0.01, respectively. Blue line indicates all SNPs

**Fig. 2**
Conjunction Manhattan plot of conjunction − log₁₀ (FDR) values for Alzheimer’s disease (AD) alone (black) and AD given body mass index (BMI; AD&BMI, red), type 2 diabetes (T2D; AD&T2D, blue), coronary artery disease (CAD; AD&CAD, pink), waist hip ratio (WHR; AD&WHR, magenta), total cholesterol (TC; AD&TC, green), triglycerides (TG; AD&TG, teal), low-density lipoprotein (LDL; &LDL, purple) and high-density lipoprotein (HDL, AD|HDL, maroon). SNPs with conjunction − log₁₀ FDR > 1.3 (i.e., FDR < 0.05) are shown with large points. A black line around the large points indicates the most significant SNP in each LD block and this SNP was annotated with the closest gene, which is listed above

**Fig. 3**
Forest plots for a rs6733839 on chromosome 2, b rs1534576 on chromosome 11, c rs3844143 on chromosome 11, d rs17125924 on chromosome 14, e rs35991721 on chromosome 7, and f rs536810 on chromosome 6

**Fig. 4**
Regional association plots for rs35991721 on chromosome 7. Linkage disequilibrium measured in the 1000 genomes European populations

**Fig. 5**
The pair-wise linkage disequilibrium patterns between rs1534576, rs11039131 rs2071305, rs10838725, and rs1057233 on chromosome 11

**Fig. 6**
Matrix plot mapping minimum conjunction FDR for the non-*APOE* AD/CV pleiotropic genes for each CV-associated RF. Asterisk indicates the conditioning RF used to identify the most significant SNP (see Table 2 and Fig. 2)

See this image and copyright information in PMC

References

1. Allen M, Carrasquillo MM, Funk C et al. (2016) Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases. Sci Data 3:160089. 10.1038/sdata.2016.89 - DOI - PMC - PubMed
1. Andreassen OA, Djurovic S, Thompson WK et al. (2013) Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. Am J Hum Genet 92:197–209. 10.1016/j.ajhg.2013.01.001 - DOI - PMC - PubMed
1. Andreassen OA, Thompson WK, Dale AM (2014) Boosting the power of schizophrenia genetics by leveraging new statistical tools. Schizophr Bull 40(1):13–17. 10.1093/schbul/sbt168 - DOI - PMC - PubMed
1. Andreassen OA, Thompson WK, Schork AJ et al. (2013) Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate. PLoS Genet 9(4):e1003455 10.1371/journal.pgen.1003455 - DOI - PMC - PubMed
1. Andreassen OA, Zuber V, Thompson WK, Schork AJ, Bettella F, Djurovic S et al. (2014) Shared common variants in prostate cancer and blood lipids. Int J Epidemiol 43:1205–1214. 10.1093/ije/dyu090 - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous