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Title | Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Desikan 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 Authors | Inflammation working group, IGAP and DemGene Investigators |
Journal | Circulation |
Volume | 131 |
Issue | 23 |
Pagination | 2061-2069 |
Date Published | 2015 Jun 09 |
ISSN | 1524-4539 |
Keywords | Aged, 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. |
DOI | 10.1161/CIRCULATIONAHA.115.015489 |
Alternate Journal | Circulation |
PubMed ID | 25862742 |
PubMed Central ID | PMC4677995 |
Grant List | U0149505 / / 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 |