The Center proposes four postulates for establishing the role of a genetic polymorphism in schizophrenia, modeled on Koch's classical postulates for infection: (1) identification of a polymorphism in a gene linked with illness, (2) demonstration of a functional effect of the polymorphism on gene function or expression, (3) relation of the polymorphism to deficits in brain function, and (4) reversal of the deficits in brain function by treatment directed at the cellular dysfunction. Most genes neurotransmitter receptors have substantial roles in the development of the brain. This project focuses on a specific portion of postulate 3, specifically the relationship of a genetic polymorphism to developmental deficits in brain function. Dr Leonard (Project 0001) has identified polymorphisms in the CHRNA7 promotor that decrease gene expression and are associated, in adults, with (a) an auditory inhibitory physiological measure (P50 sensory gating) and (b) an increased risk for schizophrenia. The gene which codes for CatechoI-O-MethyI-Transferase is a second gene associated with schizophrenia-related symptoms and neuropsychological deficits. It is critical to examine whether these associations between functional polymorphisms and physiological, neurocognitive, and symptomatic deficits can be extended to earlier periods of development, including infants, children, and young adolescents. This Project will assess, in infants, the relationship between CHRNA7 polymorphisms and inhibitory deficits utilizing EEG. (Specific Aim # 1). The relationship between genetic polymorphisms in CHRNA7 and COMT and neurocognitive deficits (Specific Aim #2) and symptomatic non-psychotic illness (e.g. ADHD;
Specific Aim #3) will be examined in children and adolescents. This Project will coordinate with developmental studies of molecular phenotyping (Project 0001), and drug development (Project 0004) to explore the role of functional genetic polymorphisms in Developmental Psychopathology. It is hoped that clarifying the developmental role of CHRNA7 will inform translational efforts in the primary prevention of schizophrenia.
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