631. Early findings from a family-based longitudinal cohort and biobank of major psychiatric illnesses in India

Abstract

Abstract Background Major psychiatric illnesses are highly heritable, yet the search for replicable genetic and neurobiological mechanisms has proven highly challenging. One of the major reasons for this non-replicability is the focus on discrete clinical disease constructs, as categorized in current classificatory systems. Studying large numbers of multiplex families with affected members having several psychiatric illnesses, and unaffected relatives, would provide the most statistically robust method for the identification of neurocognitive endophenotypes that cut across traditional diagnostic boundaries. Aims & Objectives The Centre for Brain and Mind (CBM) is such an attempt to develop a family-based longitudinal cohort and biobank of major psychiatric illnesses in India. Method CBM has longitudinal family cohorts of schizophrenia, bipolar disorder, obsessive-compulsive disorder, addiction and Alzheimer’s dementia, along with their unaffected first-degree relatives (FDR) and population healthy controls. All individuals undergo detailed clinical assessments, and a blood sample is drawn to isolate DNA and peripheral blood mononuclear cells. Genetic studies are conducted in parallel with deep endophenotype assessments (cognition, brain imaging, psychophysics and electroencephalogram) and induced pluripotent stem cell (IPSC) generation to develop a comprehensive understanding of the biology of these disorders. Results So far, we have screened ca. 5000 families and recruited 900 families (3500 individuals) with multiple affected members, and 500 population healthy controls. Deep endophenotype assessments have been performed in 700 families (2500 individuals) and 300 population healthy controls. Whole exome sequencing (N=500) and IPSC generation (N=120) have been performed for a subset of individuals. We identified general factor of cognition as a transdiagnostic endophenotype. Minor physical anomalies and gaze fixation abnormalities were found to be specific for psychotic disorders (schizophrenia and psychotic mood disorders). Adverse childhood events were found to worsen the cognitive deficits in FDRs. Whole exome sequencing identified rare damaging variants in several genes related to neurodevelopment, and subsequent studies in IPSC derived neural precursors and cortical organoids showed cell migration deficits. Specific cell signatures of lithium treatment response (mitochondrial bioenergetics) in bipolar disorder and clozapine response (actin cytoskeleton) in schizophrenia were identified. Discussion & Conclusions Overall, we find various interesting leads about the biology of major psychiatric illnesses using the CBM study sample in India. Correlating deep clinical assessments, genomic variations, and phenotypes at various levels (cell, tissue, organ and system) may help us understand the biological links related to disease mechanisms in psychiatry.