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

  • Author(s): Desikan, Rahul S
  • Schork, Andrew J
  • Wang, Yunpeng
  • Thompson, Wesley K
  • Dehghan, Abbas
  • Ridker, Paul M
  • Chasman, Daniel I
  • McEvoy, Linda K
  • Holland, Dominic
  • Chen, Chi-Hua
  • Karow, David S
  • Brewer, James B
  • Hess, Christopher P
  • Williams, Julie
  • Sims, Rebecca
  • O'Donovan, Michael C
  • Choi, Seung Hoan
  • Bis, Joshua C
  • Ikram, M Arfan
  • Gudnason, Vilmundur
  • DeStefano, Anita L
  • van der Lee, Sven J
  • Psaty, Bruce M
  • van Duijn, Cornelia M
  • Launer, Lenore
  • Seshadri, Sudha
  • Pericak-Vance, Margaret A
  • Mayeux, Richard
  • Haines, Jonathan L
  • Farrer, Lindsay A
  • Hardy, John
  • Ulstein, Ingun Dina
  • Aarsland, Dag
  • Fladby, Tormod
  • White, Linda R
  • Sando, Sigrid B
  • Rongve, Arvid
  • Witoelar, Aree
  • Djurovic, Srdjan
  • Hyman, Bradley T
  • Snaedal, Jon
  • Steinberg, Stacy
  • Stefansson, Hreinn
  • Stefansson, Kari
  • Schellenberg, Gerard D
  • Andreassen, Ole A
  • Dale, Anders M
  • Inflammation working group, IGAP and DemGene Investigators
  • et al.
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.

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