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

TitlePolygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease.
Publication TypeJournal Article
Year of Publication2015
AuthorsDesikan RS, Schork AJ, Wang Y, Thompson WK, Dehghan A, Ridker PM, Chasman DI, McEvoy LK, Holland D, Chen C-H, Karow DS, Brewer JB, Hess CP, Williams J, Sims R, O'Donovan MC, Choi SHoan, Bis JC, M Ikram A, Gudnason V, DeStefano AL, van der Lee SJ, Psaty BM, van Duijn CM, Launer L, Seshadri S, Pericak-Vance MA, Mayeux R, Haines JL, Farrer LA, Hardy J, Ulstein IDina, Aarsland D, Fladby T, White LR, Sando SB, Rongve A, Witoelar A, Djurovic S, Hyman BT, Snaedal J, Steinberg S, Stefansson H, Stefansson K, Schellenberg GD, Andreassen OA, Dale AM
Corporate AuthorsInflammation working group, IGAP and DemGene Investigators
JournalCirculation
Volume131
Issue23
Pagination2061-2069
Date Published2015 Jun 09
ISSN1524-4539
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Biomarkers, Brain, C-Reactive Protein, Dyslipidemias, Female, Genome-Wide Association Study, Humans, Inflammation, Lipids, Male, Multifactorial Inheritance, Peroxisomal Bifunctional Enzyme, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Sulfotransferases
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.

DOI10.1161/CIRCULATIONAHA.115.015489
Alternate JournalCirculation
PubMed ID25862742
PubMed Central IDPMC4677995
Grant ListU0149505 / / PHS HHS / United States
R01 MH100351 / MH / NIMH NIH HHS / United States
MR/K013041/1 / / Medical Research Council / United Kingdom
P30 AG010124 / AG / NIA NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
R01 AG031224 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
R01 GM104400 / GM / NIGMS NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
AG033193 / AG / NIA NIH HHS / United States
T32 EB005970 / EB / NIBIB NIH HHS / United States
G0902227 / / Medical Research Council / United Kingdom
MR/L501517/1 / / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
R01GM104400-01A / GM / NIGMS NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
K02 NS067427 / NS / NINDS NIH HHS / United States
R01 HD061414 / HD / NICHD NIH HHS / United States
MR/L010305/1 / / Medical Research Council / United Kingdom
R01MH100351 / MH / NIMH NIH HHS / United States
RC2 DA029475 / DA / NIDA NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States