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Use of genome-wide expression data to mine the "Gray Zone" of GWA studies leads to novel candidate obesity genes

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. In the study 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 GWA data generated in large SNP scans. We infer causality of genes with obesity by employing a unique set of Finnish 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) from the same population. 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 ENGAGE consortium (N=21,000) revealed a significant deviation of P-values from the expected (P= 4 x 10-4). 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 ~2000 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.

Publication details:

Use of genome-wide expression data to mine the "Gray Zone" of GWA studies leads to novel candidate obesity genes.
Naukkarinen J, Surakka I, Pietiläinen KH, Rissanen A, Salomaa V, Ripatti S, Yki-Järvinen H, van Duijn CM, Wichmann HE, Kaprio J, Taskinen MR, Peltonen L; ENGAGE Consortium.
PLoS Genetics 2010;. PMID: 20532202



June 2010
ENGAGE Young Investigator

Jussi Naukkarinen


FIMM, Institute for Molecular Medicine Finland, P.O. Box 20, FI-00014 University of Helsinki, Finland

Jussi wrote his thesis on the molecular genetics of common dyslipidemias in Leena Peltonenís research group as a part of his M.D., Ph.D. training. He has worked on the genetics of familial combined hyperlipidemia (FCHL), familial low-HDL as well as on the effects of acquired obesity utilizing monozygotic twins discordant for obesity. Jussiís research interests are currently concentrated on integrating genomic- and transcriptomic data with in-depth phenotyping of obesity discordant twins in order to shed light on the complex changes that take place when individuals gain fat and start to develop the pre-diabetic changes associated with type 2 diabetes and heart disease. Jussi hopes that with the ever increasing amount of data available, the underlying causes of complex diseases donít turn from being puzzles into being mysteries. The distinction, as has been noted by others, is not trivial.