Genome-wide Association Studies of Type 2 Diabetes in Mexican Americans. M.G. Hayes¹, K. Miyake¹, C.L. Hanis², G.I. Bell¹, N.J. Cox¹. 1) Medicine, Univ. Chicago, Chicago, IL; 2) Univ. Texas Health Sciences Center, Houston, TX.
   We have undertaken a genome-wide association study using the Affymetrix 100K platform to localize susceptibility genes for type 2 diabetes (T2D) in Mexican Americans from Starr County, TX. Power for our study was increased by choosing the affected sibling with youngest age at diagnosis of T2D from sibships included in previous linkage studies as the case samples (350 for first-stage screen). A random sample of Mexican Americans from Starr County comprises the control sample (350 for first-stage screen). We present results from a data freeze including 287 cases and 316 controls. Using the Affymetrix DM allele-calling algorithm, per marker call rates averaged >93%, with more than 80% of markers having call rates >90%. With the DM algorithm calls, we observed a substantial number of SNPs with departures from Hardy Weinberg equilibrium (HWE) at any threshold of significance, largely attributable to SNPs with excess homozygosity, consistent with non-random missing data (heterozygotes more likely to have missing data). Using an improved allele calling algorithm (GEL) both increased the call rate and reduced non-random missing data. We observed many more significant allelic associations than expected genome wide as empirically assessed by permutation [specifically 3 below a p of 1x10^-5 (1 expected), 38 below a p of 1x10^-4 (15 expected), and 246 below a p of 1x10^-3 (129 expected)]. Our three best signals, those with allelic association p<1x10^-5, call rates >93%, and HW departure p-values >0.001, occur on chromosomes 4q, 12q, and 20q. We are conducting admixture mapping in these same samples, and will contrast regions of interest across these methods in follow up studies in an additional 700 case and 700 random samples ascertained in the same way from Starr County. Our preliminary analyses of this genome-wide association study suggest it will successfully highlight regions of interest for follow-up in a larger case-control set. Moreover, it may reveal novel genes and pathways to further elucidate the etiology of T2D as well as new avenues for both the treatment and prevention of this complex disease.