Current understanding of complex disease genetics may include contributions of rare variants, epistasis, epigenetics and genotype–environment interactions; but more parsimoniously may just imply that complex traits truly are affected by hundreds of thousands of variants with small (or a mixture of a few genes with major effect) effects.
The use of cell cultures as appropriate surrogate markers for disease in general, and for neuropsychiatric disease in particular, has become prominent over the past decade. The use of directed genetic alteration to explore disease pathways has recently been suggested. Thus the use of peripheral cells and directed genetic variation have been used independently to further our understanding of neuropsychiatric disease. Our work will merge the two approaches, and thus provide the resolution and depth to model the genetic influences on disease.
Till date we in collaboration with NCBS colleagues are able to:
a. Establish site specific genome modification and isogenic hiPSC lines as a resource for understanding allele specific genetic load underlying disease mechanism.
b. Identify novel (rare) disease associated genetic variations. This finding is informative as it helps identify targets for the final validation step.
c. Identify and characterize peripheral signature of the disease with gene expression experiments after ligand treatment.
d. Generate of neural stem cells from hiPSC lines as a model system to understand disease mechanisms.