A low frequency AKT2 coding variant enriched in the Finnish population is associated with fasting insulin levels. A. K. Manning1,2,3, H. H. Highland4, X. Sim5, N. Grarup6, T. Tukiainen1,7,8, J. Gasser1, A. Mahajan9, M. A. Rivas9, A. E. Locke5, J. Tuomilehto10, 11, 12,13, 14, M. Laakso15, 16, S. Ripatti7,17,18, J. B. Meigs19, 20, D. Altshuler1,3,21,20,22,2,, M. Boehnke5, M. I. McCarthy9,23,24, A. L. Gloyn23, 24, C. M. Lindgren9, 1, T2D Genes, GoT2D 1) Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts, USA; 2) Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA; 3) Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA; 4) Human Genetics Center, The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center at Houston, Houston, Texas, USA; 5) Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA; 6) The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 7) Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; 8) Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA; 9) Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 10) Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia; 11) Instituto de Investigacion Sanitaria del Hospital Universario LaPaz (IdiPAZ), University; 12) Hospital LaPaz, Autonomous University of Madrid, Madrid, Spain; 13) Center for Vascular Prevention, Danube University Krems, Krems, Austria; 14) Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland; 15) Department of Medicine, University of Eastern Finland; 16) Kuopio University Hospital, Kuopio, Finland; 17) Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; 18) Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK; 19) General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA; 20) Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; 21) Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; 22) Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; 23) Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; 24) Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.

   Undertaking genetic studies in multiple ancestries can identify disease-related alleles that are common in one population but rare in others. Defects in fasting glucose (FG) and insulin (FI) regulation are hallmarks of type 2 diabetes (T2D). To increase our understanding of the role of low-frequency (minor allele frequency, MAF<5%) and rare (MAF<0.5%) coding variants in influencing these traits, we performed exome-array genotyping (N=33,392) and whole exome sequencing (N=5,108) in a multi-ethnic sample from five ancestries. We aimed to identify novel coding loci and to evaluate coding variants at known loci, thereby highlighting causal transcripts and facilitating characterization of molecular mechanisms that influence glycemic traits and T2D susceptibility. FG and log(FI) levels were adjusted for age, sex and BMI and an inverse normalized transformation was applied to cohort-specific residuals. Regression based association statistics from both the exome-array and the exome sequencing analyses were first meta-analyzed within ancestry and then across ancestries allowing for heterogeneity in genetic effects using MANTRA. Gene-based tests (SKAT and burden) were applied to multiple variant sets including: protein truncating variants (PTV); and PTV and missense variants predicted to be deleterious by 5 algorithms. In addition to replicating reported GWAS signals, we identified novel gene based associations in AKT2 (SKAT P=910-7) and NUDFAF1 (burden P=1.110-6) with FI; GIMAP8 (burden P=2.310-6) with FG; and a single variant association in AKT2 with FI (p.P50T, rs184042322, MAF from 1.2% in Finland, 0.1% in Sweden and <0.01% in other ancestries). The additive effect of p.P50T on the inverse normalized FI was 0.21 (0.14-0.29 95% CI), meta-analyzed over the GoT2D and T2D-GENES studies in which it is observed (P=3.710-7, N=19,259). We replicated this finding in 4 independent Finnish cohorts (replication P=5.410-4, N=5,833, combined P=8.610-9). Rare penetrant AKT2 mutations cause monogenic disorders of insulin signaling: kinetically inactivating mutations cause hyperinsulinemia and lipodystrophy while kinetically activating mutations lead to hypoglycemia. Our identification of a missense variant in AKT2 associated with FI levels extends the allelic spectrum for coding variants in AKT2 associated with glucose homeostasis and demonstrates the value of studying different populations where "enrichment" of rare alleles may occur.

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