Single nucleotide polymorphism identification in candidate gene systems of obesity.

We have constructed a large panel of single nucleotide polymorphisms (SNP) identified in 68 candidate genes for obesity. Our panel combines novel SNP identification methods based on EST data, with public SNP data from largescale genomic sequencing, to produce a total of 218 SNPs in the coding regions of obesity candidate genes, 178 SNPs in untranslated regions, and over 1000 intronic SNPs. These include new non-conservative amino acid changes in thyroid receptor beta, esterase D, acid phosphatase 1. Our data show evidence of negative selection among these polymorphisms implying functional impacts of the non-conservative mutations. Comparison of overlap between SNPs identified independently from EST data vs genomic sequencing indicate that together they may constitute about one half of the actual total number of amino acid polymorphisms in these genes that are common in the human population (defined here as a population allele frequency above 5%). We have analyzed our polymorphism panel to construct a database of detailed information about their location in the gene structure and effect on protein coding, available on the web at http://www.bioinformat ics.ucla.edu/snp/obesity. We believe this panel can serve as a valuable new resource for genetic and pharmacogenomic studies of the causes of obesity.