Presentation on theme: "Genetics Journal Club Robert C. Bauer January 22 nd, 2015."— Presentation transcript:
Genetics Journal Club Robert C. Bauer January 22 nd, 2015
As of 01/21/15, the catalog includes 2100 publications and 15257 SNPs.
How to identify causal gene from a GWAS? Global Lipids Genetics Consortium, Plasma Total Cholesterol Locus GLGC, Nat Genet, 2013
How to identify causal gene from a GWAS? GLGC, Nat Genet, 2013 Closest Gene Can be challenging with intergenic loci with many genes Most logical gene based on ontology/known function Lots of completely unannotated genes In Vitro assays – overexpression/Knockdown Cell type specific? Viral Somatic Overexpression Is tissue readily accessible KO Animal Models Costly to do multiple genes in mice Zebrafish allow faster testing, may not recapitulate mammals False Positives/Negatives
SNPs in the FTO genic region associate with Obesity, BMI, and Type-2 Diabetes Obesity Plot Giant Consortium, 2013 (From LocusZoom)
SNPs in FTO locus associate with BMI and T2D (mediated by BMI) Adults homozygous for risk alleles weighed +3kg SNPs in first intron of FTO associate with early onset obesity in both children and adults GWAS Identifying the FTO locus SNPs in first intron of FTO associate with BMI, hip circumference, and weight Homozygotes for the minor allele are 1.3 BMI units heavier
FTO knockout mouse has reduced body weight Fischer et al, Nature, 2009
FTO transgenic mouse has INCREASED body weight in a dose dependent manner Church et al., Nature Genet, 2010
Multiple Mouse Models support role for FTO in obesity Mouse model Body weight Fat/lean mass Energy expenditure Food intakeReference KnockoutDecreased Increased Fischer, J. et al Nature 2009 KnockoutDecreased IncreasedNot affected Church, C et al Plos Genet 2009 Over- expression Increased Not affectedIncreased Church, C. et al.Nature Genet 2010 KnockoutDecreasedNot affectedIncreased Gao, X. et al. PLoS ONE 2010 Neural specific KO DecreasedNot affectedIncreased Gao, X. et al. PLoS ONE 2010
The case against FTO – no eQTL Wahlen et al., J Lipid Res, 2008 Grunnet et al., Diabetes, 2009
Fig 4: Expression of DN Irx3 in hypothalamus phenocopies Irx3 KO mouse
Fig 4: Loss of Irx3 function in hypothalamus causes browning of WAT
Irx3 promoter interacts with the obesity-associated interval – over 400kb away Obesity associated interval contains enhancer elements with activity pattern similar to Irx3 BMI associated SNPs in the interval are associated with Irx3 expression level in human brain Irx3 knockout mice have a lean phenotype and higher energy expenditure which can be recapitulated by hypothalamus specific disruption of Irx3 function SUMMARY
COMMENTS Mouse models not sufficient for validation of GWAS loci? “We searched among 7,556 targeted mouse gene knockout models for evidence of alterations in body size, mass and growth (see Methods). Nearly one-third (2,166; 29%) of gene knockouts in mice show alteration of these phenotypes, underscoring that animal models alone are not sufficient to definitively establish a functional relationship between a given gene and long-range noncoding variants (Supplementary Table 4).”
GWAS Signal for Coronary Artery Diseases in ADAMTS7/MORF4L1 locus Adamts7 KO mice have reduced atherosclerosis
COMMENTS Mouse models not sufficient for validation of GWAS loci? Power of GWAS in identifying novel biology FTO: Nuclear whose exact physiological is not known. Proteins with smiliar homology participate in oxidative demethylation of damaged DNA/RNA. IRX3: Member of the Iroquois homeobox gene family involved in early steps of neural development. Members of this family appear to play multiple roles during pattern formation of vertebrate embryos. NEITHER GENE IMPLICATED IN OBESITY PRIOR TO THESE STUDIES
COMMENTS Mouse models not sufficient for validation of GWAS loci? Power of GWAS in identifying novel biology Irx3 KO mouse – show the KO??
COMMENTS Mouse models not sufficient for validation of GWAS loci? Power of GWAS in identifying novel biology Irx3 KO mouse – show the KO?? Mechanism? Known hormones that regulate metabolism?