SZ is a complex
disorder with an incidence of ~1% in different populations in the world. Although
exact etiology is not established, genetic, epigenetic, chemical imbalance,
brain structural abnormalities and environmental factors are implicated. The
genetic susceptibility of SZ is six-times more than its general incidence. We
are investigating the association of copy number variants (CNVs) and SNPs with
SZ in Indian patients using Illumina PsychArrays and extensive bioinformatics
using machine learning and artificial intelligence to identify patterns with
higher predictive/diagnostic value.
Human Genetics
Genome-wide studies in patients and controls have suggested a number of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) among Caucasian studies. Till date, there is only one genome-wide study from India studying the SNPs and none on the CNVs. We developed i-MLPA, an improved method of CNV detection and showed that CNVs of 15q11.2 (BP1-BP2) region are not associated with schizophrenia among Indian patients. This CNV is a variant of uncertain significance and its association with an abnormality is not clear. We also conducted the largest CNV study involving this CNV in collaboration with Baylor College of Medicine and University of Pittsburgh Medical Center and showed that deletions are associated with dysmorphic features. Currently, we are studying CNVs of 15 regions that stand a higher probability of confirming in replication studies among Indian patients.
15q11.2 region
Infinium PsychArray Analysis of SNPs identified for neurological disorders
We have been screening 50,000 SNPs associated with neurological disorders, tag SNPs and exon SNPs in schizophrenia patients and controls using Infinium PsychArrays with an aim to replicate the disease-associated variants with schizophrenia patients in India. Initial data suggests that the variants reported in Caucasian patients are not likely to be confirmed in the Indian patients. In a pilot study, we have identified ~320 variants with a high promise of replication in a larger size sample. Data is being generated to confirm many novel variants that were identified in patients.
Stem cell Models
(A) DNMT1 overexpression, schizophrenia and other neurological disorders.
High discordance
rates between monozygotic twins indicate epigenetic mechanisms in SZ. Of the main
modifications of the epigenome, we currently focus on DNA methylation
aberrations and dysregulation of DNA methylation machinery, particularly DNA
methyltransferase 1 (DNMT1). Overexpression of DNMT1 is associated with SZ, bipolar
and epilepsy disorders but the molecular basis of DNMT1 overexpression and its
relationship with abnormal neurodevelopment is unknown. Since DNMT1
overexpression results in mid-gestational lethality, we have developed
genetically modified mouse embryonic stem cells that overexpress different
levels of DNMT1 (400% and 200%) and investigating their neurodevelopmental
abnormalities using genome-wide methylation and transcriptome analysis. The
obtained results are being explored further to delineate the mechanisms
underlying SZ and other neurodevelopmental disorders such as epilepsy, autism,
bipolar disorders and neurodegenerative disorders like multiple sclerosis,
Huntington’s, etc.
