Journal
CIRCULATION
Volume 131, Issue 23, Pages 2061-2069Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.115.015489
Keywords
Alzheimer Disease; Genome-Wide Association Study; inflammation; lipids
Funding
- National Institutes of Health [K02 NS067427, T32 EB005970, R01GM104400-01A, R01MH100351, AG033193, U0149505, RC2DA029475, R01HD061414]
- Research Council of Norway [213837, 225989, 223273, 237250/EU JPND]
- South East Norway Health Authority [2013-123]
- Norwegian Health Association
- KG Jebsen Foundation
- Robert J. Glushko and Pamela Samuelson Graduate Fellowship
- NWO [916.12.154]
- Erasmus University Rotterdam Fellowship
- MRC [G0902227, MR/L023784/2, MR/L023784/1, MR/K013041/1] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PG2014-1] Funding Source: researchfish
- Medical Research Council [MR/L023784/1, G0902227, MR/L501517/1, MR/L023784/2, MR/K013041/1, MR/L010305/1] Funding Source: researchfish
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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=2.86x10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38x10(-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.
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