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<jats:p>We aggregated genome-wide genotyping data from 32 European-descent GWAS (74,124 T2D cases, 824,006 controls) imputed to high-density reference panels of &gt;30,000 sequenced haplotypes. Analysis of ˜27M variants (˜21M with minor allele frequency [MAF]&lt;5%), identified 243 genome-wide significant loci (<jats:italic>p</jats:italic>&lt;5×10<jats:sup>−8</jats:sup>; MAF 0.02%-50%; odds ratio [OR] 1.04-8.05), 135 not previously-implicated in T2D-predisposition. Conditional analyses revealed 160 additional distinct association signals (<jats:italic>p</jats:italic>&lt;10<jats:sup>−5</jats:sup>) within the identified loci. The combined set of 403 T2D-risk signals includes 56 low-frequency (0.5%≤MAF&lt;5%) and 24 rare (MAF&lt;0.5%) index SNPs at 60 loci, including 14 with estimated allelic OR&gt;2. Forty-one of the signals displayed effect-size heterogeneity between BMI-unadjusted and adjusted analyses. Increased sample size and improved imputation led to substantially more precise localisation of causal variants than previously attained: at 51 signals, the lead variant after fine-mapping accounted for &gt;80% posterior probability of association (PPA) and at 18 of these, PPA exceeded 99%. Integration with islet regulatory annotations enriched for T2D association further reduced median credible set size (from 42 variants to 32) and extended the number of index variants with PPA&gt;80% to 73. Although most signals mapped to regulatory sequence, we identified 18 genes as human validated therapeutic targets through coding variants that are causal for disease. Genome wide chip heritability accounted for 18% of T2D-risk, and individuals in the 2.5% extremes of a polygenic risk score generated from the GWAS data differed &gt;9-fold in risk. Our observations highlight how increases in sample size and variant diversity deliver enhanced discovery and single-variant resolution of causal T2D-risk alleles, and the consequent impact on mechanistic insights and clinical translation.</jats:p>

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Journal article


Cold Spring Harbor Laboratory

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