Desikan, R. S., Schork, A. J., Wang, Y., Thompson, W. K., Dehghan, A., Ridker, P. M., Chasman, D. I., McEvoy, L. K., Holland, D., Chen, C.-H., Karow, D. S., Brewer, J. B., Hess, C. P., Williams, Julie  ORCID: https://orcid.org/0000-0002-4069-0259, Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199, O'Donovan, Michael Conlon ORCID: https://orcid.org/0000-0001-7073-2379, Choi, S. H., Bis, J. C., Ikram, M. A., Gudnason, V., DeStefano, A. L., van der Lee, S. J., Psaty, B. M., van Duijn, C. M., Launer, L., Seshadri, S., Pericak-Vance, M. A., Mayeux, R., Haines, J. L., Farrer, L. A., Hardy, J., Ulstein, I. D., Aarsland, D., Fladby, T., White, L. R., Sando, S. B., Rongve, A., Witoelar, A., Djurovic, S., Hyman, B. T., Snaedal, J., Steinberg, S., Stefansson, H., Stefansson, K., Schellenberg, G. D., Andreassen, O. A. and Dale, A. M.
2015.
Polygenic overlap between C-reactive protein, plasma lipids, and Alzheimer Disease.
Circulation
131
(23)
, pp. 2061-2069.
10.1161/CIRCULATIONAHA.115.015489
|
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.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Research Institutes & Centres > MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Schools > Medicine |
| Subjects: | R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry |
| Uncontrolled Keywords: | Alzheimer's Disease, Genome-Wide Association Study, inflammation, lipids |
| Publisher: | American Heart Association |
| ISSN: | 0009-7322 |
| Date of Acceptance: | 6 April 2015 |
| Last Modified: | 31 Oct 2022 10:24 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/84741 |
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