Format

Send to

Choose Destination
Circulation. 2015 Jun 9;131(23):2061-2069. doi: 10.1161/CIRCULATIONAHA.115.015489. Epub 2015 Apr 10.

Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease.

Author information

1
Department of Radiology, University of California, San Diego, La Jolla, CA.
2
Department of Cognitive Science, University of California, San Diego, La Jolla, CA.
3
Department of Neurosciences, University of California, San Diego, La Jolla, CA.
4
NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
5
Department of Psychiatry, University of California, San Diego, La Jolla, CA.
6
Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands.
7
Center for Cardiovascular Disease Prevention, Division of Preventative Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA.
8
Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA.
9
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Wales, United Kingdom.
10
Department of Biostatistics, School of Public Health, Boston University, Boston, MA.
11
Deparment of Internal Medicine, University of Washington, Seattle, WA.
12
Deparment of Epidemiology, Erasmus MC, Rotterdam, Netherlands.
13
Departments of Radiology, Erasmus MC, Rotterdam, Netherlands.
14
Icelandic Heart Association, Kopavogur, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
15
The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA.
16
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA; Group Health Research Institute, Group Health Cooperative, Seattle, WA.
17
Laboratory of Epidemiology, Demography and Biometry, Intramural Research Program, National Institute on Aging, Washington, DC.
18
Department of Neurology, Boston University School of Medicine, Boston, MA.
19
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL.
20
Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University, New York, NY.
21
Department of Epidemiology and Biostatistics and Institute for Computational Biology, Case Western University, Cleveland, OH.
22
Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Biostatistics, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA.
23
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
24
Norwegian Centre for Dementia Research, Department of Old Age Psychiatry, Oslo University Hospital, Oslo, Norway.
25
Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Neurology, Akershus University Hospital, Norway.
26
Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
27
Department of Neurology, St Olav's Hospital, Trondheim University Hospital, Norway.
28
Department of Psychiatry, Haugesund Hospital, Haugesund, Norway.
29
Department of Medical Genetics, Oslo University Hospital, Oslo and NORMENT, KG Jebsen Centre for Psychosis Research; Department of Clinical Science, University of Bergen, Bergen, Norway.
30
Department of Neurology, Massachusetts General Hospital, Boston, MA.
31
Department of Geriatric Medicine, University Hospital Reykjavik, Iceland.
32
deCODE Genetics, Reykjavik, Iceland.
33
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
34
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
#
Contributed equally

Abstract

BACKGROUND:

Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis.

METHODS AND RESULTS:

Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05-1.11; P=2.86×10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38×10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains.

CONCLUSIONS:

We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.

KEYWORDS:

Alzheimer Disease; Genome-Wide Association Study; inflammation; lipids

Comment in

PMID:
25862742
PMCID:
PMC4677995
DOI:
10.1161/CIRCULATIONAHA.115.015489
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center