期刊
PLOS GENETICS
卷 6, 期 6, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1000976
关键词
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资金
- EVO
- special governmental subsidy for health sciences research (Helsinki University Central Hospital)
- Finnish heart Association
- Helsinki University Central Hospital
- Yrjo Jahnsson Foundation
- Jalmari Foundation
- Rauha Ahokas Foundation
- Biomedicum Helsinki Foundation
- Novo Nordisk Foundations
- Academy of Finland Center of Excellence in Complex Disease Genetics
- Finnish Academy [129494]
- Finnish Foundation for Cardiovascular Research
- Sigrid Juselius Foundation
- European Community [FP7/2007-2013]
- ENGAGE Consortium [HEALTH-F4-2007-201413]
- NHLBI [5R01HL087679-02]
- European Commission [018947, LSHG-CT-2006-01947]
- Ministry of Health of the Autonomous Province of Bolzano
- South Tyrolean Sparkasse Foundation
- NWO [904-61-090, 480-04-004, 175.010.2005.011]
- Center for Medical Systems Biology (NWO Genomics)
- Spinozapremie [SPI 56-464-14192]
- Centre for Neurogenomics and Cognitive Research (CNCR-VU)
- EU [EU/QLRT-2001-01254]
- ZonMW [10-000-1002]
- NESDA (GGZ Buitenamstel-Geestgronden, Rivierduinen, University Medical Center Groningen, GGZ Lentis, GGZ Friesland, GGZ Drenthe)
- Genetic Association Information Network of the Foundation for the US National Institutes of Health
- Helmholtz Zentrum Munchen
- Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany
- German Federal Ministry of Education and Research (BMBF)
- German National Genome Research Network (NGFN)
- Austrian Genome Research Programme GEN-AU
- Munich Center of Health Sciences (MC Health)
- LMUinnovativ
- Medical Research Council UK
- Ministry of Science, Education and Sport of the Republic of Croatia [108-1080315-0302]
- Netherlands Organisation for Scientific Research, Erasmus MC
- Centre for Medical Systems Biology (CMSB)
- Swedish Medical Research Council
- European Commission
- Scottish Executive Health Department
- Royal Society
- Wellcome Trust
To get beyond the low-hanging fruits'' so far identified by genome-wide association (GWA) studies, new methods must be developed in order to discover the numerous remaining genes that estimates of heritability indicate should be contributing to complex human phenotypes, such as obesity. Here we describe a novel integrative method for complex disease gene identification utilizing both genome-wide transcript profiling of adipose tissue samples and consequent analysis of genome-wide association data generated in large SNP scans. We infer causality of genes with obesity by employing a unique set of monozygotic twin pairs discordant for BMI (n = 13 pairs, age 24-28 years, 15.4 kg mean weight difference) and contrast the transcript profiles with those from a larger sample of non-related adult individuals (N=77). Using this approach, we were able to identify 27 genes with possibly causal roles in determining the degree of human adiposity. Testing for association of SNP variants in these 27 genes in the population samples of the large ENGAGE consortium (N=21,000) revealed a significant deviation of P-values from the expected (P=4x10(-4)). A total of 13 genes contained SNPs nominally associated with BMI. The top finding was blood coagulation factor F13A1 identified as a novel obesity gene also replicated in a second GWA set of similar to 2,000 individuals. This study presents a new approach to utilizing gene expression studies for informing choice of candidate genes for complex human phenotypes, such as obesity.
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