NIH Annual Intramural Research Report
Report Title
Genetic analysis of type II diabetes in Finnish population
2011 Fiscal Year
October 01, 2010 - September 30, 2011
Principal Investigator
Francis S Collins; MD, PhD

Research Organization
Genome Technology Branch, NHGRI
Diabetes, Gene Mapping (human), Biotechnology Research, Gene Mapping, Genetic Medicine, Genetics, Health Disparity, Human Genome Research, Kidney Disease, Obesity, Prevention
Goals and Objectives
Type 2 diabetes (T2D) is a major contributor to chronic disease and early death in the developed and developing world. Using cutting-edge technologies developed from the human genome project, we aim to identify the most important hereditary factors in T2D and related traits, and to assess their role in different populations, their functional basis, and their potential for applications to diagnosis, prevention and treatment of disease.
Type 2 diabetes (T2D) is one of the major causes of morbidity and mortality in the developed world. While environmental factors such as diet play a significant role, familial clustering indicates that there must be significant genetic susceptibility factors at work. For eighteen years we have been engaged in a large collaborative study entitled FUSION (Finland - United States Investigation of NIDDM), in which more than 30,000 individuals with diabetes (and suitable controls) from Finland are being studied, using careful phenotyping of diabetes and diabetes-associated quantitative traits, and genome-wide genetic linkage and association. Large numbers of additional samples are also now available from several collaborators around the world. We have developed and applied new high throughput genotyping approaches in the laboratory, which have allowed the collection of a massive amount of data from these Finnish diabetics and their families. Using the genome wide association study (GWAS) approach, we have now contributed to the identification of no less than 56 well-validated loci for T2D, and have identified additional loci harboring variants that have important effects on obesity, fasting glucose, LDL and HDL cholesterol, triglycerides, proinsulin levels, blood pressure, and adult height. We are now investigating the functional basis of disease risk that arises from several of these variants, including those in GCKR, IGF2BP2, and TCF7L2. This analysis includes high throughput sequencing of these loci to identify common and rare alleles that may be driving the association, analysis of the relationship between gene expression and risk haplotypes, cell culture and biochemical assays, and mouse models. We have also embarked upon large scale whole exome and whole genome sequencing of diabetics and controls, to look for rare variants of large effect that contribute to disease risk. This includes an effort to identify the cause of rare Mendelian forms of the disease such as neonatal diabetes, congential hyperinsulinemia, and unmapped loci for Maturity Onset Diabetes of the Young (MODY). A major effort has been devoted to defining the epigenome of the human pancreatic islet, by mapping a variety of chromatin marks across the entire genome. This has enabled identification of enhancers and insulators, some of which harbor variants that influence the risk of T2D. The newest component of the project involves the collection of skin, muscle, and adipose biopsies from individuals with normal glucose tolerance, impaired glucose tolerance, or early onset T2D. These will be analyzed for genotype and gene expression to identify correlates with disease. The skin biopsies are also being utilized to generate induced pluripotent stem cell lines (iPS), which in turn can be differentiated into tissues relevant to diabetes (including insulin producing cells), to study the relationships of disease risk alleles to cellular phenotype. With this kind of substantial progress, we are confident that the geneticist's nightmare (Jim Neel's description of the genetics of diabetes) may finally be coming to an end.
Publications Generated during the 2011 Reporting Period
See Project Bibliography

Ordered by author name.

1000 Genomes Project Consortium [Collins F, member] (2010) A map of human genome variation from population-scale sequencing. Nature 467:1061-73.
Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, Lindgren CM, Mägi R, Morris AP, Randall J, Johnson T, Elliott P, Rybin D, Thorleifsson G, Steinthorsdottir V, Henneman P, Grallert H, Dehghan A, Hottenga JJ, Franklin CS, Navarro P, et al. [283 more authors] (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42:105-16.
Ikram MK, Xueling S, Jensen RA, Cotch MF, Hewitt AW, Ikram MA, Wang JJ, Klein R, Klein BE, Breteler MM, Cheung N, Liew G, Mitchell P, Uitterlinden AG, Rivadeneira F, Hofman A, de Jong PT, van Duijn CM, Kao L, Cheng CY, Smith AV, Glazer NL, Lumley T, McKnight B, Psaty BM, et al. [33 more authors] (2010) Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. PLoS Genet 6:e1001184.
Jafar-Mohammadi B, Groves CJ, Gjesing AP, Herrera BM, Winckler W, Stringham HM, Morris AP, Lauritzen T, Doney AS, Morris AD, Weedon MN, Swift AJ, Kuusisto J, Laakso M, Altshuler D, Hattersley AT, Collins FS, Boehnke M, Hansen T, Pedersen O, Palmer CN, Frayling TM, DIAGRAM Consortium, Gloyn AL, McCarthy MI (2011) A role for coding functional variants in HNF4A in type 2 diabetes susceptibility. Diabetologia 54:111-9.
Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Willer CJ, Jackson AU, Vedantam S, Raychaudhuri S, Ferreira T, Wood AR, Weyant RJ, Segrè AV, Speliotes EK, Wheeler E, Soranzo N, Park JH, Yang J, Gudbjartsson D, Heard-Costa NL, Randall JC, Qi L, Vernon Smith A, Mägi R, et al. [268 more authors] (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467:832-8.
Mills RE, Walter K, Stewart C, Handsaker RE, Chen K, Alkan C, Abyzov A, Yoon SC, Ye K, Cheetham RK, Chinwalla A, Conrad DF, Fu Y, Grubert F, Hajirasouliha I, Hormozdiari F, Iakoucheva LM, Iqbal Z, Kang S, Kidd JM, Konkel MK, Korn J, Khurana E, Kural D, Lam HY, et al. [33 more authors] (2011) Mapping copy number variation by population-scale genome sequencing. Nature 470:59-65.
Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Allen HL, Lindgren CM, Luan J, Mägi R, Randall JC, Vedantam S, Winkler TW, Qi L, Workalemahu T, Heid IM, Steinthorsdottir V, Stringham HM, Weedon MN, Wheeler E, Wood AR, Ferreira T, Weyant RJ, Segrè AV, Estrada K, et al. [352 more authors] (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42:937-48.
Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, Gudnason V, Eiriksdottir G, Garcia ME, Launer LJ, Nalls MA, Clark JM, Mitchell BD, Shuldiner AR, Butler JL, Tomas M, Hoffmann U, Hwang SJ, Massaro JM, O'Donnell CJ, Sahani DV, Salomaa V, Schadt EE, Schwartz SM, Siscovick DS, et al. [13 more authors] (2011) Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 7:e1001324.
Stančáková A, Paananen J, Soininen P, Kangas AJ, Bonnycastle LL, Morken MA, Collins FS, Jackson AU, Boehnke ML, Kuusisto J, Ala-Korpela M, Laakso M (2011) Effects of 34 risk loci for type 2 diabetes or hyperglycemia on lipoprotein subclasses and their composition in 6,580 nondiabetic Finnish men. Diabetes 60:1608-16.
Stitzel ML, Sethupathy P, Pearson DS, Chines PS, Song L, Erdos MR, Welch R, Parker SC, Boyle AP, Scott LJ, NISC Comparative Sequencing Program, Margulies EH, Boehnke M, Furey TS, Crawford GE, Collins FS (2010) Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metab 12:443-55.
Strawbridge RJ, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, Petrie JR, Travers ME, Bouatia-Naji N, Dimas AS, Nica A, Wheeler E, Chen H, Voight BF, Taneera J, Kanoni S, Peden JF, Turrini F, Gustafsson S, Zabena C, Almgren P, Barker DJ, Barnes D, Dennison EM, Eriksson JG, et al. [83 more authors] (2011) Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes. Diabetes 60:2624-2634.
Sudmant PH, Kitzman JO, Antonacci F, Alkan C, Malig M, Tsalenko A, Sampas N, Bruhn L, Shendure J, 1000 Genomes Project [Collins F, member], Eichler EE (2010) Diversity of human copy number variation and multicopy genes. Science 330:641-6.
Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segrè AV, van Hoek M, Navarro P, et al. [135 more authors] (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42:579-89.
Wain LV, Verwoert GC, O'Reilly PF, Shi G, Johnson T, Johnson AD, Bochud M, Rice KM, Henneman P, Smith AV, Ehret GB, Amin N, Larson MG, Mooser V, Hadley D, Dörr M, Bis JC, Aspelund T, Esko T, Janssens AC, Zhao JH, Heath S, Laan M, Fu J, Pistis G, et al. [207 more authors] (2011) Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet 43:1005-11.