» Articles » PMID: 29955165

Rediscovering the Value of Families for Psychiatric Genetics Research

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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References
1.
Sullivan P, Agrawal A, Bulik C, Andreassen O, Borglum A, Breen G . Psychiatric Genomics: An Update and an Agenda. Am J Psychiatry. 2017; 175(1):15-27. PMC: 5756100. DOI: 10.1176/appi.ajp.2017.17030283. View

2.
Hirschhorn J, Daly M . Genome-wide association studies for common diseases and complex traits. Nat Rev Genet. 2005; 6(2):95-108. DOI: 10.1038/nrg1521. View

3.
Sugitani Y . [Studies on positive brain scintigrams associated with cerebrovascular accidents (author's transl)]. Nihon Naika Gakkai Zasshi. 1973; 62(8):898-906. View

4.
Flint J, Mott R . Finding the molecular basis of quantitative traits: successes and pitfalls. Nat Rev Genet. 2001; 2(6):437-45. DOI: 10.1038/35076585. View

5.
Pritchard J, Cox N . The allelic architecture of human disease genes: common disease-common variant...or not?. Hum Mol Genet. 2002; 11(20):2417-23. DOI: 10.1093/hmg/11.20.2417. View