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

Rahul S. Desikan; Andrew J. Schork; Yunpeng Wang; Wesley K. Thompson; Abbas Dehghan; Paul M. Ridker; Daniel I. Chasman; Linda K. Mcevoy; Dominic Holland; Chi Hua Chen; David S. Karow; James B. Brewer; Christopher P. Hess; Julie Williams; Rebecca Sims; Michael C. O'donovan; Seung Hoan Choi; Joshua C. Bis; M. Arfan Ikram; Vilmundur Gudnason; Anita L. Destefano; Sven J. Van Der Lee; Bruce M. Psaty; Cornelia M. Van Duijn; Lenore Launer; Sudha Seshadri; Margaret A. Pericak-Vance; Richard Mayeux; Jonathan L. Haines; Lindsay A. Farrer; John Hardy; Ingun Dina Ulstein; Dag Aarsland; Tormod Fladby; Linda R. White; Sigrid B. Sando; Arvid Rongve; Aree Witoelar; Srdjan Djurovic; Bradley T. Hyman; Jon Snaedal; Stacy Steinberg; Hreinn Stefansson; Kari Stefansson; Gerard D. Schellenberg; Ole A. Andreassen; Anders M. Dale

doi:10.1161/CIRCULATIONAHA.115.015489

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

Rahul S. Desikan, Andrew J. Schork, Yunpeng Wang, Wesley K. Thompson, Abbas Dehghan, Paul M. Ridker, Daniel I. Chasman, Linda K. Mcevoy, Dominic Holland, Chi Hua Chen, David S. Karow, James B. Brewer, Christopher P. Hess, Julie Williams, Rebecca Sims, Michael C. O'donovan, Seung Hoan Choi, Joshua C. Bis, M. Arfan Ikram, Vilmundur GudnasonAnita L. Destefano, Sven J. Van Der Lee, Bruce M. Psaty, Cornelia M. Van Duijn, Lenore Launer, Sudha Seshadri, Margaret A. Pericak-Vance, Richard Mayeux, Jonathan L. Haines, Lindsay A. Farrer, John Hardy, Ingun Dina Ulstein, Dag Aarsland, Tormod Fladby, Linda R. White, Sigrid B. Sando, Arvid Rongve, Aree Witoelar, Srdjan Djurovic, Bradley T. Hyman, Jon Snaedal, Stacy Steinberg, Hreinn Stefansson, Kari Stefansson, Gerard D. Schellenberg, Ole A. Andreassen, Anders M. Dale

Research output: Contribution to journal › Article › peer-review

107 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2061-2069
Number of pages	9
Journal	Circulation
Volume	131
Issue number	23
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.115.015489
State	Published - 2015
Externally published	Yes

Keywords

Alzheimer disease
Genome-wide association study
Inflammation
Lipids

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

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10.1161/CIRCULATIONAHA.115.015489

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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., ... Dale, A. M. (2015). Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease. Circulation, 131(23), 2061-2069. https://doi.org/10.1161/CIRCULATIONAHA.115.015489

Desikan, RS, Schork, AJ, Wang, Y, Thompson, WK, Dehghan, A, Ridker, PM, Chasman, DI, Mcevoy, LK, Holland, D, Chen, CH, Karow, DS, Brewer, JB, Hess, CP, Williams, J, Sims, R, O'donovan, MC, Choi, SH, Bis, JC, Ikram, MA, Gudnason, V, Destefano, AL, Van Der Lee, SJ, Psaty, BM, Van Duijn, CM, Launer, L, Seshadri, S, Pericak-Vance, MA, Mayeux, R, Haines, JL, Farrer, LA, Hardy, J, Ulstein, ID, Aarsland, D, Fladby, T, White, LR, Sando, SB, Rongve, A, Witoelar, A, Djurovic, S, Hyman, BT, Snaedal, J, Steinberg, S, Stefansson, H, Stefansson, K, Schellenberg, GD, Andreassen, OA & Dale, AM 2015, 'Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease', Circulation, vol. 131, no. 23, pp. 2061-2069. https://doi.org/10.1161/CIRCULATIONAHA.115.015489

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title = "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.",

keywords = "Alzheimer disease, Genome-wide association study, Inflammation, Lipids",

author = "Desikan, {Rahul S.} and Schork, {Andrew J.} and Yunpeng Wang and Thompson, {Wesley K.} and Abbas Dehghan and Ridker, {Paul M.} and Chasman, {Daniel I.} and Mcevoy, {Linda K.} and Dominic Holland and Chen, {Chi Hua} and Karow, {David S.} and Brewer, {James B.} and Hess, {Christopher P.} and Julie Williams and Rebecca Sims and O'donovan, {Michael C.} and Choi, {Seung Hoan} and Bis, {Joshua C.} and Ikram, {M. Arfan} and Vilmundur Gudnason and Destefano, {Anita L.} and {Van Der Lee}, {Sven J.} and Psaty, {Bruce M.} and {Van Duijn}, {Cornelia M.} and Lenore Launer and Sudha Seshadri and Pericak-Vance, {Margaret A.} and Richard Mayeux and Haines, {Jonathan L.} and Farrer, {Lindsay A.} and John Hardy and Ulstein, {Ingun Dina} and Dag Aarsland and Tormod Fladby and White, {Linda R.} and Sando, {Sigrid B.} and Arvid Rongve and Aree Witoelar and Srdjan Djurovic and Hyman, {Bradley T.} and Jon Snaedal and Stacy Steinberg and Hreinn Stefansson and Kari Stefansson and Schellenberg, {Gerard D.} and Andreassen, {Ole A.} and Dale, {Anders M.}",

note = "Publisher Copyright: {\textcopyright} 2015 American Heart Association, Inc.",

year = "2015",

doi = "10.1161/CIRCULATIONAHA.115.015489",

language = "English (US)",

volume = "131",

pages = "2061--2069",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "23",

}

TY - JOUR

T1 - Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease

AU - Desikan, Rahul S.

AU - Schork, Andrew J.

AU - Wang, Yunpeng

AU - Thompson, Wesley K.

AU - Dehghan, Abbas

AU - Ridker, Paul M.

AU - Chasman, Daniel I.

AU - Mcevoy, Linda K.

AU - Holland, Dominic

AU - Chen, Chi Hua

AU - Karow, David S.

AU - Brewer, James B.

AU - Hess, Christopher P.

AU - Williams, Julie

AU - Sims, Rebecca

AU - O'donovan, Michael C.

AU - Choi, Seung Hoan

AU - Bis, Joshua C.

AU - Ikram, M. Arfan

AU - Gudnason, Vilmundur

AU - Destefano, Anita L.

AU - Van Der Lee, Sven J.

AU - Psaty, Bruce M.

AU - Van Duijn, Cornelia M.

AU - Launer, Lenore

AU - Seshadri, Sudha

AU - Pericak-Vance, Margaret A.

AU - Mayeux, Richard

AU - Haines, Jonathan L.

AU - Farrer, Lindsay A.

AU - Hardy, John

AU - Ulstein, Ingun Dina

AU - Aarsland, Dag

AU - Fladby, Tormod

AU - White, Linda R.

AU - Sando, Sigrid B.

AU - Rongve, Arvid

AU - Witoelar, Aree

AU - Djurovic, Srdjan

AU - Hyman, Bradley T.

AU - Snaedal, Jon

AU - Steinberg, Stacy

AU - Stefansson, Hreinn

AU - Stefansson, Kari

AU - Schellenberg, Gerard D.

AU - Andreassen, Ole A.

AU - Dale, Anders M.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Alzheimer disease

KW - Genome-wide association study

KW - Inflammation

KW - Lipids

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U2 - 10.1161/CIRCULATIONAHA.115.015489

DO - 10.1161/CIRCULATIONAHA.115.015489

M3 - Article

C2 - 25862742

AN - SCOPUS:84936161018

SN - 0009-7322

VL - 131

SP - 2061

EP - 2069

JO - Circulation

JF - Circulation

IS - 23

ER -

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

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