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Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease
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نویسنده
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mäkinen v.-p. ,civelek m. ,meng q. ,zhang b. ,zhu j. ,levian c. ,huan t. ,segrè a.v. ,ghosh s. ,vivar j. ,nikpay m. ,stewart a.f.r. ,nelson c.p. ,willenborg c. ,erdmann j. ,blakenberg s. ,o'donnell c.j. ,märz w. ,laaksonen r. ,epstein s.e. ,kathiresan s. ,shah s.h. ,hazen s.l. ,reilly m.p. ,lusis a.j. ,samani n.j. ,schunkert h. ,quertermous t. ,mcpherson r. ,yang x. ,assimes t.l.
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منبع
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plos genetics - 2014 - دوره : 10 - شماره : 7
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چکیده
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The majority of the heritability of coronary artery disease (cad) remains unexplained,despite recent successes of genome-wide association studies (gwas) in identifying novel susceptibility loci. integrating functional genomic data from a variety of sources with a large-scale meta-analysis of cad gwas may facilitate the identification of novel biological processes and genes involved in cad,as well as clarify the causal relationships of established processes. towards this end,we integrated 14 gwas from the cardiogram consortium and two additional gwas from the ottawa heart institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of cad-relevant tissues in humans,2) metabolic and signaling pathways from public databases,and 3) data-driven,tissue-specific gene networks from a multitude of human and mouse experiments. we not only detected cad-associated gene networks of lipid metabolism,coagulation,immunity,and additional networks with no clear functional annotation,but also revealed key driver genes for each cad network based on the topology of the gene regulatory networks. in particular,we found a gene network involved in antigen processing to be strongly associated with cad. the key driver genes of this network included glyoxalase i (glo1) and peptidylprolyl isomerase i (ppil1),which we verified as regulatory by sirna experiments in human aortic endothelial cells. our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to cad risk. the key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions. © 2014 mäkinen et al.
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آدرس
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department of integrative biology and physiology,university of california,los angeles,los angeles,ca,united states,south australian health and medical research institute,adelaide,sa,australia,school of molecular and biomedical science,university of adelaide,adelaide,sa, Australia, department of medicine/division of cardiology,david geffen school of medicine,university of california los angeles,los angeles,ca, United States, department of integrative biology and physiology,university of california,los angeles,los angeles,ca, United States, department of genetics and genomic sciences,icahn school of medicine at mount sinai,new york,ny, United States, department of genetics and genomic sciences,icahn school of medicine at mount sinai,new york,ny, United States, department of integrative biology and physiology,university of california,los angeles,los angeles,ca, United States, national heart,lung,and blood institute's framingham heart study,framingham,ma, United States, broad institute of harvard and mit,cambridge,ma, United States, department of cardiovascular and metabolic research,biomedical biotechnology research institute,north carolina central university,durham,nc,united states,program in cardiovascular and metabolic disorders and centre for computational biology,duke-nus graduate medical school, Singapore, department of cardiovascular and metabolic research,biomedical biotechnology research institute,north carolina central university,durham,nc, United States, atherogenomics laboratory,university of ottawa heart institute,ottawa,on, Canada, john and jennifer ruddy canadian cardiovascular research center,university of ottawa heart institute,ottawa,on, Canada, department of cardiovascular sciences,university of leicester,glenfield hospital,leicester,united kingdom,national institute for health research (nihr),leicester cardiovascular biomedical research unit,glenfield hospital,leicester, United Kingdom, institut für integrative und experimentelle genomik,university of lübeck,lübeck, Germany, institut für integrative und experimentelle genomik,university of lübeck,lübeck,germany,dzhk (german research centre for cardiovascular research),partner site hamburg,kiel,lübeck, Germany, clinic for general and interventional cardiology,university heart center hamburg,hamburg, Germany, national heart,lung,and blood institute's framingham heart study,framingham,ma,united states,cardiology division,center for human genetic research,massachusetts general hospital and harvard medical school,boston,ma, United States, mannheim institute of public health,social and preventive medicine,university of heidelberg,mannheim,germany,synlab academy,mannheim, Germany, science center,tampere university hospital,tampere, Finland, cardiovascular research institute,washington hospital center,washington,dc, United States, national heart,lung,and blood institute's framingham heart study,framingham,ma,united states,cardiology division,center for human genetic research,massachusetts general hospital and harvard medical school,boston,ma,united states,cardiovascular research center,massachusetts general hospital and harvard medical school,boston,ma, United States, department of medicine,duke university medical center,durham,nc, United States, cleveland clinic,cleveland,oh, United States, cardiovascular institute,perelman school of medicine at the university of pennsylvania,philadelphia,pa, United States, department of medicine/division of cardiology,david geffen school of medicine,university of california los angeles,los angeles,ca, United States, department of cardiovascular sciences,university of leicester,glenfield hospital,leicester,united kingdom,national institute for health research (nihr),leicester cardiovascular biomedical research unit,glenfield hospital,leicester, United Kingdom, dzhk (german research centre for cardiovascular research),partner site munich heart alliance,munich,germany,deutsches herzzentrum münchen,technische universität münchen,munich, Germany, department of medicine,stanford university school of medicine,stanford,ca, United States, atherogenomics laboratory,university of ottawa heart institute,ottawa,on, Canada, department of integrative biology and physiology,university of california,los angeles,los angeles,ca, United States, department of medicine,stanford university school of medicine,stanford,ca, United States
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Authors
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