Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease.
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 SH., Bis JC., Ikram MA., 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 ID., 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., Inflammation working group, IGAP and DemGene Investigators None.
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.