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Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae: evidence for linkage to chromosome 2q

Molecular Psychiatry volume 8, pages 695–705 (2003)Cite this article

Abstract

It is widely accepted that founder populations hold promise for mapping loci for complex traits. However, the outcome of these mapping efforts will most likely depend on the individual demographic characteristics and historical circumstances surrounding the founding of a given genetic isolate. The ‘ideal’ features of a founder population are currently unknown. The Micronesian islandic population of Kosrae, one of the four islands comprising the Federated States of Micronesia (FSM), was founded by a small number of settlers and went through a secondary genetic ‘bottleneck’ in the mid-19th century. The potential for reduced etiological (genetic and environmental) heterogeneity, as well as the opportunity to ascertain extended and statistically powerful pedigrees makes the Kosraen population attractive for mapping schizophrenia susceptibility genes. Our exhaustive case ascertainment from this islandic population identified 32 patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder. Three of these were siblings in one nuclear family, and 27 were from a single large and complex schizophrenia kindred that includes a total of 251 individuals. One of the most startling findings in our ascertained sample was the great difference in male and female disease rates. A genome-wide scan provided initial suggestive evidence for linkage to markers on chromosomes 1, 2, 3, 7, 13, 15, 19, and X. Follow-up multipoint analyses gave additional support for a region on 2q37 that includes a schizophrenia locus previously identified in another small genetic isolate, with a well-established recent genealogical history and a small number of founders, located on the eastern border of Finland. In addition to providing further support for a schizophrenia susceptibility locus at 2q37, our results highlight the analytic challenges associated with extremely large and complex pedigrees, as well as the limitations associated with genetic studies of complex traits in small islandic populations.

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Acknowledgements

We thank all the families that participated in the study and the Department of Health Services in Kosrae for making the study possible. We also thank Dr Athena Papadakos for diagnostic assessments, Joyce Sigrah for help with the assessments, Elizabeth Gillanders for help with the genotyping, and Steven Auerbach for his input during the initial phases of the project. We also gratefully acknowledge the support from Jeffrey Friedman, Marcus Stoffel and Jan Breslow. Finally, we thank Dr Nicola Chapman for assistance with the pedigree drawing in Figure 1. The study was supported by NIH MH61399 and a young investigator award from the National Alliance for Research on Shizophrenia and Depression (MK).

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Authors and Affiliations

  1. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA

    E M Wijsman

  2. Department of Biostatistics, University of Washington, Seattle, WA, USA

    E M Wijsman & E A Rosenthal

  3. Human Neurogenetics Laboratory, The Rockefeller University, New York, NY, USA

    D Hall, M L Blundell, C Sobin & M Karayiorgou

  4. Centre National de Génotypage, Evry, France

    S C Heath

  5. Kosrae Department of Health Services, Kosrae, Federated States of Micronesia

    R Williams

  6. Laboratory of Genetics, National Institute of Mental Health, Bethesda, MD, USA

    M J Brownstein

  7. Department of Physiology & Cellular Biophysics, Center for Neurobiology & Behavior, College of Physicians & Surgeons, Columbia University, New York, NY, USA

    J A Gogos

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  1. E M Wijsman
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  2. E A Rosenthal
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  3. D Hall
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Correspondence to M Karayiorgou.

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Electronic-database information

ABI, http://www2.perkin-elmer.com/ab/apply/dr/lmsv2/index.html (for the ABI markers)

Marshfield Medical Research Foundation, Center for Medical Genetics, http://research.marshfieldclinic.org/genetics (for the Marshfield maps)

Pangaea web site, http://www.stat.washington.edu/thompson/Genepi/pangaea.shtml (for the program Pedpack).

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Wijsman, E., Rosenthal, E., Hall, D. et al. Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae: evidence for linkage to chromosome 2q. Mol Psychiatry 8, 695–705 (2003). https://doi.org/10.1038/sj.mp.4001356

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