Whole Genome Sequencing in Psychiatric Disorders: the WGSPD Consortium

Abstract

As technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome, through pilot WGS projects, will be critical to determine which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The WGSPD consortium will integrate data for 18,000 individuals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls.

Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia

“…Burden in annotations experimentally derived from human brain: Annotations from appropriate tissues help predict functional variants 7,28 . We compared case/control burden of noncoding URVs in constrained regions (as defined above CDTS <1% or GERP ≥ 4) within functional annotations experimentally derived from human brain tissue known to effect gene expression.…”

“…The analysis of noncoding variants from WGS data is challenging due to the sheer volume of the noncoding genome and limited methods to predict functional changes 28,30,46 . Recently the category-wise association study (CWAS) framework has been developed and applied to WGS studies of autism spectrum disorder using 7608 samples from 1902 families 28,30,46 . The CWAS approach applies multiple annotation methods to define tens of thousands of annotation categories each of which are tested for association and accounted for multiple testing.…”

Defining the Genetic, Genomic, Cellular, and Diagnostic Architectures of Psychiatric Disorders

“…As whole-exome and whole-genome sequencing (WES, WGS) have become mainstream, the Whole Genome Sequencing for Psychiatric Disorders consortium is adopting a similar approach as the PGC but for modern resequencing (Sanders et al, 2017). Investigators conducting WES for ASD have formed multiple consortia.…”

Lost in Translation: Traversing the Complex Path from Genomics to Therapeutics in Autism Spectrum Disorder

“…Over the past two decades, the genetics of autism spectrum disorder (ASD) have advanced spectacularly. From the early hard-won successes cloning genes for monogenic forms of intellectual and social disability (European Chromosome 16 Tuberous Sclerosis Consortium, 1993;van Slegtenhorst et al, 1997;Verkerk et al, 1991) to current large-scale studies utilizing wholegenome sequencing (Brandler et al, 2018;Sanders et al, 2017;Turner et al, 2017;Werling et al, 2018;Yuen et al, 2015), the field has evolved to a point where discovery in so-called idiopathic or ''non-syndromic'' forms of the syndrome (nsASD) is now highly reliable and reproducible, yielding dozens of well-established risk genes (De Rubeis et al, 2014;Dong et al, 2014;Iossifov et al, 2012Iossifov et al, , 2014Neale et al, 2012;O'Roak et al, 2011O'Roak et al, , 2012bSanders et al, 2012Sanders et al, , 2015. Importantly, in contrast to later-onset psychiatric disorders, such as schizophrenia, bipolar disorder, and major depression, where genomic studies aimed at identifying individual genes have mainly highlighted a highly polygenic risk architecture involving the simultaneous contribution of multiple alleles of very small effect (Bipolar Disorder and Schizophrenia Working Group, 2018;Lee et al, 2013;Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014;Wray et al, 2018), progress in nsASD has been notable for the discovery of rare, de novo, germline, coding, heterozygous mutations carrying large effects in the individual.…”