Abundant Genetic Overlap between Blood Lipids and Immune-Mediated Diseases Indicates Shared Molecular Genetic Mechanisms

被引：35

作者：

Andreassen, Ole A. ^{[1
,2
]}

Desikan, Rahul S. ^{[3
,4
]}

Wang, Yunpeng ^{[1
,2
,3
]}

Thompson, Wesley K.

Schork, Andrew J. ^{[3
,5
,6
]}

Zuber, Verena ^{[1
,2
,7
,8
]}

Doncheva, Nadezhda T. ^{[9
]}

Ellinghaus, Eva ^{[10
]}

Albrecht, Mario ^{[9
,11
,12
,13
]}

Mattingsdal, Morten ^{[1
,2
,14
]}

Franke, Andre ^{[10
]}

Lie, Benedicte A. ^{[13
]}

Mills, Ian ^{[7
,8
,16
,17
]}

Aukrust, Pal ^{[15
,19
]}

McEvoy, Linda K. ^{[3
]}

Djurovic, Srdjan ^{[1
,2
,15
]}

Karlsen, Tom H. ^{[18
,20
,21
]}

Dale, Anders M. ^{[4
,22
,23
]}

机构：

[1] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Psychosis Res, NORMENT, N-0407 Oslo, Norway

[2] Oslo Univ Hosp, Div Mental Hlth & Addict, N-0407 Oslo, Norway

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

[4] Univ Calif San Diego, Multimodal Imaging Lab, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA

[6] Univ Calif San Diego, Cognit Sci Grad Program, La Jolla, CA 92093 USA

[7] Univ Calif San Diego, Ctr Human Dev, La Jolla, CA 92093 USA

[8] Univ Oslo, Nord EMBL Partnership, Ctr Mol Med Norway, N-0407 Oslo, Norway

[9] Oslo Univ Hosp, N-0407 Oslo, Norway

[10] Max Planck Inst Informat, D-66123 Saarbrucken, Germany

[11] Univ Kiel, Inst Clin Mol Biol, D-24118 Kiel, Germany

[12] Univ Med Greifswald, Inst Biometr & Med Informat, Dept Bioinformat, D-17475 Greifswald, Germany

[13] Graz Univ Technol, Inst Knowledge Discovery, A-8010 Graz, Austria

[14] BioTechMed Graz, A-8010 Graz, Austria

[15] Sorlandet Hosp, N-3000 Kristiansand, Norway

[16] Univ Oslo, Dept Med Genet, N-0407 Oslo, Norway

[17] Oslo Univ Hosp, Inst Canc Res, Dept Canc Prevent, N-0407 Oslo, Norway

[18] Oslo Univ Hosp, Dept Urol, N-0407 Oslo, Norway

[19] Oslo Univ Hosp, Rikshosp, KG Jebsen Inflammat Res Ctr, Internal Med Res Inst,Div Canc Med Surg & Transpl, N-0407 Oslo, Norway

[20] Oslo Univ Hosp, Sect Clin Immunol & Infect Dis, N-0407 Oslo, Norway

[21] Univ Bergen, Inst Med, Div Gastroenterol, N-5000 Bergen, Norway

[22] Oslo Univ Hosp, Rikshosp, Norwegian PSC Res Ctr, Dept Transplantat Med,Div Canc Med Surg & Transpl, N-0407 Oslo, Norway

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

来源：

PLOS ONE | 2015年 / 10卷 / 04期

关键词：

GENOME-WIDE ASSOCIATION; COMMON VARIANTS; RHEUMATOID-ARTHRITIS; CROHN DISEASE; PUBLIC-HEALTH; IDENTIFIES; 7; RISK LOCUS; ATHEROSCLEROSIS; INFLAMMATION; METABOLISM;

D O I：

10.1371/journal.pone.0123057

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n similar to 200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

引用

页数：17

共 63 条

[1] Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47 [J].

Anderson, Carl A. ;

Boucher, Gabrielle ;

Lees, Charlie W. ;

Franke, Andre ;

D'Amato, Mauro ;

Taylor, Kent D. ;

Lee, James C. ;

Goyette, Philippe ;

Imielinski, Marcin ;

Latiano, Anna ;

Lagace, Caroline ;

Scott, Regan ;

Amininejad, Leila ;

Bumpstead, Suzannah ;

Baidoo, Leonard ;

Baldassano, Robert N. ;

Barclay, Murray ;

Bayless, Theodore M. ;

Brand, Stephan ;

Buening, Carsten ;

Colombel, Jean-Frederic ;

Denson, Lee A. ;

De Vos, Martine ;

Dubinsky, Marla ;

Edwards, Cathryn ;

Ellinghaus, David ;

Fehrmann, Rudolf S. N. ;

Floyd, James A. B. ;

Florin, Timothy ;

Franchimont, Denis ;

Franke, Lude ;

Georges, Michel ;

Glas, Juergen ;

Glazer, Nicole L. ;

Guthery, Stephen L. ;

Haritunians, Talin ;

Hayward, Nicholas K. ;

Hugot, Jean-Pierre ;

Jobin, Gilles ;

Laukens, Debby ;

Lawrance, Ian ;

Lemann, Marc ;

Levine, Arie ;

Libioulle, Cecile ;

Louis, Edouard ;

McGovern, Dermot P. ;

Milla, Monica ;

Montgomery, Grant W. ;

Morley, Katherine I. ;

Mowat, Craig .

NATURE GENETICS, 2011, 43 (03) :246-U94

[2] Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci [J].

Andreassen, O. A. ;

Harbo, H. F. ;

Wang, Y. ;

Thompson, W. K. ;

Schork, A. J. ;

Mattingsdal, M. ;

Zuber, V. ;

Bettella, F. ;

Ripke, S. ;

Kelsoe, J. R. ;

Kendler, K. S. ;

O'Donovan, M. C. ;

Sklar, P. ;

McEvoy, L. K. ;

Desikan, R. S. ;

Lie, B. A. ;

Djurovic, S. ;

Dale, A. M. .

MOLECULAR PSYCHIATRY, 2015, 20 (02) :207-214

[3] Shared common variants in prostate cancer and blood lipids [J].

Andreassen, Ole A. ;

Zuber, Verena ;

Thompson, Wesley K. ;

Schork, Andrew J. ;

Bettella, Francesco ;

Djurovic, Srdjan ;

Desikan, Rahul S. ;

Mills, Ian G. ;

Dale, Anders M. .

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 2014, 43 (04) :1205-1214

[4] Identifying Common Genetic Variants in Blood Pressure Due to Polygenic Pleiotropy With Associated Phenotypes [J].

Andreassen, Ole A. ;

McEvoy, Linda K. ;

Thompson, Wesley K. ;

Wang, Yunpeng ;

Reppe, Sjur ;

Schork, Andrew J. ;

Zuber, Verena ;

Barrett-Connor, Elizabeth ;

Gautvik, Kaare ;

Aukrust, Pal ;

Karlsen, Tom H. ;

Djurovic, Srdjan ;

Desikan, Rahul S. ;

Dale, Anders M. .

HYPERTENSION, 2014, 63 (04) :819-826

[5] Boosting the Power of Schizophrenia Genetics by Leveraging New Statistical Tools [J].

Andreassen, Ole A. ;

Thompson, Wesley K. ;

Dale, Anders M. .

SCHIZOPHRENIA BULLETIN, 2014, 40 (01) :13-17

[6] Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate [J].

Andreassen, Ole A. ;

Thompson, Wesley K. ;

Schork, Andrew J. ;

Ripke, Stephan ;

Mattingsdal, Morten ;

Kelsoe, John R. ;

Kendler, Kenneth S. ;

O'Donovan, Michael C. ;

Rujescu, Dan ;

Werge, Thomas ;

Sklar, Pamela ;

Roddey, J. Cooper ;

Chen, Chi-Hua ;

McEvoy, Linda ;

Desikan, Rahul S. ;

Djurovic, Srdjan ;

Dale, Anders M. .

PLOS GENETICS, 2013, 9 (04)

[7] Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors [J].

Andreassen, Ole A. ;

Djurovic, Srdjan ;

Thompson, Wesley K. ;

Schork, Andrew J. ;

Kendler, Kenneth S. ;

O'Donovan, Michael C. ;

Rujescu, Dan ;

Werge, Thomas ;

van de Bunt, Martijn ;

Morris, Andrew P. ;

McCarthy, Mark I. ;

Roddey, J. Cooper ;

McEvoy, Linda K. ;

Desikan, Rahul S. ;

Dale, Anders M. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2013, 92 (02) :197-209

[8] Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes [J].

Barrett, Jeffrey C. ;

Clayton, David G. ;

Concannon, Patrick ;

Akolkar, Beena ;

Cooper, Jason D. ;

Erlich, Henry A. ;

Julier, Cecile ;

Morahan, Grant ;

Nerup, Jorn ;

Nierras, Concepcion ;

Plagnol, Vincent ;

Pociot, Flemming ;

Schuilenburg, Helen ;

Smyth, Deborah J. ;

Stevens, Helen ;

Todd, John A. ;

Walker, Neil M. ;

Rich, Stephen S. .

NATURE GENETICS, 2009, 41 (06) :703-707

[9] Inflammatory and Autoimmune Mechanisms in the Induction of Atherosclerotic Damage in Systemic Rheumatic Diseases: Two Faces of the Same Coin [J].

Bartoloni, Elena ;

Shoenfeld, Yehuda ;

Gerli, Roberto .

ARTHRITIS CARE & RESEARCH, 2011, 63 (02) :178-183

[10] Dyslipidemia and lipoprotein profiles in patients with inflammatory bowel disease [J].

Biyyani, Raja Shekhar R. Sappati ;

Putka, Brian S. ;

Mullen, Kevin D. .

JOURNAL OF CLINICAL LIPIDOLOGY, 2010, 4 (06) :478-482

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