The goal of this study is to localize and characterize genes that influence normal maturation-related changes in neurocognitive, neuroanatomic and neurophysiological indices. A substantial number of brain-related traits exhibit gene by age interactions, suggesting a heritable basis for neurocognitive, neuroanatomic and neurophysiological changes with age and highlighting the potential role of genes in differential brain maturation. We will utilize novel analytical approaches to investigate genetic and environmental influences on variation in brain, cognition, and behavior from a developmental perspective, modeling complex effects in both the genetic and environmental realms, and potential interactions between them, while allowing for changes in these effects across development, in the Philadelphia Neurodevelopmental Cohort (PNC). The PNC includes ~9500 individuals between the ages of 8 - 21 years who have been characterized for brain, behavior, and genetic variables. All participants were assessed neuropsychiatrically and completed a Computerized Neurocognitive Battery (CNB). Interviews included assessment of demographics, life events and stressors, school performance, medical history, and screening for psychopathology and presence and duration of associated symptoms. The CNB included an estimate of IQ as well as 14 tests designed to assess five neurobehavioral functions. A subset of ~1450 participants underwent neuroimaging, including structural and functional MRI and diffusion tensor imaging. Approximately 8700 PNC participants have been genotyped for 500K - 950K genome-wide SNPs, obtained on a diverse variety of genotyping platforms. The large size of this data set, combined with the rich and detailed assessments in a variety of phenotypic domains, provides an unparalleled opportunity to study gene-by-age and gene-by-environment interactions in neurodevelopment and their potential contribution to risk of mental illness.
The specific aims of the proposed study are to: 1) Localize genes influencing variation in neurodevelopment in the PNC; 2) Assess whether these genetic effects change with age and identify additional loci exhibiting gene- by-age interactions; and 3) Assess complex environmental effects on neurodevelopment and test whether they interact with, and moderate or mediate, genetic effects. Laura Almasy, Texas Biomedical Research Institute, is contact PI of this application and co-PIs David Glahn, Yale University, and Raquel Gur, University of Pennsylvania, will lead subcontracts. Dr. Almasy provides expertise in genetic analysis of complex phenotypes, including gene-by-age and gene-by-environment interactions. Drs. Glahn and Gur provide expertise in cognitive neuropsychology, neuroimaging, and psychiatry.
The biological mechanisms responsible for age-related changes in neuroanatomy, neurophysiology and neurocognition during the process of maturation are largely unknown. We propose to study the Philadelphia Neurodevelopmental Cohort, a sample of youths age 8-21, to search for genetic factors that influence normal neurodevelopment and thus may contribute to risk of psychiatric illness when these normal maturational processes are disrupted.
