Participating sites, PIs & NIMH grant numbers:
University of California, Los Angeles, USA; Carrie E Bearden, [U01 MH119736-01]
University of Pennsylvania, Philadelphia, USA; Raquel E. Gur [U01 MH119738-01]
University of Montreal, Canada; Sebastien Jacquemont [U01 MH119739-01]
Children’s Hospital of Philadelphia, USA; Donna M. McDonald-McGinn, [U01 MH119737-01]
University of California, San Diego, USA; Jonathan Sebat, [U01 MH119746-01]
Katholieke Universiteit Leuven, Belgium; Ann Swillen, [U01 MH119759-01]
Maastricht University, the Netherlands; Therese AMJ van Amelsvoort [U01 MH119740-01]
Cardiff University, Wales, United Kingdom; Marianne van den Bree [U01 MH119758-01]
University of Toronto, Canada; Jacob AS Vorstman [U01 MH119741-01]
In this collaborative project nine institutions across the United States, Canada and Europe work together to elucidate the mechanisms that influence the expression of the frequent neuropsychiatric manifestations in individuals with copy number variants (CNVs) at 22q11.2 and 16p11.2.
The objectives are to collect dimensional measures of neuropsychiatric symptoms and examine convergence and specificity of these phenotypes across the four CNV subpopulations. In addition, we aim to increase our understanding of the observed variable expression of neuropsychiatric phenotypes in carriers of the same pathogenic CNV, with a specific focus on the influence of additional genetic factors (rare and common) as well as environmental factors. In collaboration with the NIMH, data and analytic algorithms will be made available in the public research domain.
Methods: a cohort of 2,000 individuals with CNVs (deletions or duplications) at either 22q11.2 or 16p11.2 (500 per group), and their relatives whenever possible, are recruited in the different participating sites of this project. Prospective phenotype data will be collected in this cohort, including dimensional measures of psychopathology and cognition. In all individuals whole genome sequencing (WGS) will be performed (except for some individuals with WGS data available from previous studies). The influence of common risk variants on the neuropsychiatric expression will be examined using polygenic risk scores derived from available large sized genome-wide association studies. In addition, information on family and environmental factors will be collected to study their influence on neuropsychiatric expression in this population.
While deletions and duplications at 16p11.2 and 22q11.2 exert a large main effect on the variable psychopathologic manifestations in individual carriers, the nature and degree of phenotypic expression is likely multifactorial, with contributions from additional rare and common genetic variants, as well as environmental factors. Therefore, dissecting the effects of major CNV hits as well as additional rare and common variants on dimensional measures of psychopathology, as proposed in this project, can elucidate the combined contribution of genetic mechanisms to psychiatric conditions and build models of risk prediction. Notably, the presentation and course of psychopathology in the CNVs resemble these features in idiopathic disorders. Therefore, beyond the specific genetic syndromes investigated, such across-CNV effort will identify convergent risk mechanisms for developmental neuropsychiatric disorders that are of relevance to the broader population.