The major objective of Project 3 is to localize and identify the genes underlying previously detected QTLs for obesity-related phenotypes in the San Antonio Family Heart Study (SAFHS) which contribute to variation in risk of cardiovascular disease (CVD). This work is based upon large extended Mexican American families ascertained without regard to disease status. This sample represents -1400 family members which have been genotyped for >400 short tandem repeat markers in an 8 centimorgan map and for which genome-wide linkage analysis has been performed for a variety of phenotypes associated with obesity and which are recognized risk factors for CVD. In this project we will make use of recent advancements in high-throughput SNP typing and sequencing to saturate our areas of interest to further refine the region and help select positional candidate genes based on association implemented in a novel Bayesian quantitative trait nucleotide (BQTN) analysis designed to make use of complex family data sets. The identification and selection of these positional candidate genes will be further refined based on the application of an objective bioinformatics search routine along with insights provided by evidence of strong cis regulation of genes in the specific regions of interest identified from our unique whole genome transcript data for this population. Once strong positional candidate genes have been identified within our regions of interest, they will be resequenced within the set of founders for this sample to identify all common polymorphisms. Characterization of these polymorphisms will permit the remaining individuals to be genotyped and BQTN analysis will again be employed to identify the presence of potential functional variants in these positional candidate genes. When significant evidence of potential functional variants has been detected these polymorphisms will be typed in two additional family samples of Mexican Americans in order to look for replication.
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