5. BRIDGING THE POPULATION DIVERSITY GAPS IN PSYCHIATRY GENOMICS AND BIOLOGY: FINDINGS FROM A FAMILY BASED COHORT STUDY FROM INDIA

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. Methods 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. 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. 18680 families and recruited 1294 families (3479 individuals) with multiple affected members, and 570 population healthy controls. Deep endophenotype assessments have been performed in 919 families (2508 individuals) and 474 population healthy controls. Whole exome sequencing (N=400) and IPSC generation (N=129) have been performed for a subset of individuals. We identified general factor of cognition as a transdiagnostic endophenotype. A family history of schizophrenia, higher depression scores and poor socioeconomic status predicted general cognitive deficits in unaffected individuals. A family history of bipolar disorder predicted social cognition deficits, while impaired cognitive flexibility was associated with a family history of OCD. Structural brain imaging analysis showed alterations that encompass several cerebral, cerebellar and sub-cortical regions across all disorders. Strongest effects were seen in those with a diagnosis of AUD, SCZ and BD, while those in OCD were much fewer. Subtle alterations in temporal and cingulate cortices were associated with being unaffected but having familial risk across the disorders. Whole exome sequencing identified rare damaging variants in several genes related to neurodevelopment, and subsequent studies in IPSC derived neurons and glia identified abnormal bioenergetics. Discussion 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.