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The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l⁻¹, P = 2.5 × 10⁻³⁵) and serum insulin (β = 165 pmol l⁻¹, P = 1.5 × 10⁻²⁰) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers …