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

被引：108

作者：

Desikan, Rahul S. ^{[1
]}

Schork, Andrew J. ^{[2
]}

Wang, Yunpeng ^{[3
,5
,6
]}

Thompson, Wesley K. ^{[4
]}

Dehghan, Abbas ^{[9
]}

Ridker, Paul M. ^{[11
]}

Chasman, Daniel I. ^{[11
]}

McEvoy, Linda K. ^{[1
]}

Holland, Dominic ^{[3
]}

Chen, Chi-Hua ^{[1
,5
,6
]}

Karow, David S. ^{[1
]}

Brewer, James B. ^{[1
,3
]}

Hess, Christopher P. ^{[12
]}

Williams, Julie ^{[13
]}

Sims, Rebecca ^{[13
]}

O'Donovan, Michael C. ^{[13
]}

Choi, Seung Hoan ^{[14
]}

Bis, Joshua C. ^{[15
,18
]}

Ikram, M. Arfan ^{[9
,10
]}

Gudnason, Vilmundur ^{[19
,20
]}

DeStefano, Anita L. ^{[14
,21
]}

van der Lee, Sven J. ^{[9
]}

Psaty, Bruce M. ^{[16
,17
,22
]}

van Duijn, Cornelia M.

Launer, Lenore ^{[23
]}

Seshadri, Sudha ^{[21
,24
]}

Pericak-Vance, Margaret A. ^{[28
]}

Mayeux, Richard ^{[29
,30
]}

Haines, Jonathan L. ^{[31
,32
]}

Farrer, Lindsay A. ^{[25
,26
,27
]}

Hardy, John ^{[33
]}

Ulstein, Ingun Dina ^{[7
]}

Aarsland, Dag ^{[34
,35
,36
]}

Fladby, Tormod ^{[5
,37
]}

White, Linda R. ^{[38
,39
]}

Sando, Sigrid B. ^{[38
,39
]}

Rongve, Arvid ^{[40
]}

Witoelar, Aree ^{[5
,6
]}

Djurovic, Srdjan ^{[8
,41
]}

Hyman, Bradley T. ^{[42
]}

Snaedal, Jon ^{[43
]}

Steinberg, Stacy ^{[44
]}

Stefansson, Hreinn ^{[44
]}

Stefansson, Kari ^{[20
,44
]}

Schellenberg, Gerard D. ^{[45
]}

Andreassen, Ole A. ^{[4
,5
,6
]}

Dale, Anders M. ^{[1
,2
,3
,5
,6
]}

机构：

[1] Univ Calif San Diego, Dept Radiol, 8950 Villa Jolla Dr,Ste C10, La Jolla, CA 92037 USA

[2] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[5] Univ Oslo, Inst Clin Med, NORMENT, N-0316 Oslo, Norway

[6] Oslo Univ Hosp, Div Mental Hlth & Addict, N-0450 Oslo, Norway

[7] Oslo Univ Hosp, Norwegian Ctr Dementia Res, Dept Old Age Psychiat, N-0450 Oslo, Norway

[8] Oslo Univ Hosp, Dept Med Genet, N-0450 Oslo, Norway

[9] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[10] Erasmus MC, Dept Radiol, Rotterdam, Netherlands

[11] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Cardiovasc Dis Prevent,Div Preventat Med, Boston, MA 02115 USA

[12] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA

[13] Cardiff Univ, Sch Med, Med Res Council Ctr Neuropsychiatr Genet & Gen, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales

[14] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[15] Univ Washington, Dept Internal Med, Seattle, WA 98195 USA

[16] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med Epidemiol, Seattle, WA 98195 USA

[17] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA

[18] Univ Washington, Seattle, WA 98195 USA

[19] Iceland Heart Assoc, Kopavogur, Iceland

[20] Univ Iceland, Fac Med, Reykjavik, Iceland

[21] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA

[22] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA

[23] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Washington, DC USA

[24] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA

[25] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02215 USA

[26] Boston Univ, Sch Med, Dept Neurol Ophthalmol, Boston, MA 02215 USA

[27] Boston Univ, Sch Med, Dept Biostat & Epidemiol, Boston, MA 02215 USA

[28] Univ Miami, John P Hussman Inst Human Genom, Coral Gables, FL 33124 USA

[29] Columbia Univ, Dept Neurol, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA

[30] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA

[31] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA

[32] Case Western Reserve Univ, Inst Computat Biol, Cleveland, OH 44106 USA

[33] UCL Inst Neurol, Dept Mol Neurosci, London, England

[34] Karolinska Inst, Alzheimers Dis Res Ctr, Dept Neurobiol, Care Sci & Soc, Stockholm, Sweden

[35] Stavanger Univ Hosp, Ctr Age Related Med, Stavanger, Norway

[36] Akershus Univ Hosp, Dept Geriatr Psychiat, Oslo, Norway

[37] Akershus Univ Hosp, Dept Neurol, Akershus, Norway

[38] Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway

[39] Univ Trondheim Hosp, St Olavs Hosp, Dept Neurol, Trondheim, Norway

[40] Haugesund Hosp, Dept Psychiat, Haugesund, Norway

[41] Univ Bergen, NORMENT, KG Jebsen Ctr Psychosis Res, Dept Clin Sci, N-5020 Bergen, Norway

[42] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[43] Univ Hosp Reykjavik, Dept Geriatr Med, Reykjavik, Iceland

[44] deCODE Genet, Reykjavik, Iceland

[45] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA

来源：

CIRCULATION | 2015年 / 131卷 / 23期

基金：

美国国家卫生研究院;

关键词：

Alzheimer Disease; Genome-Wide Association Study; inflammation; lipids; COMMON VARIANTS; RISK; ASSOCIATION; ONSET; LOCI; METAANALYSIS; PLEIOTROPY;

D O I：

10.1161/CIRCULATIONAHA.115.015489

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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=2.86x10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38x10(-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.

引用

页码：2061 / 2069

页数：9

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