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.
SUMMARY
Meta-analyses of genome-wide association studies (GWAS) have identified >240
loci associated with type 2 diabetes (T2D)
1
,
2
, however most loci have been identified in analyses
of European-ancestry individuals. To examine T2D risk in East Asian individuals, we
meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we
identified 301 distinct association signals at 183 loci, and across T2D association models with
and without consideration of body mass index and sex, we identified 61 loci newly implicated in
T2D predisposition. Common variants associated with T2D in both East Asian and European
populations exhibited strongly correlated effect sizes. New associations include signals
in/near
GDAP1
,
PTF1A
,
SIX3, ALDH2,
a
microRNA cluster, and genes that affect muscle and adipose differentiation
3
. At another locus, eQTLs at two overlapping T2D signals affect
two genes,
NKX6-3
and
ANK1
, in different tissues
4
–
6
.
Association studies in diverse populations identify additional loci and elucidate disease
genes, biology, and pathways.
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