Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies
Susan Service1,
Joseph DeYoung2,
Maria Karayiorgou3,
J Louw Roos4,
Herman Pretorious4,
Gabriel Bedoya5,
Jorge Ospina6,
Andres Ruiz-Linares5,7,
António Macedo8,
Joana Almeida Palha9,
Peter Heutink10,11,
Yurii Aulchenko12,
Ben Oostra12,
Cornelia van Duijn12,
Marjo-Riitta Jarvelin13,14,
Teppo Varilo15,16,
Lynette Peddle17,
Proton Rahman18,
Giovanna Piras19,
Maria Monne19,
Sarah Murray20,
Luana Galver20,
Leena Peltonen15,16,
Chiara Sabatti21,22,
Andrew Collins23 &
Nelson Freimer1,24,25
Nature Genetics volume 38, pages 556–560 (2006)Cite this article
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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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.).
Center for Neurobehavioral Genetics, University of California, Los Angeles, 90095, California, USA
Susan Service & Nelson Freimer
Southern California Genotyping Consortium, University of California, Los Angeles, 90095, California, USA
Joseph DeYoung
Rockefeller University, New York, 10021, New York, USA
Maria Karayiorgou
Department of Psychiatry & Weskoppies Hospital, University of Pretoria, Pretoria, 0001, Republic of South Africa
J Louw Roos & Herman Pretorious
Laboratory of Molecular Genetics, University of Antioquia, Medellin, Colombia
Gabriel Bedoya & Andres Ruiz-Linares
Department of Psychiatry, University of Antioquia, Medellin, Colombia
Jorge Ospina
Department of Biology (Wolfson House), The Galton Laboratory, University College London, London, NW1 2HE, UK
Andres Ruiz-Linares
Institute of Medical Psychology, Faculty of Medicine, University of Coimbra, Coimbra, 3000-033, Portugal
António Macedo
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4704-553, Portugal
Joana Almeida Palha
Department of Human Genetics, Section of Medical Genomics, Vrije University and Vrije University Medical Center, Amsterdam, 1081 BT, The Netherlands
Peter Heutink
Center for Neurogenomics and Cognitive Research, Vrije University and Vrije University Medical Center, Amsterdam, 1081 BT, The Netherlands
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
Department of Public Health Science and General Practice, University of Oulu, Oulu, 90220, Finland
Marjo-Riitta Jarvelin
Department of Epidemiology and Public Health, Imperial College London, London, W2 1PG, UK
Department of Medical Genetics, University of Helsinki, Helsinki, Finland, 00290
Teppo Varilo & Leena Peltonen
Department of Molecular Medicine, National Public Health Institute, Biomedicum Helsinki, Helsinki, 00290, Finland
Newfound Genomics, 187 Lemarchant Road, St. John's, A1C 2H5, Newfoundland, Canada
Lynette Peddle
Memorial University of Newfoundland, St. John's, A1C 5S7, Newfoundland, Canada
Proton Rahman
Division of Haematology, 'San Francesco' Hospital, Nuoro, ASL3, Italy
Giovanna Piras & Maria Monne
Illumina, Inc., 9885 Towne Centre Dr., San Diego, 92121, California, USA
Sarah Murray & Luana Galver
Department of Human Genetics, University of California, Los Angeles, 90095, California, USA
Chiara Sabatti
Department of Statistics, University of California, Los Angeles, 90095, California, USA
Human Genetics Research Division, University of Southampton, Southampton General Hospital, Tremona Road, SO16 6YA, Southampton, UK
The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, 90095, California, USA
Nelson Freimer
Department of Psychiatry, University of California, Los Angeles, 90095, California, USA
Susan Service
J Louw Roos
Herman Pretorious
Gabriel Bedoya
Yurii Aulchenko
Ben Oostra
Cornelia van Duijn
Teppo Varilo
Giovanna Piras
Maria Monne
Sarah Murray
Luana Galver
Leena Peltonen
Correspondence to Nelson Freimer.
S.M. and L.G. are employed by Illumina, Inc.
Supplementary Table 1
Demographic history of population isolates. (PDF 20 kb)
Supplementary Methods (PDF 20 kb)
Supplementary Note (PDF 77 kb)
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
Issue Date: 01 May 2006
DOI: https://doi.org/10.1038/ng1770
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