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<sup>-8</sup>) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38×10<sup>-8</sup>). 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.

Alzheimer disease, Genome-wide association study, Inflammation, Lipids
dx.doi.org/10.1161/CIRCULATIONAHA.115.015489, hdl.handle.net/1765/87407
Circulation (Baltimore)
Department of Radiology

Desikan, R.S, Schork, N.J, Wang, Y, Thompson, W.K, Dehghan, A, Ridker, P.M, … Dale, A.M. (2015). Polygenic overlap between C-reactive protein, plasma lipids, and Alzheimer disease. Circulation (Baltimore), 131(23), 2061–2069. doi:10.1161/CIRCULATIONAHA.115.015489