Discovering the biology of neuropsychiatric syndromes in india

Syndromes of schizophrenia, bipolar disorder, obsessive-compulsive disorder, substance use disorders and Alzheimer's dementia are highly heritable. About 10-20% of subjects have another affected first degree relative (FDR), and thus represent a 'greater' genetic susceptibility. Understanding the biology of these syndromes needs a combination of many methods - multiplex family based approach, endophenotype assessments, clinical follow-ups, next generation sequencing and stem cell based models. We used a combination of these approaches in a transdiagnostic clinical cohort based in India. The identification of the index participants occured at well-established specialty clinics. The selected individuals had a strong family history (with at least another affected FDR) of mental illness. We also recruited healthy controls without family history of such illness. All recruited individuals underwent brief clinical assessments and a blood sample was drawn for isolation of DNA and peripheral blood mononuclear cells (PBMCs). The individuals were assessed on several additional assessments [detailed clinical assessments, endophenotype measures (neuroimaging- structural and functional, neuropsychology, psychophysics-electroencephalography, functional near infrared spectroscopy, eye movement tracking)], with repeated measurements planned every alternate year. PBMCs from a subset were used to generate induced pluripotent stem cell lines and also underwent whole exome sequencing. A total of 2300 participants have been part of the first phase of the study. There were psychiatric syndromes and symptoms transcending traditional diagnostic boundaries in a large proportion of these families. Exome sequencing identified many rare damaging variants in neurodevelopmental genes, and genes involved in other mendelian disorders related to the brain. There was evidence of selection in genes related to immune system in these exomes. Multiple neurobiological measures were abnormal in affected and unaffected members, some were psychosis specific (e.g., minor physical anomalies, smooth pursuit eye movements), and some were transdiagnostic (e.g., global cognition). Adverse childhood events were found to accelerate the onset of mental illness and interact with family genetics to lead to worse neurocognitive outcome. The IPSC derived neural stem cells showed abnormal migration, proliferation and mitochondrial bioenergetics, which were partly reversed with the in-vitro application of drugs which were clinically used in these patients. The repository of biomaterials as well as digital datasets of clinical parameters generated in this study will serve as a valuable resource for understanding the biology of psychiatric syndromes in India. Early results from the dense family cohort indicate that there are rare damaging variants which influence cellular behavior. The adverse childhood events interact with family genetics to influence cognitive and behavioural outcomes. Future research will focus on identifying the neuro-progression of endophenotype measures, and its relationship to genetic factors and clinical outcomes.