PROJECT SUMMARY
The International Consortium on Brain and Behavior Copy Number Variants (IBBC-CNVs) is a collaborative
effort of 9 institutions with complementary experience and expertise in phenomics and genomics. The 22q11.2
and 16p11.2 loci are associated with significant risk for neuropsychiatric disorders across the lifespan. The
clinical presentations are heterogeneous, manifesting in a range of developmental neuropsychiatric disorders,
including Attention Deficit Hyperactivity, Anxiety, Autism Spectrum, and Psychosis Spectrum Disorders. Taking
a ‘genetics first’ approach of ascertaining patients based on known, homogeneous genetic etiologies will allow
us to overcome barriers posed by the genetic and phenotypic complexity of idiopathic developmental
neuropsychiatric disorders. We postulate that CNVs exert a large main effect on psychopathology, but the
nature and degree of psychopathology observed in CNV carriers is 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 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 a
cross-CNV effort will identify convergent risk mechanisms for developmental neuropsychiatric disorders that
are of relevance to the broader population.
We propose to dissect dimensional measures of psychosis, social-emotional processing and neurocognition,
and their genetic and environmental modifiers, to elucidate the architecture of risk for neuropsychiatric
disorders in CNV carriers. Prospective evaluation with dimensional measures relevant to neuropsychiatric
disorders will be applied to a cohort of 2000 individuals with 22q11.2 and 16p11.2 deletions and duplications
(500 per group) and their relatives as feasible. In addition, categorical psychiatric diagnoses will be assessed
in CNV carriers. Recruitment for prospective phenotyping will leverage existing large cohorts that carry these
reciprocal CNVs, many of whom have already been ascertained and characterized with a range of phenotypic
measures. New whole genome sequencing (WGS) will be performed in CNV carriers that have not yet been
sequenced. We will also utilize existing genetic data from the largest available case-control samples
diagnosed with SZ, ASD, and ADHD in the PGC to generate polygenic risk scores. Finally, we will examine
family and environmental factors that contribute to the heterogeneity of presentation and developmental course
in CNV carriers. This project will establish common phenomic and genomic resources. Our ability to conceive
such a large-scale study capitalizes on our existing successful collaborations, complementary expertise, and
institutional commitments to achieve these goals.