MENTAL HEALTH MULTIMORBIDITY AND RECURRENT CNVS; FINDINGS FROM THE GENES 2 MENTAL HEALTH CONSORTIUM

Overall Abstract Rare pathogenic genetic variants, particularly recurrent deletions or duplications at chromosomal regions 16p11.2 and 22q11.2, have broad effects on neurodevelopment, cognition, and psychiatric outcomes. Although prior work has established elevated rates of neurodevelopmental and psychiatric diagnoses in carriers of these copy number variants (CNVs), less is known about how multiple psychiatric conditions cluster within individuals, how multimorbidity relates to cognitive function and impacts adaptive functioning, and how these outcomes are modified by the broader genomic background beyond the primary CNV. We present findings from 1,292 participants in the Genes to Mental Health (G2MH) study (729 with 22q11.2 deletions, 219 with 22q11.2 duplications, 222 with 16p11.2 deletions, and 122 with 16p11.2 duplications; median age 16.0 years, 52% females). We will first introduce the phenotype harmonization strategy, which enabled standardized collection and analysis of lifetime clinical and subclinical data across nine DSM-5–anchored psychopathology domains: psychotic disorders, bipolar disorder, depression, obsessive compulsive disorder, anxiety disorders, attention deficit hyperactivity disorder, oppositional defiant disorder, autism spectrum disorder, and intellectual disability. This framework reveals variant-specific profiles of psychopathology, quantifies patterns of multimorbidity across CNV groups, and provides a dimensional view of psychiatric burden for downstream analyses. We will then present neuropsychological findings from the Penn Computerized Neurobehavioral Battery, showing that multimorbidity is associated not only with diagnosis burden and daily functioning, but also with distinct cognitive profiles. These analyses motivate multimorbidity as a biologically meaningful outcome for genetic modeling. A central focus of the symposium is how gene dosage effects in recurrent CNVs are shaped by the broader genetic background. We will report analyses examining how the primary CNV, additional rare variant burden, and common variant burden jointly influence the number of affected psychopathology domains and cognitive traits. We will also discuss how integrating CNV dosage, rare and common variant background, neurocognitive measures, and early developmental milestones can improve prediction of psychiatric and functional outcomes in this population. Collectively, this symposium provides a comprehensive and genetically informed update on psychopathology, cognition, and multimorbidity in individuals with recurrent pathogenic CNVs. By combining deep phenotyping with analyses of gene dosage, rare variant burden, and polygenic background, these presentations provide new perspectives on patterns of multimorbidity, and move beyond single-variant models toward a more complete understanding of how genomic context shapes cognitive traits and psychiatric trajectories.