Home LiteratureArticle Details
PMID: 9326338 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Association mapping of disease loci, by use of a pooled DNA genomic screen.

American journal of human genetics ·Vol. 61 ·No. 3 ·1997-09-00 ·Pages 734-47

Barcellos LF, Klitz W, Field LL, Tobias R, Bowcock AM, Wilson R, Nelson MP, Nagatomi J, Thomson G

Abstract

Genomic screening to map disease loci by association requires automation, pooling of DNA samples, and 3,000-6,000 highly polymorphic, evenly spaced microsatellite markers. Case-control samples can be used in an initial screen, followed by family-based data to confirm marker associations. Association mapping is relevant to genetic studies of complex diseases in which linkage analysis may be less effective and to cases in which multigenerational data are difficult to obtain, including rare or late-onset conditions and infectious diseases. The method can also be used effectively to follow up and confirm regions identified in linkage studies or to investigate candidate disease loci. Study designs can incorporate disease heterogeneity and interaction effects by appropriate subdivision of samples before screening. Here we report use of pooled DNA amplifications-the accurate determination of marker-disease associations for both case-control and nuclear family-based data-including application of correction methods for stutter artifact and preferential amplification. These issues, combined with a discussion of both statistical power and experimental design to define the necessary requirements for detecting of disease loci while virtually eliminating false positives, suggest the feasibility and efficiency of association mapping using pooled DNA screening.

MeSH Terms
Case-Control Studies Child Chromosome Mapping/methods Computer Simulation DNA/blood Female Gene Frequency Genetic Testing/methods Hemochromatosis/genetics Humans Male Microsatellite Repeats
Chemicals
DNA
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Barcellos L F
Department of Integrative Biology, University of California, Berkeley 94720, USA.
Klitz W
Field L L
Tobias R
Bowcock A M
Wilson R
Nelson M P
Nagatomi J
Thomson G
References (63)
63 references, click to expand
  1. A genome-wide search for human type 1 diabetes susceptibility genes.
    Nature. 1994 Sep 8;371(6493):130-6 PMID: 8072542
  2. General score tests for associations of genetic markers with disease using cases and their parents.
    Genet Epidemiol. 1996;13(5):423-49 PMID: 8905391
  3. Genetic dissection of complex traits.
    Science. 1994 Sep 30;265(5181):2037-48 PMID: 8091226
  4. A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC).
    Science. 1994 Sep 30;265(5181):2049-54 PMID: 8091227
  5. The 1993-94 Généthon human genetic linkage map.
    Nat Genet. 1994 Jun;7(2 Spec No):246-339 PMID: 7545953
  6. Chromosome-specific microsatellite sets for fluorescence-based, semi-automated genome mapping.
    Nat Genet. 1994 Jul;7(3):390-5 PMID: 7920657
  7. The HOXD8 locus (2q31) is linked to type I diabetes. Interaction with chromosome 6 and 11 disease susceptibility genes.
    Diabetes. 1995 Jan;44(1):132-6 PMID: 7813807
  8. Linkage disequilibrium as a gene-mapping tool.
    Am J Hum Genet. 1995 Jan;56(1):11-4 PMID: 7825565
  9. Refining the position of Wilson disease by linkage disequilibrium with polymorphic microsatellites.
    Am J Hum Genet. 1994 Jan;54(1):79-87 PMID: 8279473
  10. Linkage disequilibrium between the juvenile neuronal ceroid lipofuscinosis gene and marker loci on chromosome 16p 12.1.
    Am J Hum Genet. 1994 Jan;54(1):88-94 PMID: 8279474
  11. Localization of predisposition to Hodgkin disease in the HLA class II region.
    Am J Hum Genet. 1994 Mar;54(3):497-505 PMID: 8116619
  12. Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region.
    Am J Hum Genet. 1994 May;54(5):884-98 PMID: 8178829
  13. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland.
    Nat Genet. 1992 Nov;2(3):204-11 PMID: 1345170
  14. Linkage disequilibrium patterns vary with chromosomal location: a case study from the von Willebrand factor region.
    Am J Hum Genet. 1994 Aug;55(2):348-55 PMID: 7913583
  15. A locus on chromosome 15q26 (IDDM3) produces susceptibility to insulin-dependent diabetes mellitus.
    Nat Genet. 1994 Oct;8(2):189-94 PMID: 7842018
  16. The role of the human genome project in disease prevention.
    Prev Med. 1994 Sep;23(5):591-4 PMID: 7845920
  17. A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci.
    Am J Hum Genet. 1995 Mar;56(3):777-87 PMID: 7887434
  18. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31-q33.
    Nat Genet. 1995 Jan;9(1):80-5 PMID: 7704030
  19. Use of a DNA pooling strategy to identify a human obesity syndrome locus on chromosome 15.
    Hum Mol Genet. 1995 Jan;4(1):9-13 PMID: 7711739
  20. Towards fully automated genotyping: use of an X linked recessive spastic paraplegia family to test alternative analysis methods.
    Hum Genet. 1995 May;95(5):483-90 PMID: 7759066
  21. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus.
    Nat Genet. 1995 Mar;9(3):284-92 PMID: 7773291
  22. Novel approaches to linkage mapping.
    Curr Opin Genet Dev. 1995 Jun;5(3):335-41 PMID: 7549428
  23. Toward fully automated genotyping: genotyping microsatellite markers by deconvolution.
    Am J Hum Genet. 1995 Nov;57(5):1199-210 PMID: 7485172
  24. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.
    Am J Hum Genet. 1995 Dec;57(6):1284-97 PMID: 8533757
  25. Discordant patterns of linkage disequilibrium of the peptide-transporter loci within the HLA class II region.
    Am J Hum Genet. 1995 Dec;57(6):1436-44 PMID: 8533774
  26. Polygenic disease: methods for mapping complex disease traits.
    Trends Genet. 1995 Dec;11(12):513-9 PMID: 8533170
  27. A collection of tri- and tetranucleotide repeat markers used to generate high quality, high resolution human genome-wide linkage maps.
    Hum Mol Genet. 1995 Oct;4(10):1837-44 PMID: 8595404
  28. New polymorphic microsatellite markers place the haemochromatosis gene telomeric to D6S105.
    Hum Mol Genet. 1995 Oct;4(10):1869-74 PMID: 8595409
  29. A map to the future.
    Nat Genet. 1996 Feb;12(2):117-8 PMID: 8563743
  30. Approach to genotyping errors caused by nontemplated nucleotide addition by Taq DNA polymerase.
    Genome Res. 1995 Oct;5(3):312-7 PMID: 8593617
  31. A comprehensive genetic map of the human genome based on 5,264 microsatellites.
    Nature. 1996 Mar 14;380(6570):152-4 PMID: 8600387
  32. Simplified hot start PCR.
    Nature. 1996 May 30;381(6581):445-6 PMID: 8632804
  33. Pendred syndrome maps to chromosome 7q21-34 and is caused by an intrinsic defect in thyroid iodine organification.
    Nat Genet. 1996 Apr;12(4):424-6 PMID: 8630498
  34. The effect of a selected locus on linked neutral loci.
    Genetics. 1977 Apr;85(4):753-88 PMID: 863244
  35. Nonuniform recombination within the human beta-globin gene cluster.
    Am J Hum Genet. 1984 Nov;36(6):1239-58 PMID: 6097112
  36. Insulin-gene sharing in sib pairs with insulin-dependent diabetes mellitus: no evidence for linkage.
    Am J Hum Genet. 1988 Jan;42(1):167-72 PMID: 2892397
  37. Statistical properties of the haplotype relative risk.
    Genet Epidemiol. 1989;6(1):127-30 PMID: 2731704
  38. HLA and insulin gene associations with IDDM.
    Genet Epidemiol. 1989;6(1):155-60 PMID: 2567257
  39. The Friedreich ataxia gene is assigned to chromosome 9q13-q21 by mapping of tightly linked markers and shows linkage disequilibrium with D9S15.
    Am J Hum Genet. 1990 Jan;46(1):133-7 PMID: 2294745
  40. Detection of linkage disequilibrium between the myotonic dystrophy locus and a new polymorphic DNA marker.
    Am J Hum Genet. 1991 Jul;49(1):68-75 PMID: 2063878
  41. MHC class-II molecules and autoimmunity.
    Annu Rev Immunol. 1991;9:493-525 PMID: 1910687
  42. Strong allelic association between the torsion dystonia gene (DYT1) andloci on chromosome 9q34 in Ashkenazi Jews.
    Am J Hum Genet. 1992 Mar;50(3):619-28 PMID: 1347197
  43. Molecular genetic approaches to the analysis and diagnosis of human inherited disease: an overview.
    Ann Med. 1992 Feb;24(1):29-42 PMID: 1575958
  44. Evidence for linkage disequilibrium between D16S94 and the adult onset polycystic kidney disease (PKD1) gene.
    J Med Genet. 1992 Apr;29(4):247-8 PMID: 1583644
  45. Significant linkage disequilibrium between the Huntington disease gene and the loci D4S10 and D4S95 in the Dutch population.
    Am J Hum Genet. 1992 Oct;51(4):730-5 PMID: 1415218
  46. A second-generation linkage map of the human genome.
    Nature. 1992 Oct 29;359(6398):794-801 PMID: 1436057
  47. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).
    Am J Hum Genet. 1993 Mar;52(3):506-16 PMID: 8447318
  48. The haplotype-relative-risk (HRR) method for analysis of association in nuclear families.
    Am J Hum Genet. 1993 Jun;52(6):1085-93 PMID: 8503442
  49. Localization of the hemochromatosis gene close to D6S105.
    Am J Hum Genet. 1993 Aug;53(2):347-52 PMID: 8328453
  50. Identification of repeat sequence heterogeneity at the polymorphic short tandem repeat locus HUMTH01[AATG]n and reassignment of alleles in population analysis by using a locus-specific allelic ladder.
    Am J Hum Genet. 1993 Oct;53(4):953-8 PMID: 8105685
  51. A review of the recent epidemiological data on the worldwide incidence of type 1 (insulin-dependent) diabetes mellitus. World Health Organization DIAMOND Project Group.
    Diabetologia. 1993 Oct;36(10):883-92 PMID: 8243865
  52. 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
  53. A cerebellar ataxia locus identified by DNA pooling to search for linkage disequilibrium in an isolated population from the Cayman Islands.
    Hum Mol Genet. 1996 Apr;5(4):525-31 PMID: 8845847
  54. Confirmation of three susceptibility genes to insulin-dependent diabetes mellitus: IDDM4, IDDM5 and IDDM8.
    Hum Mol Genet. 1996 May;5(5):693-8 PMID: 8733139
  55. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.
    Nat Genet. 1996 Aug;13(4):399-408 PMID: 8696333
  56. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22.
    Nat Genet. 1996 Aug;13(4):464-8 PMID: 8696343
  57. A full genome search in multiple sclerosis.
    Nat Genet. 1996 Aug;13(4):472-6 PMID: 8696345
  58. A putative vulnerability locus to multiple sclerosis maps to 5p14-p12 in a region syntenic to the murine locus Eae2.
    Nat Genet. 1996 Aug;13(4):477-80 PMID: 8696346
  59. An autosomal recessive nonsyndromic-hearing-loss locus identified by DNA pooling using two inbred Bedouin kindreds.
    Am J Hum Genet. 1996 Aug;59(2):385-91 PMID: 8755925
  60. An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees.
    Am J Med Genet. 1996 May 31;67(3):254-63 PMID: 8725744
  61. Detection of obesity QTLs on mouse chromosomes 1 and 7 by selective DNA pooling.
    Genomics. 1996 Jun 15;34(3):389-98 PMID: 8786140
  62. The future of genetic studies of complex human diseases.
    Science. 1996 Sep 13;273(5281):1516-7 PMID: 8801636
  63. Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q.
    Nature. 1994 Sep 8;371(6493):161-4 PMID: 8072544
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/515512
Published
1997-09-00
Pages
734-47
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1715937
Subset
IM
Grants
NIAMS NIH HHS · AR43177 · United States
NIGMS NIH HHS · GM35326 · United States
NIGMS NIH HHS · GM56688 · United States
External Links
PubMed source DOI: 10.1086/515512 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