Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
Current Diabetes Reports
Erschienen in: Current Diabetes Reports 7/2016

01.07.2016 | Genetics (AP Morris, Section Editor)

Genetics of Type 2 Diabetes: the Power of Isolated Populations

verfasst von: Mette Korre Andersen, Casper-Emil Tingskov Pedersen, Ida Moltke, Torben Hansen, Anders Albrechtsen, Niels Grarup

Erschienen in: Current Diabetes Reports | Ausgabe 7/2016

Einloggen, um Zugang zu erhalten

Abstract

Type 2 diabetes (T2D) affects millions of people worldwide. Improving the understanding of the underlying mechanisms and ultimately improving the treatment strategies are, thus, of great interest. To achieve this, identification of genetic variation predisposing to T2D is important. A large number of variants have been identified in large outbred populations, mainly from Europe and Asia. However, to elucidate additional variation, isolated populations have a number of advantageous properties, including increased amounts of linkage disequilibrium, and increased probability for presence of high frequency disease-associated variants due to genetic drift. Collectively, this increases the statistical power to detect association signals in isolated populations compared to large outbred populations. In this review, we elaborate on why isolated populations are a powerful resource for the identification of complex disease variants and describe their contributions to the understanding of the genetics of T2D.
Literatur
1.
2.
Medici F, Hawa M, Ianari A, et al. Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis. Diabetologia. 1999;42:146–50.CrossRefPubMed
3.
Morris AP, Voight BF, Teslovich TM, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012;44:981–90.CrossRefPubMedPubMedCentral
4.•
Mahajan A, Go MJ, Zhang W, et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet. 2014;46:234–44. The first major meta-analysis of type 2 diabetes genetics across multiple ancestries.CrossRefPubMed
5.
Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26:76–80.CrossRefPubMed
6.
Nielsen E-MD, Hansen L, Carstensen B, et al. The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes. 2003;52:573–7.CrossRefPubMed
7.
Lim ET, Würtz P, Havulinna AS, et al. Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 2014;10:e1004494.CrossRefPubMedPubMedCentral
8.••
Lohmueller KE. The impact of population demography and selection on the genetic architecture of complex traits. PLoS Genet. 2014;10:e1004379. Carefully demonstrates the effect of recent population growth on the genetic architecture of complex traits.CrossRefPubMedPubMedCentral
9.
10.
Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet. 1999;22:139–44.CrossRefPubMed
11.
Zuk O, Schaffner SF, Samocha K, et al. Searching for missing heritability: designing rare variant association studies. Proc Natl Acad Sci. 2014;111:E455–64.CrossRefPubMedPubMedCentral
12.•
Moltke I, Fumagalli M, Korneliussen TS, et al. Uncovering the genetic history of the present-day Greenlandic population. Am J Hum Genet. 2015;96:54–69. Careful studies of the genetic history of the Greenlandic population.CrossRefPubMedPubMedCentral
13.
Service S, DeYoung J, Karayiorgou M, et al. Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies. Nat Genet. 2006;38:556–60.CrossRefPubMed
14.
Weiss KM, Terwilliger JD. How many diseases does it take to map a gene with SNPs? Nat Genet. 2000;26:151–7.CrossRefPubMed
15.
16.
17.
Newman DL, Abney M, McPeek MS, et al. The importance of genealogy in determining genetic associations with complex traits. Am J Hum Genet. 2001;69:1146–8.CrossRefPubMedPubMedCentral
18.
Norio R. Finnish disease heritage I: characteristics, causes, background. Hum Genet. 2003;112:441–56.PubMed
19.
Lohmueller KE. The distribution of deleterious genetic variation in human populations. Curr Opin Genet Dev. 2014;29:139–46.CrossRefPubMed
20.
Casals F, Hodgkinson A, Hussin J, et al. Whole-exome sequencing reveals a rapid change in the frequency of rare functional variants in a founding population of humans. PLoS Genet. 2013;9:e1003815.CrossRefPubMedPubMedCentral
21.
22.
23.
Lohmueller KE, Indap AR, Schmidt S, et al. Proportionally more deleterious genetic variation in European than in African populations. Nature. 2008;451:994–7.CrossRefPubMedPubMedCentral
24.
Simons YB, Turchin MC, Pritchard JK, et al. The deleterious mutation load is insensitive to recent population history. Nat Genet. 2014;46:220–4.CrossRefPubMedPubMedCentral
25.
Fu W, Gittelman RM, Bamshad MJ, et al. Characteristics of neutral and deleterious protein-coding variation among individuals and populations. Am J Hum Genet. 2014;95:421–36.CrossRefPubMedPubMedCentral
26.•
Henn BM, Botigué LR, Bustamante CD, et al. Estimating the mutation load in human genomes. Nat Rev Genet. 2015;16:333–43. Highlights how deleterious mutations can evolve as if they were neutral, and shows why this leads to a correlation between burden of mutations and distance to Africa.CrossRefPubMed
27.
Do R, Balick D, Li H, et al. No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans. Nat Genet. 2015;47:126–31.CrossRefPubMedPubMedCentral
28.
Henn BM, Botigué LR, Peischl S, et al. Distance from sub-Saharan Africa predicts mutational load in diverse human genomes. Proc Natl Acad Sci. 2016;113:E440–9.CrossRefPubMed
29.
Wright AF, Carothers AD, Pirastu M. Population choice in mapping genes for complex diseases. Nat Genet. 1999;23:397–404.CrossRefPubMed
30.
Jørgensen ME, Borch-Johnsen K, Stolk R, et al. Fat distribution and glucose intolerance among Greenland Inuit. Diabetes Care. 2013;36:2988–94.CrossRefPubMedPubMedCentral
31.
32.
33.
Hsueh WC, Mitchell BD, Aburomia R, et al. Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish family diabetes study. Diabetes Care. 2000;23:595–601.CrossRefPubMed
34.
35.
Scott LJ, Mohlke KL, Bonnycastle LL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316:1341–5.CrossRefPubMedPubMedCentral
36.
Diabetes Genetics Initiative of Broad Institute of Harvard and MIT and Novartis Institutes of BioMedical Research LU, Saxena R, Voight BF, Lyssenko V, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316:1331–6.CrossRef
37.
Grant SF, Thorleifsson G, Reynisdottir I, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38:320–3.CrossRefPubMed
38.••
Steinthorsdottir V, Thorleifsson G, Sulem P, et al. Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. Nat Genet. 2014;46:294–8. A well-designed study demonstrating the power of combining cutting-edge genotyping technology and extensive genealogical information to identify rare and low-frequency variants associated with type 2 diabetes.CrossRefPubMed
39.
Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet. 2007;39:770–5.CrossRefPubMed
40.••
Flannick J, Thorleifsson G, Beer NL, et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet. 2014;46:357–63. Major study identifying type 2 diabetes protective rare loss-of-function variants in beta cell expressed SLC30A8, and pinpoints this protein as a potential treatment target.CrossRefPubMedPubMedCentral
41.••
Moltke I, Grarup N, Jørgensen ME, et al. A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature. 2014;512:190–3. Elegant study identifying a type 2 diabetes risk variant in TBC1D4, and determining its functional role in relation to diabetes, and thereby demonstrating the power of the Greenlandic population in genetic association studies.CrossRefPubMed
42.
Hanson RL, Muller YL, Kobes S, et al. A genome-wide association study in American Indians implicates DNER as a susceptibility locus for type 2 diabetes. Diabetes. 2014;63:369–76.CrossRefPubMed
43.•
Baier LJ, Muller YL, Remedi MS, et al. ABCC8 R1420H loss-of-function variant in a Southwest American Indian community: association with increased birth weight and doubled risk of type 2 diabetes. Diabetes. 2015;64:4322–32. Example of successful identification of a type 2 diabetes associated variant by targeted sequencing in an isolated population.CrossRefPubMed
44.
Rampersaud E, Damcott CM, Fu M, et al. Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations. Diabetes. 2007;56:3053–62.CrossRefPubMed
45.
Wang SR, Agarwala V, Flannick J, et al. Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland. Am J Hum Genet. 2014;94:710–20.CrossRefPubMedPubMedCentral
46.
47.
Kittles RA, Bergen AW, Urbanek M, et al. Autosomal, mitochondrial, and Y chromosome DNA variation in Finland: evidence for a male-specific bottleneck. Am J Phys Anthropol. 1999;108:381–99.CrossRefPubMed
48.
Helgason A, Nicholson G, Stefánsson K, et al. A reassessment of genetic diversity in Icelanders: strong evidence from multiple loci for relative homogeneity caused by genetic drift. Ann Hum Genet. 2003;67:281–97.CrossRefPubMed
49.
Kushner JA, Ciemerych MA, Sicinska E, et al. Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Mol Cell Biol. 2005;25:3752–62.CrossRefPubMedPubMedCentral
50.
Huyghe JR, Jackson AU, Fogarty MP, et al. Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion. Nat Genet. 2013;45:197–201.CrossRefPubMed
51.
Yaghootkar H, Stancáková A, Freathy RM, et al. Association analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion. Diabetes. 2015;64:2279–85.CrossRefPubMed
52.
Thanabalasingham G, Owen KR. Diagnosis and management of maturity onset diabetes of the young (MODY). BMJ. 2011;343:d6044.CrossRefPubMed
53.
Edghill EL, Khamis A, Weedon MN, et al. Sequencing PDX1 (insulin promoter factor 1) in 1788 UK individuals found 5% had a low frequency coding variant, but these variants are not associated with type 2 diabetes. Diabet Med. 2011;28:681–4.CrossRefPubMedPubMedCentral
54.
Raghavan M, DeGiorgio M, Albrechtsen A, et al. The genetic prehistory of the New World Arctic. Science. 2014;345:1255832.CrossRefPubMed
55.
Jeppesen C, Jørgensen ME, Bjerregaard P. Assessment of consumption of marine food in Greenland by a food frequency questionnaire and biomarkers. Int J Circumpolar Health. 2012;71:18361.CrossRefPubMed
56.•
Fumagalli M, Moltke I, Grarup N, et al. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science. 2015;349:1343–7. This study demonstrates the existence of several genetic regions influenced by adaptation in the Greenlandic population.CrossRefPubMed
57.
Sano H, Kane S, Sano E, et al. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem. 2003;278:14599–602.CrossRefPubMed
58.
Williams RC, Long JC, Hanson RL, et al. Individual estimates of European genetic admixture associated with lower body-mass index, plasma glucose, and prevalence of type 2 diabetes in Pima Indians. Am J Hum Genet. 2000;66:527–38.CrossRefPubMed
59.
Rong R, Hanson RL, Ortiz D, et al. Association analysis of variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B with type 2 diabetes and related quantitative traits in Pima Indians. Diabetes. 2009;58:478–88.CrossRefPubMedPubMedCentral
60.
Haiman CA, Fesinmeyer MD, Spencer KL, et al. Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium. Diabetes. 2012;61:1642–7.CrossRefPubMedPubMedCentral
61.
Guo T, Hanson RL, Traurig M, et al. TCF7L2 is not a major susceptibility gene for type 2 diabetes in Pima Indians: analysis of 3,501 individuals. Diabetes. 2007;56:3082–8.CrossRefPubMed
62.
Hanson RL, Bogardus C, Duggan D, et al. A search for variants associated with young-onset type 2 diabetes in American Indians in a 100K genotyping array. Diabetes. 2007;56:3045–52.CrossRefPubMed
63.
Deng Z, Shen J, Ye J, et al. Association between single nucleotide polymorphisms of delta/notch-like epidermal growth factor (EGF)-related receptor (DNER) and Delta-like 1 Ligand (DLL 1) with the risk of type 2 diabetes mellitus in a Chinese Han population. Cell Biochem Biophys. 2015;71:331–5.CrossRefPubMed
64.
Bar Y, Efrat S. The NOTCH pathway in β-cell growth and differentiation. Vitam Horm. 2014;95:391–405.CrossRefPubMed
65.
Huang K, Nair AK, Muller YL, et al. Whole exome sequencing identifies variation in CYB5A and RNF10 associated with adiposity and type 2 diabetes. Obesity. 2014;22:984–8.CrossRefPubMed
66.
Flanagan SE, Patch A-M, Mackay DJG, et al. Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes. 2007;56:1930–7.CrossRefPubMed
67.
Gloyn AL, Weedon MN, Owen KR, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes. 2003;52:568–72.CrossRefPubMed
68.
Florez JC, Burtt N, de Bakker PI, et al. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes. 2004;53:1360–8.CrossRefPubMed
69.
Pearson ER. Dissecting the etiology of type 2 diabetes in the Pima Indian population. Diabetes. 2015;64:3993–5.CrossRefPubMed
70.
Proks P, Reimann F, Green N, et al. Sulfonylurea stimulation of insulin secretion. Diabetes. 2002;51 Suppl 3:S368–76.CrossRefPubMed
71.
Hegele RA, Cao H, Harris SB, et al. The hepatocyte nuclear factor-1 alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. JCEM. 1999;84:1077–82.PubMed
72.
Estrada K, Aukrust I, Bjørkhaug L, et al. Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population. JAMA. 2014;311:2305–14.CrossRefPubMed
73.
74.
Damcott CM, Pollin TI, Reinhart LJ, et al. Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance. Diabetes. 2006;55:2654–9.CrossRefPubMed
75.
Mounier C, Lavoie L, Dumas V, et al. Specific inhibition by hGRB10zeta of insulin-induced glycogen synthase activation: evidence for a novel signaling pathway. Mol Cell Endocrinol. 2001;173:15–27.CrossRefPubMed
76.
Deng Y, Bhattacharya S, Swamy OR, et al. Growth factor receptor-binding protein 10 (Grb10) as a partner of phosphatidylinositol 3-kinase in metabolic insulin action. J Biol Chem. 2003;278:39311–22.CrossRefPubMed
77.
Langlais P, Dong LQ, Ramos FJ, et al. Negative regulation of insulin-stimulated mitogen-activated protein kinase signaling by Grb10. Mol Endocrinol. 2004;18:350–8.CrossRefPubMed
78.
Metadaten
Titel
Genetics of Type 2 Diabetes: the Power of Isolated Populations
verfasst von
Mette Korre Andersen
Casper-Emil Tingskov Pedersen
Ida Moltke
Torben Hansen
Anders Albrechtsen
Niels Grarup
Publikationsdatum
01.07.2016
Verlag
Springer US
Erschienen in
Current Diabetes Reports / Ausgabe 7/2016
Print ISSN: 1534-4827
Elektronische ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-016-0757-z

Weitere Artikel der Ausgabe 7/2016

Current Diabetes Reports 7/2016 Zur Ausgabe

Pediatric Type 2 Diabetes (PS Zeitler, Section Editor)

Cardiac Abnormalities in Youth with Obesity and Type 2 Diabetes

Immunology and Transplantation (L Piemonti and V Sordi, Section Editors)

Gut Immunity and Type 1 Diabetes: a Mélange of Microbes, Diet, and Host Interactions?

Genetics (AP Morris, Section Editor)

Putting the Genome in Context: Gene-Environment Interactions in Type 2 Diabetes

Psychosocial Aspects (S Jaser and KK Hood, Section Editors)

Patterns of User Engagement with Mobile- and Web-Delivered Self-Care Interventions for Adults with T2DM: A Review of the Literature

Economics and Policy in Diabetes (ES Huang and AA Baig, Section Editors)

Will the Affordable Care Act (ACA) Improve Racial/Ethnic Disparity of Eye Examination Among US Working-Age Population with Diabetes?

Pediatric Type 2 Diabetes (PS Zeitler, Section Editor)

Insulin Resistance of Puberty

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

25.04.2024 | Hypotonie | Nachrichten

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 | Hypertonie | Nachrichten

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 | Parkinson-Krankheit | Nachrichten

Viel Bewegung in der Parkinsonforschung

25.04.2024 | Nierenkarzinom | Nachrichten

Adjuvante Immuntherapie verlängert Leben bei RCC
weitere anzeigen

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise