Once thought to spare the central nervous system, 17q12 copy number variants (CNVs) are now known to con- fer a very high risk for ASD, schizophrenia, and other related neuropsychiatric disorders. In addition to neuro- psychiatric risk, 17q12 CNVs exemplify the pleiotropy and variable expressivity that characterizes many rare genetic variants: Although the association of 17q12 CNVs with categorical psychiatric diagnosis has been estab- lished, we do not yet know its impact on dimensional neurobehavioral traits, how diverse medical comorbidi- ties correlate with the expression of psychiatric phenotypes, how background common genetic variation may affect the expression of associated medical and behavioral phenotypes, or how these change over time. There is a pressing need for a scalable strategy to study the impact of individual rare genetic variants to understand their contribution towards human phenotypes and their biological consequences. The overall aim of this K-23 proposal is to use 17q12 CNVs as an archetype to broaden our understanding of the risk for schizophrenia and autism conferred by rare genetic variants and the factors that modulate it. While other CNVs have also been associated with neuropsychiatric risk, 17q12 is strategically important as only two breakpoints are involved in this rearrangement, meaning that CNVs at this locus include the same unique genomic sequence, facilitating comparisons across individuals. In addition, single nucleotide variants (SNVs) in genes within the region have been associated with specific medical, but not psychiatric, phenotypes, offering an opportunity to understand how diverse genes within the region may contribute to increased risk. Finally, recurrent CNVs offer an oppor- tunity over SNVs to investigate gene dosage effects, an advantage we are already capitalizing on with animal and stem cell studies of 17q12 CNVs currently underway in the laboratory of the primary mentor of this pro- posal, Dr. Eric Morrow. The PI proposes to leverage his longstanding association as a scientific board member of the 17q12 foundation to develop an international collaborative, multidisciplinary group focused on under- standing of how the deletion and duplication confer risk for neurobehavioral phenotypes. To achieve our over- all aim and close the gap outlined above, we propose to longitudinally assess sixty individuals with 17q12 dele- tions and sixty individuals with 17q12 duplications. In his project, ?A genomic approach to autism and schizo- phrenia risk through 17q12 CNVs?, Dr. Moreno De Luca will achieve these research and career objectives through a period of protected time for research, seminars, coursework, scientific meetings, and the expert guid- ance and support of his mentor and collaborators. The PI proposes advanced training in developing novel di- mensional assessments based on RDoC, translational endophenotypes and the ethics of human genetic re- search.
Although rare genetic abnormalities can collectively explain up to 35% of cases of autism and strongly contrib- ute towards schizophrenia risk, the study of individual rare genetic variants is often hampered by their low fre- quency in the population and the absence of standardized remote assessments that can uncover and character- ize the pleiotropy that is often a hallmark of these rare genetic variants. This proposal will study individuals with copy number variants in 17q12 (deletions and duplications) as a model of a rare genetic variant that con- fers high neuropsychiatric risk using mobile based platforms for categorical and dimensional neuropsychiatric and somatic assessments, and to evaluate the contribution of common genetic variation towards the expression of somatic and psychiatric phenotypes, setting the grounds for a strategy that can be expanded to other rare genetic variants that confer high risk for neuropsychiatric disorders.
