Exome analysis in 65,653 European samples identifies novel low-frequency and common variants for type 2 diabetes. C. Fuchsberger1, A. Mahajan2, J. Flannick3, D. Pasko4, N. Grarup5, N. Robertson2, X. Sim1, N. Burtt3, A. Morris2 on behalf of the GoT2D Consortium 1) Ctr Statistical Genetics, Univ Michigan, Ann Arbor, MI, USA; 2) Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; 3) Broad Institute of MIT and Harvard, Cambridge, MA, USA; 4) University of Exeter, Exeter, UK; 5) University of Copenhagen, Copenhagen, Denmark.

   Genome-wide association studies have led to impressive advances in the identification of common genetic variants associated with type 2 diabetes (T2D). The next challenge is to explore the role of low-frequency (LF; 1-5% MAF) and rare (<1% MAF) coding variants in T2D. Custom genotyping arrays, such as the Illumina HumanExome Beadchip, provide a cost-effective alternative to sequencing and based on our comparison with ~5,000 European individuals with deep (>70x) sequenced exomes capture 83.7% of the genetic variation with MAF >0.5%. To discover novel T2D loci and examine whether LF and rare coding alleles could explain established common variant GWAS association signals, we studied 23,483 T2D cases and 42,080 controls of European ancestry from 7 studies. We tested single variants for association with T2D using a linear mixed model (EMMAX) that accounts also for sample structure. In a fixed-effects meta-analysis of up to 175,403 high-quality autosomal variants, we identified one LF non-synonymous variant approaching study-wide significance (P<2.8x10-7) in a gene not mapping to an established T2D locus: FAM63A (missense Y285N; odds ratio (OR) 1.37 95% CI [1.22-1.53]; P=3.4x10-7, 1.6% MAF). The T2D risk allele of this variant was associated with increased fasting plasma glucose in 33,553 non-diabetic individuals (P=0.009). Three common variants in previously unreported T2D loci achieved study-wide significance: PAM (missense D563G; OR 1.17 [1.10-1.25]; P=1.1x10-7; 5.6% MAF), GPSM1 (missense S391L; OR 1.09 [1.06-1.12]; P=2.6x10-8; 25% MAF), and BAG6 (intronic; OR 1.09 [1.05-1.13]; P=2.9x10-8; 36% MAF). ). The T2D risk alleles of two of these SNPs were also associated with reduced insulinogenic index. Gene-level tests (SKAT-o) of rare non-synonymous variants did not reveal any study-wide significant genes supported by multiple studies. These results highlight that LF variants with moderate effects are also contribute to T2D risk, but that LF coding variants of large effect (OR>1.5) are unlikely to be frequently associated with T2D.

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