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


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.).

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Correspondence to Nelson Freimer.

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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).

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