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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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.
Conflict of interest
The authors declare that they have no conflict of interest.
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Glahn, D.C., Nimgaonkar, V.L., Raventós, H. et al. Rediscovering the value of families for psychiatric genetics research. Mol Psychiatry 24, 523–535 (2019). https://doi.org/10.1038/s41380-018-0073-x
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