Evidence for a susceptibility gene for type 2 diabetes on chromosome 11.

M.R. Erdos(1), H.M. Stringham(2), P.S. Chines(1), N. Narisu(1), A.U. Jackson(2), W.L. Duren(2), L.L. Bonnycastle(1), C.J. Willer(2), L.J. Scott(2), K.F. Doheny(3), E.W. Pugh(3), N.L. Riebow(1), T.T. Valle(4), R.M. Watanabe(5), T.A. Buchanan(5), R.N. Bergman(5), J. Tuomilehto(4), K.L. Mohlke(6), M. Boehnke(2) and F.S. Collins(1)

(1) NHGRI, NIH, Bethesda, MD; (2) U. Michigan, Ann Arbor, MI; (3) CIDR, Johns Hopkins U., Baltimore, MD; (4) National Public Health Institute, Helsinki, Finland; (5) U. Southern California, Los Angeles, CA; (6) U. North Carolina, Chapel Hill, NC

The FUSION study of the genetics of type 2 diabetes mellitus (T2D) previously performed microsatellite linkage scans of two samples of Finnish affected sib pair families in an attempt to identify the genetic variants conferring susceptibility to T2D. The strongest genome-wide evidence for linkage was found on chromosome 11 at 82.0 cM (LOD = 2.98). Subsequent SNP genotyping on pools of 748 probands, 228 older controls, and 182 spouses in the 12.4 Mb linkage region (achieving an average SNP density of 33.6 kb) identified a closely spaced cluster of associated SNPs with an estimated maximum allele frequency difference > .10 (p = 4.6 x 10-5). Follow up genotyping of individual cases, spouses, and controls confirmed three SNPs with allele frequency differences between cases and controls > .054 (p < .001). An additional 28 SNPs were typed in the same region; 18 of these identified a block of linkage disequilibrium (LD) of approximately 210 kb showing association with T2D. Located within this block is the GRB-2 associated binding protein 2 (GAB2) gene, a plausible candidate for T2D. We are now performing genome-wide association (GWA) analysis using the Illumina Human Hap300 panel, which includes 1,459 SNPs typed in this chromosome 11 linkage region on 1171 cases and 1186 controls from the FUSION study and the Finrisk 2002 population-based study. Initial analysis of the GWA data on 885 cases and 885 controls has identified 61 SNPs with T2D association p-value < .05 adjusted for testing three genetic models per SNP in the linkage region. Although no SNPs in the GAB2 gene show p < .05, the best T2D association result (p = 0.0011) is located 1.9Mb proximal to GAB2 and four additional SNPs show association (p < .003) within 1.0Mb distal to the gene.