Genomics of Developmental Trajectories in Twins

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DESCRIPTION (provided by applicant): A tremendous amount of research energy has been dedicated to demonstrating the importance of genetic influences on developmental psychopathologies in children. To date a convincing argument can be made that all of the developmental psychopathologies are influenced, at least in part, by genetic factors. Behavioral genetic approaches have yielded heritability estimates as high as 80% for some phenotypes (Attention Deficit Hyperactivity Disorder), with the majority of disorders influenced in roughly equal parts by genetic and environmental influences (e.g. Anxious/ Depression). The search for the specific genomic influences has included a wide variety of molecular approaches. Among these the most common approach has been to study the relations between putative candidate genes and the disorder of interest in 'association studies'. To date these studies have yielded modest replicable results leading to the perception that multiple approaches using large samples will be needed to better understand how genetic factors contribute to complex disorders like the child psychopathologies across development. Investigators have used linkage and more recently Genome Wide Association (GWAS) studies in order to search the entire genome for clues. Recent studies provide evidence that genes in CNV regions are more variably expressed than genes in non- CNV regions and further that CNVs have 'global influence' on the entire transcriptome (3). CNV studies in singletons have led to significant discoveries in developmental psychopathology with 5 studies reporting an increased number of de novo CNV's in the study of Autism simplex cases (4). CNV effects, whether de novo or pedigree based, contributing to risk for complex traits such as common developmental psychopathology like childhood ADHD, Obsessive Compulsive Disorder (OCD), Oppositional Defiant Disorder (ODD) have not yet been reported in the literature. This application proposes the first single nucleotide polymorphism (SNP)/copy number variation and (CNV) genome-wide association study of common childhood psychopathologies using an extended twin-sibling family study design. DNA has already been collected from a large sample (N=4,414) of children and siblings who have been followed from birth until age 22 and their parents. This study will allow us to identify new genetic influences on child psychiatric illness which in turn will lead to improved diagnostic and treatment approaches. PUBLIC HEALTH RELEVANCE: This application proposes the first single nucleotide polymorphism (SNP)/copy number variation and (CNV) genome-wide association study of common childhood psychopathologies using an extended twin-sibling family study design. DNA has already been collected from a large sample of children and siblings who have been followed from birth until age 22 and their parents. This study will allow us to identify new genetic influences on child psychiatric illness which in turn will lead to improved diagnostic and treatment approaches.