- 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
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.