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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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