Abstract

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the “Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders” consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.

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Acknowledgements

This research was supported by National Institute of Mental Health grants U01 MH105630 (DCG), U01 MH105634 (REG), U01 MH105632 (JB), R01 MH078143 (DCG), R01 MH083824 (DCG & JB), R01 MH078111 (JB), R01 MH061622 (LA), R01 MH042191 (REG), and R01 MH063480 (VLN). We thank Dr. Steve Hyman for his continued support for psychiatric genetics.

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Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    • David C. Glahn
    • , Emma E. M. Knowles
    •  & Samuel R. Mathias
  2. Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT, USA

    • David C. Glahn
  3. Departments of Psychiatry and Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    • Vishwajit L. Nimgaonkar
  4. Centro de Investigación Biología Celular y Molecular, Universidad de Costa Rica, San José, CR, USA

    • Henriette Raventós
    •  & Javier Contreras
  5. Escuela de Biología, Universidad de Costa Rica, San José, CR, USA

    • Henriette Raventós
  6. Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK

    • Andrew M. McIntosh
  7. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK

    • Andrew M. McIntosh
    •  & Pippa A. Thomson
  8. Centre for Genomic and Experimental Medicine, MRC Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    • Pippa A. Thomson
  9. Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Crawley, WA, Australia

    • Assen Jablensky
    •  & Nina S. McCarthy
  10. Centre for the Genetic Origins of Health and Disease, School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia

    • Nina S. McCarthy
  11. Cooperative Research Centre for Mental Health, Carlton, VIC, Australia

    • Nina S. McCarthy
  12. Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia

    • Jac C. Charlesworth
  13. South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas of the Rio Grande Valley, Brownsville, TX, USA

    • Nicholas B. Blackburn
    • , Juan Manuel Peralta
    • , Joanne E. Curran
    •  & John Blangero
  14. Department of Psychiatry, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA

    • Seth A. Ament
  15. Human Genetics Branch and Genetic Basis of Mood and Anxiety Disorders Section, National Institute of Mental Health, Intramural Research Program, Bethesda, MD, USA

    • Francis J. McMahon
  16. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Ruben C. Gur
    • , Laura Almasy
    •  & Raquel E. Gur
  17. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Maja Bucan
    •  & Laura Almasy
  18. Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    • Laura Almasy

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The authors declare that they have no conflict of interest.

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Correspondence to David C. Glahn.

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DOI

https://doi.org/10.1038/s41380-018-0073-x