The Molecular Genetics laboratory of the Dept of Psychiatry has been active in training post-graduates in genetics methods, conducting research, as well as providing diagnostic testing for certain neurodegenerative disorders. More than 20 MD Theses (genetics of addiction, OCD, dementia, schizophrenia, bipolar disorder, intra-cranial aneurysms, Parkinson’s disease, Huntington’s disease, DMD) have been carried out. Doctoral work (Psychiatry, Psychology, Clinical Neuroscience) has focussed on the genetics of psychoses and dementia, and correlations with both clinical, and other empirical measurements (MRI and neuro-psychological).The DNA repository now includes several thousand samples from patients with various neuropsychiatric syndromes.
Over the past five years, various aspects of genetic correlates in psychiatric and neurological disease have been investigated. Variations in dopamine receptor and metabolizing pathways perhaps mediate the action of anti-psychotics; and we identified variation in these and their relation to drug response. We also compared the distribution of these alleles with diverse populations, and this could help account for some proportion of the differences in drug response across populations. A modest association of both schizophrenia and bipolar disorder, with variations at the DISC1 locus was reported. The effect of genetic variation of clusters of symptoms in obsessive-compulsive disorder, alcohol dependence and complications; and outcomes in schizophrenia was also evaluated. We have continued to identify enriched families for more detailed analyses, and these include a 100-member family with more than 35 individuals affected with bipolar disorder, and many other families with more than 4 affected first-degree relatives. Several linkage regions of interest have been identified, and these are being evaluated in more detail using a combination of genetic tools.
A major focus on neurodegenerative disorders has also emerged. We confirmed the association of the ApoE4 allele on risk of dementia in the elderly, and also its effects on depression in the elderly; and possible interaction with co-morbid diabetes. We also evaluated the effect of ApoE4 variation, and other alleles, on brain morphology and activity (MRI-based), and cognitive functioning. We were able to confirm the mutations causing ataxia syndromes, and HD, in more than 200 subjects. The correlations of this mutation, with various clinical parameters (EEG, autonomic function, MRI) were reported; as also the patterns of prevalence. These distributions suggest multiple founders for these syndromes, and suggest need for more in-depth studies to describe the genetic correlates in more detail.
Epigenetic studies are in progress to study the effect of alcohol addiction, stress and psychiatric illness on DNA methylation. We showed that early life stress influences the HPA axis and causes higher DNA methylation of the serotonin transporter gene in high risk children of alcoholic parents. The lab is also the biorepository for the cVEDA study which aims to study the influence of environment and early life stress on externalising disorders and addictions.
As part of CoE grant (with the NCBS/TIFR), we have developed lymphocyte cultures from individuals with dementia, who have affected first degree relatives, as also those who carry the ApoE4 allele, and those without the risk alleles. These cultures are being further evaluated using both site-directed changes (using CRISPR), and also conversion to induced pluripotent cells and neuronal lineage cells. These approaches will be very useful in understanding the mechanisms by which risk alleles modify cell biology to produce the disease phenotype. A large multi centric study has been initiated to study family based neuropsychiatric illness at the genetic and cellular level.
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