Dataset Information

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

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.

SUBMITTER: Desikan RS

PROVIDER: S-EPMC4677995 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Desikan Rahul S RS Schork Andrew J AJ Wang Yunpeng Y Thompson Wesley K WK Dehghan Abbas A Ridker Paul M PM Chasman Daniel I DI McEvoy Linda K LK Holland Dominic D Chen Chi-Hua CH Karow David S DS Brewer James B JB Hess Christopher P CP Williams Julie J Sims Rebecca R O'Donovan Michael C MC Choi Seung Hoan SH Bis Joshua C JC Ikram M Arfan MA Gudnason Vilmundur V DeStefano Anita L AL van der Lee Sven J SJ Psaty Bruce M BM van Duijn Cornelia M CM Launer Lenore L Seshadri Sudha S Pericak-Vance Margaret A MA Mayeux Richard R Haines Jonathan L JL Farrer Lindsay A LA Hardy John J Ulstein Ingun Dina ID Aarsland Dag D Fladby Tormod T White Linda R LR Sando Sigrid B SB Rongve Arvid A Witoelar Aree A Djurovic Srdjan S Hyman Bradley T BT Snaedal Jon J Steinberg Stacy S Stefansson Hreinn H Stefansson Kari K Schellenberg Gerard D GD Andreassen Ole A OA Dale Anders M AM

Circulation 20150410 23

<h4>Background</h4>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.<h4>Methods and results</h4>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 ...[more]

PMID: 25862742

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Project description:Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia.We defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36?989 cases and 113?075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance.We combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029).Our results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism.US National Institutes of Health.

Dataset Information

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

Publications

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

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