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- Title
Genome-Wide Association Analysis in UK Subjects Provides Evidence for a Novel Type 2 Diabetes Susceptibility Gene in the CDKAL1 Region of Chromosome 6.
- Authors
Zeggini, Eleftheria; Weedon, Michael N.; Lindgren, Cecilia M.; Lango, Hana; Timpson, Nicholas J.; Rayner, Nigel W.; Elliott, Kate; Groves, Christopher J.; Perry, John; Hitman, Graham A.; Walker, Mark; Barrett, Jeffrey C.; Donnelly, Peter; Clayton, David G.; Morris, Andrew P.; Cardon, Lon R.; Palmer, Colin N.; Morris, Andrew; Frayling, Timothy M.; Hattersley, Andrew T.
- Abstract
The capacity to undertake systematic surveys of common variation through genome-wide association analysis has the potential to deliver substantial insights into type 2 diabetes (T2D) pathogenesis. We recently completed genotyping of 1954 T2D cases (enriched for positive family history/early onset) and 2922 population-based controls (all UK origin) on the Affymetrix 500k chip as part of the Wellcome Trust Case-Control Consortium. The preliminary analyses reported here are based on ∼309,000 SNPs with exemplary quality control and minor allele frequency (MAF)>5% [estimated to provide ∼60% coverage of CEU HapMap (MAF>5%, pairwise, r²>0.8)]. Variants within TCF7L2 emerge as the strongest cluster of susceptibility variants (12 SNPs, best = rs7901695, p=9.9x 10[sup -13]), but we find an additional 5 signals achieving nominal genome-wide significance with additive model p<6x10[sup -6] (controlling the false discovery rate at 0.05). These signals (located on chromosomes 1, 2, 6, 12 and 16) include a cluster of 5 SNPs with p< 10[sup -4] at ∼20.8Mbp on chr6, in a region including the CDK5 regulatory subunit associated protein 1-like 1 gene (CDKAL1) [for example, rs9465871, OR(95%CIs) for allele T (MAF∼80%) dominance: 0.51(0.37-0.70), exact p=1x10[sup -5]]. Extensive replication studies in 3073 T2D cases and 3879 controls (0.70(0.53-0.92), exact p=0.005) and meta-analysis across all ∼11800 subjects (0.61 (0.49-0.75), exact p=5.7x 10[sup -7]) provide supporting evidence for this finding. Haplotype-based analyses across a 2Mb region surrounding rs9465871 show no additional signal. Based on HapMap CEU data, rs9465871 is in perfect LD with several other intronic variants within CDKAL1; we have thus far covered ∼60% of common variation in the region (r²>0.8). Whilst further replication studies and fine-mapping will be required to refine the allelic architecture of this locus, these findings provide strong preliminary evidence that the CDKAL1 region harbours a novel locus affecting T2D risk.
- Subjects
UNITED Kingdom; TYPE 2 diabetes; CHROMOSOMES; GENOMES; PROTEINS
- Publication
Diabetes, 2007, Vol 56, pA302
- ISSN
0012-1797
- Publication type
Article