Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease.
Circulation
; 131(23): 2061-2069, 2015 Jun 09.
Article
em En
| MEDLINE
| ID: mdl-25862742
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 ANDRESULTS:
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteína C-Reativa
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Herança Multifatorial
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Dislipidemias
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Estudo de Associação Genômica Ampla
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Doença de Alzheimer
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Inflamação
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Lipídeos
Tipo de estudo:
Etiology_studies
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Evaluation_studies
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Prognostic_studies
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Risk_factors_studies
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Systematic_reviews
Limite:
Aged
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Aged80
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Female
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Humans
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Male
Idioma:
En
Revista:
Circulation
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Canadá