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.

Fig. 1

Demonstration of rare variant inheritance in a large extended pedigree. One hundred and forty-eight individuals from a single large pedigree sampled in our ongoing “Genetics of Brain Structure and Function” study are represented. Based on the principals of Mendelian inheritance, the pedigree could maximally provide 105 copies of a rare or even private mutation originating in a single founder (filled). The figure was created with CraneFoot [150]

Fig. 2

Biological effect size for rare variants as a function of minor allele copies (MAC). The blue dashed line shows the biological effect size that can be detected at 80% power for a fixed number of observed heterozygotes in the pedigree in Fig. 1. As the number of captured MACs increases, power to detect moderate biological effect sizes improves. The effect of augmenting this pedigree with an additional 20,000 unrelated controls is presented in the orange line. For the case of the rarest of variants, there is a relatively minor improvement in power with increased numbers of controls who are highly unlikely to harbor the rare variant