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Trans-eqtls reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes,with a major role for the hla
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نویسنده
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fehrmann r.s.n. ,jansen r.c. ,veldink j.h. ,westra h.-j. ,arends d. ,bonder m.j. ,fu j. ,deelen p. ,groen h.j.m. ,smolonska a. ,weersma r.k. ,hofstra r.m.w. ,buurman w.a. ,rensen s. ,wolfs m.g.m. ,platteel m. ,zhernakova a. ,elbers c.c. ,festen e.m. ,trynka g. ,hofker m.h. ,saris c.g.j. ,ophoff r.a. ,van den berg l.h. ,van heel d.a. ,wijmenga c. ,meerman g.j. ,franke l.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 8
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چکیده
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For many complex traits,genetic variants have been found associated. however,it is still mostly unclear through which downstream mechanism these variants cause these phenotypes. knowledge of these intermediate steps is crucial to understand pathogenesis,while also providing leads for potential pharmacological intervention. here we relied upon natural human genetic variation to identify effects of these variants on trans-gene expression (expression quantitative trait locus mapping,eqtl) in whole peripheral blood from 1,469 unrelated individuals. we looked at 1,167 published trait- or disease-associated snps and observed trans-eqtl effects on 113 different genes,of which we replicated 46 in monocytes of 1,490 different individuals and 18 in a smaller dataset that comprised subcutaneous adipose,visceral adipose,liver tissue,and muscle tissue. hla single-nucleotide polymorphisms (snps) were 10-fold enriched for trans-eqtls: 48% of the trans-acting snps map within the hla,including ulcerative colitis susceptibility variants that affect plausible candidate genes aoah and trbv18 in trans. we identified 18 pairs of unlinked snps associated with the same phenotype and affecting expression of the same trans-gene (21 times more than expected,p<10 -16). this was particularly pronounced for mean platelet volume (mpv): two independent snps significantly affect the well-known blood coagulation genes gp9 and f13a1 but also c19orf33,samd14,vcl,and gng11. several of these snps have a substantially higher effect on the downstream trans-genes than on the eventual phenotypes,supporting the concept that the effects of these snps on expression seems to be much less multifactorial. therefore,these trans-eqtls could well represent some of the intermediate genes that connect genetic variants with their eventual complex phenotypic outcomes. © 2011 fehrmann et al.
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آدرس
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department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, groningen bioinformatics centre,groningen biomolecular sciences and biotechnology institute,university of groningen,haren, Netherlands, department of neurology,rudolf magnus institute of neuroscience,university medical centre utrecht,utrecht, Netherlands, department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, groningen bioinformatics centre,groningen biomolecular sciences and biotechnology institute,university of groningen,haren, Netherlands, department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, department of pulmonology,university medical center groningen and university of groningen,groningen, Netherlands, department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, department of genetics,university medical center groningen and university of groningen,groningen,netherlands,department of gastroenterology and hepatology,university medical centre groningen and university of groningen,groningen, Netherlands, department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, nutrim school for nutrition,toxicology,and metabolism,department of general surgery,maastricht university medical center,maastricht, Netherlands, nutrim school for nutrition,toxicology,and metabolism,department of general surgery,maastricht university medical center,maastricht, Netherlands, department of pathology and medical biology,medical biology section,molecular genetics,university medical center groningen and university of groningen,groningen, Netherlands, department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, department of rheumatology,leiden university medical center,leiden, Netherlands, department of genetics,university of pennsylvania,philadelphia,pa, United States, department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, department of pathology and medical biology,medical biology section,molecular genetics,university medical center groningen and university of groningen,groningen, Netherlands, department of neurology,rudolf magnus institute of neuroscience,university medical centre utrecht,utrecht, Netherlands, department of neurology,rudolf magnus institute of neuroscience,university medical centre utrecht,utrecht,netherlands,department of medical genetics,university medical center utrecht,utrecht,netherlands,center for neurobehavioral genetics,university of california los angeles,los angeles,ca, United States, department of neurology,rudolf magnus institute of neuroscience,university medical centre utrecht,utrecht, Netherlands, blizard institute of cell and molecular science,barts and the london school of medicine and dentistry,queen mary university of london,london, United Kingdom, department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, department of genetics,university medical center groningen and university of groningen,groningen, Netherlands, department of genetics,university medical center groningen and university of groningen,groningen,netherlands,blizard institute of cell and molecular science,barts and the london school of medicine and dentistry,queen mary university of london,london, United Kingdom
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Authors
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