Home LiteratureArticle Details
PMID: 11484155 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q.

American journal of human genetics ·Vol. 69 ·No. 3 ·2001-09-00 ·Pages 553-69

Wiltshire S, Hattersley AT, Hitman GA, Walker M, Levy JC, Sampson M, O'Rahilly S, Frayling TM, Bell JI, Lathrop GM, Bennett A, Dhillon R, Fletcher C, Groves CJ, Jones E, Prestwich P, Simecek N, Rao PV, Wishart M, Bottazzo GF, Foxon R, Howell S, Smedley D, Cardon LR, Menzel S, McCarthy MI

Abstract

Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.

MeSH Terms
Chromosome Mapping Chromosomes, Human, Pair 1 Diabetes Mellitus, Type 2/genetics Female Genetic Predisposition to Disease Genetic Testing Genotype Humans Male Molecular Sequence Data Pedigree United Kingdom/epidemiology Whites/genetics
Authors & Affiliations
26 authors, click to expand affiliations / ORCID
Wiltshire S
Imperial College Genetics and Genomics Research Institute & Division of Medicine, Imperial College, London, United Kingdom.
Hattersley A T
Hitman G A
Walker M
Levy J C
Sampson M
O'Rahilly S
Frayling T M
Bell J I
Lathrop G M
Bennett A
Dhillon R
Fletcher C
Groves C J
Jones E
Prestwich P
Simecek N
Rao P V
Wishart M
Bottazzo G F
Foxon R
Howell S
Smedley D
Cardon L R
Menzel S
McCarthy M I
References (62)
62 references, click to expand
  1. Mapping genes in diabetes. Genetic epidemiological perspective.
    Diabetes. 1990 Nov;39(11):1315-9 PMID: 2227105
  2. Linkage strategies for genetically complex traits. I. Multilocus models.
    Am J Hum Genet. 1990 Feb;46(2):222-8 PMID: 2301392
  3. Localization of the gene encoding insulin-degrading enzyme to human chromosome 10, bands q23----q25.
    Cytogenet Cell Genet. 1991;57(4):184-6 PMID: 1743072
  4. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease.
    Diabetes. 1993 Feb;42(2):359-62 PMID: 8425674
  5. Detection of GAD65 antibodies in diabetes and other autoimmune diseases using a simple radioligand assay.
    Diabetes. 1994 Mar;43(3):459-67 PMID: 8314020
  6. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA.
    N Engl J Med. 1994 Apr 7;330(14):962-8 PMID: 8121460
  7. A genome-wide search for human type 1 diabetes susceptibility genes.
    Nature. 1994 Sep 8;371(6493):130-6 PMID: 8072542
  8. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.
    Nat Genet. 1995 Nov;11(3):241-7 PMID: 7581446
  9. Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat.
    Nat Genet. 1996 Jan;12(1):31-7 PMID: 8528247
  10. Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat.
    Nat Genet. 1996 Jan;12(1):38-43 PMID: 8528248
  11. A comprehensive genetic map of the human genome based on 5,264 microsatellites.
    Nature. 1996 Mar 14;380(6570):152-4 PMID: 8600387
  12. Parametric and nonparametric linkage analysis: a unified multipoint approach.
    Am J Hum Genet. 1996 Jun;58(6):1347-63 PMID: 8651312
  13. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2.
    Nat Genet. 1996 Jun;13(2):161-6 PMID: 8640221
  14. Modulation of non-templated nucleotide addition by Taq DNA polymerase: primer modifications that facilitate genotyping.
    Biotechniques. 1996 Jun;20(6):1004-6, 1008-10 PMID: 8780871
  15. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families.
    Nat Genet. 1996 Sep;14(1):90-4 PMID: 8782826
  16. The future of genetic studies of complex human diseases.
    Science. 1996 Sep 13;273(5281):1516-7 PMID: 8801636
  17. New susceptibility locus for NIDDM is localized to human chromosome 20q.
    Diabetes. 1997 May;46(5):876-81 PMID: 9133558
  18. Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy.
    Diabetes. 1997 May;46(5):882-6 PMID: 9133559
  19. Relationship estimation in affected sib pair analysis of late-onset diseases.
    Eur J Hum Genet. 1997 Mar-Apr;5(2):69-77 PMID: 9195155
  20. Accurate inference of relationships in sib-pair linkage studies.
    Am J Hum Genet. 1997 Aug;61(2):423-9 PMID: 9311748
  21. Allele-sharing models: LOD scores and accurate linkage tests.
    Am J Hum Genet. 1997 Nov;61(5):1179-88 PMID: 9345087
  22. Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers.
    Diabetes. 1997 Nov;46(11):1701-10 PMID: 9356015
  23. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group.
    Lancet. 1997 Nov 1;350(9087):1288-93 PMID: 9357409
  24. PedCheck: a program for identification of genotype incompatibilities in linkage analysis.
    Am J Hum Genet. 1998 Jul;63(1):259-66 PMID: 9634505
  25. Sometimes it's hot, sometimes it's not.
    Nat Genet. 1998 Jul;19(3):213-4 PMID: 9662386
  26. An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians.
    Am J Hum Genet. 1998 Oct;63(4):1130-8 PMID: 9758619
  27. A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10.
    Nat Genet. 1998 Nov;20(3):304-8 PMID: 9806554
  28. Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians.
    Diabetologia. 1998 Dec;41(12):1511-5 PMID: 9867219
  29. Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans.
    Nat Genet. 1999 Feb;21(2):213-5 PMID: 9988276
  30. Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs.
    Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2198-203 PMID: 10051618
  31. Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans.
    Am J Hum Genet. 1999 Apr;64(4):1127-40 PMID: 10090898
  32. A radiation hybrid map of the rat genome containing 5,255 markers.
    Nat Genet. 1999 May;22(1):27-36 PMID: 10319858
  33. A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians.
    Diabetes. 1999 May;48(5):1175-82 PMID: 10331426
  34. Replication of linkage studies of complex traits: an examination of variation in location estimates.
    Am J Hum Genet. 1999 Sep;65(3):876-84 PMID: 10441592
  35. Meta-analysis of 23 type 2 diabetes linkage studies from the International Type 2 Diabetes Linkage Analysis Consortium.
    Hum Hered. 2008;66(1):35-49 PMID: 18223311
  36. Insulin-degrading enzyme: stable expression of the human complementary DNA, characterization of its protein product, and chromosomal mapping of the human and mouse genes.
    Mol Endocrinol. 1990 Aug;4(8):1125-35 PMID: 2293021
  37. Evidence of a novel type 2 diabetes locus 50 cM centromeric to NIDDM2 on chromosome 12q.
    Diabetes. 1999 Nov;48(11):2246-51 PMID: 10535461
  38. Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus.
    J Clin Invest. 1999 Nov;104(9):R41-8 PMID: 10545531
  39. Pathophysiological and genetic characterization of the major diabetes locus in GK rats.
    Diabetes. 1999 Dec;48(12):2463-70 PMID: 10580437
  40. Application of an ordered subset analysis approach to the genetics of alcoholism.
    Genet Epidemiol. 1999;17 Suppl 1:S385-90 PMID: 10597467
  41. Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles.
    Diabetes. 2000 Jan;49(1):126-30 PMID: 10615960
  42. Effects of stratification in the analysis of affected-sib-pair data: benefits and costs.
    Am J Hum Genet. 2000 Feb;66(2):567-75 PMID: 10677317
  43. No evidence for linkage at candidate type 2 diabetes susceptibility loci on chromosomes 12 and 20 in United Kingdom Caucasians.
    J Clin Endocrinol Metab. 2000 Feb;85(2):853-7 PMID: 10690901
  44. Detailed comparative gene map of rat chromosome 1 with mouse and human genomes and physical mapping of an evolutionary chromosomal breakpoint.
    Genomics. 2000 Feb 15;64(1):32-43 PMID: 10708516
  45. A multipoint method for detecting genotyping errors and mutations in sibling-pair linkage data.
    Am J Hum Genet. 2000 Apr;66(4):1287-97 PMID: 10739757
  46. Allegro, a new computer program for multipoint linkage analysis.
    Nat Genet. 2000 May;25(1):12-3 PMID: 10802644
  47. All LODs are not created equal.
    Am J Hum Genet. 2000 Aug;67(2):282-8 PMID: 10884360
  48. Identification and analysis of error types in high-throughput genotyping.
    Am J Hum Genet. 2000 Sep;67(3):727-36 PMID: 10924406
  49. Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats.
    Hum Mol Genet. 2000 Sep 1;9(14):2149-58 PMID: 10958757
  50. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.
    Nat Genet. 2000 Sep;26(1):76-80 PMID: 10973253
  51. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.
    Nat Genet. 2000 Oct;26(2):163-75 PMID: 11017071
  52. The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes.
    Am J Hum Genet. 2000 Nov;67(5):1174-85 PMID: 11032783
  53. The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. II. An autosomal genome scan for diabetes-related quantitative-trait loci.
    Am J Hum Genet. 2000 Nov;67(5):1186-200 PMID: 11032784
  54. Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24.
    Am J Hum Genet. 2000 Dec;67(6):1470-80 PMID: 11067779
  55. Genomewide search for type 2 diabetes susceptibility genes in four American populations.
    Am J Hum Genet. 2000 Jun;66(6):1871-81 PMID: 10793009
  56. Initial sequencing and analysis of the human genome.
    Nature. 2001 Feb 15;409(6822):860-921 PMID: 11237011
  57. A genome scan for type 2 diabetes susceptibility loci in a genetically isolated population.
    Diabetes. 2001 Mar;50(3):681-5 PMID: 11246891
  58. Association study designs for complex diseases.
    Nat Rev Genet. 2001 Feb;2(2):91-9 PMID: 11253062
  59. Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4.
    Am J Hum Genet. 2001 May;68(5):1197-206 PMID: 11309685
  60. The impact of genotyping error on family-based analysis of quantitative traits.
    Eur J Hum Genet. 2001 Feb;9(2):130-4 PMID: 11313746
  61. A simple method to detect linkage for rare recessive diseases: an application to juvenile diabetes.
    Clin Genet. 1979 Feb;15(2):126-36 PMID: 367641
  62. Banting lecture 1988. Role of insulin resistance in human disease.
    Diabetes. 1988 Dec;37(12):1595-607 PMID: 3056758
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/323249
Published
2001-09-00
Epub
2001-00-01
Pages
553-69
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1235485
Subset
IM
Grants
Wellcome Trust · United Kingdom
NEI NIH HHS · R01 EY012562 · United States
NEI NIH HHS · EY-12562 · United States
Databases
OMIM
125853, 146680, 150330, 180247, 238600, 605286
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1086/323249 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2