Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease
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Published:2015-06-09
Issue:23
Volume:131
Page:2061-2069
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ISSN:0009-7322
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Container-title:Circulation
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language:en
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Short-container-title:Circulation
Author:
Desikan Rahul S.1, Schork Andrew J.1, Wang Yunpeng1, Thompson Wesley K.1, Dehghan Abbas1, Ridker Paul M1, Chasman Daniel I.1, McEvoy Linda K.1, Holland Dominic1, Chen Chi-Hua1, Karow David S.1, Brewer James B.1, Hess Christopher P.1, Williams Julie1, Sims Rebecca1, O’Donovan Michael C.1, Choi Seung Hoan1, Bis Joshua C.1, Ikram M. Arfan1, Gudnason Vilmundur1, DeStefano Anita L.1, van der Lee Sven J.1, Psaty Bruce M.1, van Duijn Cornelia M.1, Launer Lenore1, Seshadri Sudha1, Pericak-Vance Margaret A.1, Mayeux Richard1, Haines Jonathan L.1, Farrer Lindsay A.1, Hardy John1, Ulstein Ingun Dina1, Aarsland Dag1, Fladby Tormod1, White Linda R.1, Sando Sigrid B.1, Rongve Arvid1, Witoelar Aree1, Djurovic Srdjan1, Hyman Bradley T.1, Snaedal Jon1, Steinberg Stacy1, Stefansson Hreinn1, Stefansson Kari1, Schellenberg Gerard D.1, Andreassen Ole A.1, Dale Anders M.1
Affiliation:
1. From Departments of Radiology (R.S.D., L.K.M., C.-H.C., D.S.K., J.B.B., A.M.D.), Cognitive Science (A.J.S., A.M.D.), Neurosciences (Y.W., D.H., J.B.B., A.M.D.), and Psychiatry (W.K.T., O.A.A.), University of California, San Diego, La Jolla; NORMENT, Institute of Clinical Medicine, University of Oslo, Norway (Y.W., C.-H.C., A.W., O.A.A., A.M.D., T.F.); Division of Mental Health and Addiction (Y.W., C.-H.C., A.W., O.A.A., A.M.D.), Norwegian Centre for Dementia Research, Department of Old Age...
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
131 articles.
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