TITLE:

POPULATION SEQUENCING AND FUNCTIONAL ANNOTATION OF TARGETED GENOMIC INTERVALS

DATE:

Friday, September 17th, 2010

TIME:

3:30 PM

LOCATION:

GMCS 214

SPEAKER:

Kelly A. Frazer, Moores UCSD Cancer Center and Department of Pediatrics, University of California San Diego

ABSTRACT:

Population sequencing of intervals in the human genome has been proposed as a method for identifying the causal common variants underlying the statistical associations of Genome Wide Association (GWA) studies. We re-sequenced a 196-kb interval on 9p21 which is associated with Coronary Artery Disease (CAD) and Type 2 Diabetes (T2D) in 50 individuals of European descent. We identify sets of 154 and 23 variants, which likely contain the functional variants underlying the association with CAD and T2D, respectively. Chromatin profiling identified 23 enhancer elements and 2 insulators; the interval is 10 times denser than the whole genome for such enhancer signatures (p < 1.3×10^-15). The activity of 3 of these enhancers is affected by regulatory variants that show allelic differences in DNA-protein affinity and are strongly associated with either CAD or T2D. Our study shows that the 9p21 gene desert is significantly enriched in enhancer elements and suggests the associations with CAD and T2D likely result from the cumulative contributions of multiple regulatory variants.

Population sequencing of intervals has also been proposed as a method for identifying rare variants contributing to complex traits of interest. We re-sequenced 188 kilobases surrounding the Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) genes in a sample of 289 individuals of European descent. FAAH and MGLL are enzymes of the endocannabinoid (EC) pathway, catabolizing anandamide (AEA) and 2-arachidonyl glycerol (2-AG) respectively. Deregulation of the EC pathway has been shown in overweight and eating disorders, and increased level of EC in many tissues is linked to obesity (Osei-Hyiaman et al. 2005). Half of the individuals sequenced had morbid obesity with a body mass index (BMI) > 40 and the other half had a BMI < 30. To investigate association with morbid obesity, we analyzed the presence of rare alleles (MAF < 0.1) by a model-free method (RareCover), and identified exactly one significantly associated region (containing a combination of rare variants) in each gene, each about 5-kb in the upstream regulatory regions.

HOST:

Paul Paolini

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