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

Desikan, Rahul S., Schork, Andrew J., Wang, Yunpeng, Thompson, Wesley K., Dehghan, Abbas, Ridker, Paul M, Chasman, Daniel I., McEvoy, Linda K. +39 more·2015·Circulation
DOI 10.1161/circulationaha.115.015489PMC PMC4677995
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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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  • Previous analyses have prioritized ECHDC3, as it is upregulated in AD post-mortem brains and an eQTL for ECHDC3 was seen in whole blood, though it did not colocalize with the GWAS SNP.

    “Previous analyses have prioritized ECHDC3, as it is upregulated in AD post-mortem brains53,54, and an eQTL for ECHDC3 was seen in whole blood55, though it did not colocalize with the GWAS SNP23.”

    From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [54]

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Authors
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, J., Sims, R., O’Donovan, M. C., 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., & Dale, A. M.
Affiliations
From Departments of Radiology (R.S.D., L.K.M., C.-H.C., D.S.K., J.B.B., A.M.D.), Cognitive Science (A.J.S., A.M.D.), Neurosciences (Y.W., D.H., J.B.B., A.M.D.), and Psychiatry (W.K.T., O.A.A.), University of California, San Diego, La Jolla; NORMENT, Institute of Clinical Medicine, University of Oslo, Norway (Y.W., C.-H.C., A.W., O.A.A., A.M.D., T.F.); Division of Mental Health and Addiction (Y.W., C.-H.C., A.W., O.A.A., A.M.D.), Norwegian Centre for Dementia Research, Department of Old Age...
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2015-06-09
Volume
131
Issue
23
Pages
2061-2069
ISSN
  • 0009-7322
  • 1524-4539
DOI
10.1161/circulationaha.115.015489
PMC
PMC4677995
Cited by
135
References
9
Language
en

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