Look up the schizophrenia association of rare coding variants in the IBBC 22q11.2DS cohort:
22q11.2 deletion syndrome (22q11.2DS) is a severe developmental disorder, caused predominantly by a 3-Mb genomic deletion (in ~85% of cases). It is one of the most common chromosomal abnormalities (~1 in 4000 live births, ~1 in 1000 fetuses). Neuropsychiatric dysfunction is a prominent feature among its heterogeneous phenotypic presentations: About one in four individuals with 22q11.2DS develops schizophrenia (SCZ), usually in late adolescence or early adulthood. 22q11.2DS has been widely used as a model to study SCZ due to its highly increased disease risk and clinical features compatible with the more common, idiopathic form. Thus, identifying genetic risk factors for SCZ in addition to 22q11.2 deletion in those with 22q11.2DS has high clinical and scientific value. In addition to 22q11.2 deletion and common variants associated with SCZ, increasing evidence shows that many rare variants may act as the 'second hits' for SCZ in 22q11.2DS and thus contribute to its variable expressivity. Identifying rare coding variants separate from the common polygenic risk can complement risk prediction of 22q11.2DS-associated SCZ and pinpoint genes that play a role in its pathophysiology. Analyzing such modifier genes may reveal important biological processes in the development of syndromic SCZ and their connection to disease risk genes in the 22q11.2 deletion regions. To uncover genetic variation that contributes to the high prevalence of SCZ in 22q11.2DS, the International 22q11.2DS Brain and Behavior Consortium (IBBC) assembled and whole-genome sequenced (WGS) a cohort of 519 22q11.2DS patients with and without SCZ, providing an indispensable resource to identify modifier rare coding variants that change the disease risk of the 22q11.2 deletion in syndromic SCZ. Although the cohort is by far the largest to date, the conventional rare variant association tests failed to identify significant associations with SCZ for any gene or pathway after multiple test correction, likely due to insufficient statistical power from the moderate sample size. Therefore, it is imperative to use a different approach. We developed an integrated method – the integrated gene signal processing (IGSP) – that can substantially increase the power to identify risk genes implicated by rare coding variants in case-control sequencing studies using gene networks and mouse knockout phenotypes. Importantly, IGSP follows a 'discovery-driven' strategy to score risk genes without relying on prior disease-specific knowledge to avoid scoring bias. In this study, we describe an analytic framework that incorporates IGSP to uncover modifier rare coding variants associated with SCZ in 22q11.2DS and elucidate the functional connection between modifier genes and 22q11.2 deletion in brain development.
Rare coding variants as risk modifiers of the 22q11.2 deletion implicate postnatal cortical development in syndromic schizophrenia. Lin JR, Zhao Y, Jabalameli MR, Nguyen N, Mitra J, International 22q11.2DS Brain and Behavior Consortium, Swillen A, Vorstman JAS, Chow EWC, van den Bree M, Emanuel BS, Vermeesch JR, Owen MJ, Williams NM, Bassett AS, McDonald-McGinn DM, Gur RE, Bearden CE, Morrow BE, Lachman HM, Zhang ZD (2023) Mol Psychiatry. JOURNAL PUBMED REPRINT
