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.

Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

“…136 Family study data are central to establishment of the origin of mutations, that is, inherited or de novo, from both sequencing and structural variation data, and play a vital role in establishing the inheritance of both phenotypes and genotypes across generations. 137 Evaluation of families will allow for the evaluation of both common and rare variants, as well allowing researchers to evaluate environmental risk factors in a way that is not possible in case-control studies. Specifically including sex differences in the study design and prospectively studying sex differences across development in families will be vitally important to examining potential genetic and environmental mechanisms for sex differences.…”

Impaired neural habituation to neutral faces in families genetically enriched for social anxiety disorder

“…However, the results presented here are in line with findings from a multigenerational family study in rhesus monkeys, revealing the significant heritability of metabolic activity predictive of anxious temperament in hippocampal regions, but not in the amygdala (Oler et al, ). Together, these findings suggest that the impaired habituation response in the amygdala, although associated with SA, does not meet the endophenotype criterion of heritability , illustrating the distinction between disease‐related neurobiological traits (biomarkers) and endophenotypes with the latter having a genetic link with the disorder (cf., Lenzenweger, ) and underscoring the value of studies using a family design (Glahn et al, ). Furthermore, these findings support the notion that both genes and environment play a role in the development of SAD (Bas‐Hoogendam, Roelofs, Westenberg, & van der Wee, ) and indicate that research on the interaction between these factors is important.…”

Un cuarto de siglo de investigación genética en los trastornos neuropsiquiátricos en Costa Rica

“…Existe actualmente, por lo tanto, una tendencia al regreso a estudios con familias en búsqueda de variantes raras. Un estudio nuestro vigente consiste en secuenciar el genoma completo en familias con al menos tres casos de trastornos mentales mayores (bipolar y esquizofrenia) y va en la línea de buscar CNVs y SNPs poco comunes e incluso privados (Glahn et al, 2018). Los tríos inicialmente reclutados hace 20 años van a ser útiles para la búsqueda de variantes de novo.…”