To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
The genetic architecture of common traits, including the number,
frequency, and effect sizes of inherited variants that contribute to individual
risk, has been long debated. Genome-wide association studies have identified
scores of common variants associated with type 2 diabetes, but in aggregate,
these explain only a fraction of heritability. To test the hypothesis that
lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES
consortia performed whole genome sequencing in 2,657 Europeans with and without
diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral
groups. To increase statistical power, we expanded sample size via genotyping
and imputation in a further 111,548 subjects. Variants associated with type 2
diabetes after sequencing were overwhelmingly common and most fell within
regions previously identified by genome-wide association studies. Comprehensive
enumeration of sequence variation is necessary to identify functional alleles
that provide important clues to disease pathophysiology, but large-scale
sequencing does not support a major role for lower-frequency variants in
predisposition to type 2 diabetes.
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