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Mol Psychiatry. 2018 Jun 28. doi: 10.1038/s41380-018-0073-x. [Epub ahead of print]

Rediscovering the value of families for psychiatric genetics research.

Author information

1
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. david.glahn@yale.edu.
2
Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT, USA. david.glahn@yale.edu.
3
Departments of Psychiatry and Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
4
Centro de Investigación Biología Celular y Molecular, Universidad de Costa Rica, San José, CR, USA.
5
Escuela de Biología, Universidad de Costa Rica, San José, CR, USA.
6
Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
7
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
8
Centre for Genomic and Experimental Medicine, MRC Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
9
Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Crawley, WA, Australia.
10
Centre for the Genetic Origins of Health and Disease, School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia.
11
Cooperative Research Centre for Mental Health, Carlton, VIC, Australia.
12
Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
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.
14
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
15
Department of Psychiatry, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
16
Human Genetics Branch and Genetic Basis of Mood and Anxiety Disorders Section, National Institute of Mental Health, Intramural Research Program, Bethesda, MD, USA.
17
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
18
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
19
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

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.

PMID:
29955165
DOI:
10.1038/s41380-018-0073-x

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