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Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies

Nature Genetics volume 38, pages 556–560 (2006)Cite this article

Abstract

The genome-wide distribution of linkage disequilibrium (LD) determines the strategy for selecting markers for association studies, but it varies between populations. We assayed LD in large samples (200 individuals) from each of 11 well-described population isolates and an outbred European-derived sample, using SNP markers spaced across chromosome 22. Most isolates show substantially higher levels of LD than the outbred sample and many fewer regions of very low LD (termed 'holes'). Young isolates known to have had relatively few founders show particularly extensive LD with very few holes; these populations offer substantial advantages for genome-wide association mapping.

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Figure 1: Result of non-metric multidimensional scaling applied to Nei's genetic distance between all pairs of populations.
Figure 2: Distribution of linkage disequilibrium on chromosome 22.
Figure 3: Quantitative comparison of the LD maps of the 12 populations and physical and genetic maps.
Figure 4: Distribution of LD holes (defined as a gap in the LD map of ≥2.5 LDU) by population.
Figure 5: Box plots of r2 values between markers surrounding LD holes and in non-hole regions.

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Acknowledgements

We thank all of the study participants; the Center of Medical Systems Biology (CMSB); D. Ruano (Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal); M.J. Soares, J. Valente and M.H. Azevedo (Instituto de Psicologia Médica, Faculdade de Medicina, Coimbra, Portugal); C. Pato and M.T. Pato (Center for Psychiatric and Molecular Genetics, and Department of Psychiatry, State University of New York, Syracuse, New York, and the Veterans Administration Medical Center, Washington, D.C.); A. Gabbas (Haematology Division and Bone Marrow Transplantation Unit, San Francesco Hospital, Nuoro, Italy); R. van Wyk, C. Botha and G. Valencia (Universidad de Antioquia) and P. Snijders for recruitment of subjects; M. Almonte and E. Slaten for genotyping assistance; R. Ophoff for comments on the manuscript and M. Levinson for assistance with graphics. We acknowledge funding from the Biotechnology and Biological Sciences Research Council (A.C.), the US National Institutes of Health (N.F., M.K., A.R.-L.), Newfound Genomics (P.R.), Colciencias (A.R.-L.), the Universidad de Antioquia (A.R.-L.), the National Alliance for Research in Schizophrenia and Depression (A.R.-L.), the Wellcome Trust (A.R.-L.), the Netherlands Organisation for Scientific Research (C. van D.), the Netherlands Diabetes Fund (C. van D.), the Netherlands Kidney Fund (C. van D.), the Netherlands Heart Foundation (C. van D.), the International Alzheimer Organisation (C. van D.), the Netherlands Brain Fund (C. van D.), the Center of Excellence of the Academy of Finland (L.P.), Nordic Center of Excellence in Disease Genetics (L.P.) and Biocentrum Helsinki, Finland (L.P.).

Author information

Authors and Affiliations

  1. Center for Neurobehavioral Genetics, University of California, Los Angeles, 90095, California, USA

    Susan Service & Nelson Freimer

  2. Southern California Genotyping Consortium, University of California, Los Angeles, 90095, California, USA

    Joseph DeYoung

  3. Rockefeller University, New York, 10021, New York, USA

    Maria Karayiorgou

  4. Department of Psychiatry & Weskoppies Hospital, University of Pretoria, Pretoria, 0001, Republic of South Africa

    J Louw Roos & Herman Pretorious

  5. Laboratory of Molecular Genetics, University of Antioquia, Medellin, Colombia

    Gabriel Bedoya & Andres Ruiz-Linares

  6. Department of Psychiatry, University of Antioquia, Medellin, Colombia

    Jorge Ospina

  7. Department of Biology (Wolfson House), The Galton Laboratory, University College London, London, NW1 2HE, UK

    Andres Ruiz-Linares

  8. Institute of Medical Psychology, Faculty of Medicine, University of Coimbra, Coimbra, 3000-033, Portugal

    António Macedo

  9. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4704-553, Portugal

    Joana Almeida Palha

  10. Department of Human Genetics, Section of Medical Genomics, Vrije University and Vrije University Medical Center, Amsterdam, 1081 BT, The Netherlands

    Peter Heutink

  11. Center for Neurogenomics and Cognitive Research, Vrije University and Vrije University Medical Center, Amsterdam, 1081 BT, The Netherlands

    Peter Heutink

  12. Departments of Epidemiology & Biostatistics and Clinical Genetics, Genetic Epidemiology Unit, Erasmus Medical Center, Rotterdam, 3000 DR, The Netherlands

    Yurii Aulchenko, Ben Oostra & Cornelia van Duijn

  13. Department of Public Health Science and General Practice, University of Oulu, Oulu, 90220, Finland

    Marjo-Riitta Jarvelin

  14. Department of Epidemiology and Public Health, Imperial College London, London, W2 1PG, UK

    Marjo-Riitta Jarvelin

  15. Department of Medical Genetics, University of Helsinki, Helsinki, Finland, 00290

    Teppo Varilo & Leena Peltonen

  16. Department of Molecular Medicine, National Public Health Institute, Biomedicum Helsinki, Helsinki, 00290, Finland

    Teppo Varilo & Leena Peltonen

  17. Newfound Genomics, 187 Lemarchant Road, St. John's, A1C 2H5, Newfoundland, Canada

    Lynette Peddle

  18. Memorial University of Newfoundland, St. John's, A1C 5S7, Newfoundland, Canada

    Proton Rahman

  19. Division of Haematology, 'San Francesco' Hospital, Nuoro, ASL3, Italy

    Giovanna Piras & Maria Monne

  20. Illumina, Inc., 9885 Towne Centre Dr., San Diego, 92121, California, USA

    Sarah Murray & Luana Galver

  21. Department of Human Genetics, University of California, Los Angeles, 90095, California, USA

    Chiara Sabatti

  22. Department of Statistics, University of California, Los Angeles, 90095, California, USA

    Chiara Sabatti

  23. Human Genetics Research Division, University of Southampton, Southampton General Hospital, Tremona Road, SO16 6YA, Southampton, UK

    Andrew Collins

  24. The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, 90095, California, USA

    Nelson Freimer

  25. Department of Psychiatry, University of California, Los Angeles, 90095, California, USA

    Nelson Freimer

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  1. Susan Service
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Corresponding author

Correspondence to Nelson Freimer.

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Competing interests

S.M. and L.G. are employed by Illumina, Inc.

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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 38, 556–560 (2006). https://doi.org/10.1038/ng1770

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