A plethora of genetic and environmental factors fundamentally define a complex disease. Concurrently, identification and precise measurement of such contributing factors are challenging because effect of a single factor might be masked or confounded by other factors. Nonetheless, the genetic dissection of complex diseases can immensely be aided by distinctions between, i) individual-level complexity and population-level complexity and ii) gene identification and gene effect characterization. Our research is focused on understanding genetic basis of complex traits that affect vision and neurodegeneration with greater attention to these distinctions through integration of relevant concepts and knowledge that include high throughput omics analyses amalgamated with appropriate in-silico and functional studies. We believe this approach would result in definitive genotype-phenotype correlation, eventually leading to a deterministic path of genomic medicine and therefore be beneficial to patients suffering from complex diseases of visual and neuronal origin.
1. Genome-wide association study of phenotypic extremes in primary angle closure glaucoma
Primary angle closure glaucoma (PACG) constitutes a major proportion of all glaucoma among patients with an estimated prevalence of 1-4 % in the Indian population over the age of 40 years. In this study we use a novel design consisting of “older anatomically suspect controls” and “young onset PACG cases” to improve power to detect genetic factors considerably. The rationale of this design is that, young onset cases are likely to be enriched in genetic susceptibility factors. Similarly, older anatomical suspect controls (PACS), who do not develop angle-closure are likely lacking genetic factors responsible for angle-closure.
2. Dissecting the Functional Genomic basis of Rare Eye Diseases in Children
Rare Eye Diseases (RED) in children occur due to a variety of reasons that are mediated through a complex cascade of activities. REDs are associated with diverse clinical and genetic heterogeneity with severe effect on tissues of the anterior segment of the eye and on retinal ganglion cells and optic nerve. We hypothesize that altered regulations of certain biochemical pathways are responsible for the pathogenesis in REDs and their varied clinical manifestations. We therefore use whole exome sequencing across the chosen RED phenotypes followed by bioinformatics analyses integrated with functional studies to delineate biological pathways of underlying pathogenesis in REDs.
3. Towards understanding genetic architecture underlying hereditary non-syndromic hearing loss (NSHL)
Deafness is one of the most common sensory disorders in humans affecting 1 in 1000 new-borns. Over half of these are due to genetic reasons. In geographic regions with increased rates of consanguinity, the incidence of congenital deafness is higher. Inability to hear affects speech and language development as well as cognitive and psychosocial development. It compromises social, emotional, educational and vocational aspects of life. Early detection of hearing loss is extremely important for early intervention, normal speech and language development and proper rehabilitation of the affected individuals. In this collaborative project, we propose to address genetic architecture underlying hereditary hearing loss in a systematic way.
4. Disease-Phenotype Deconvolution in Genetic Eye Diseases
Capturing organ-specific phenomes in genetic diseases is an uphill task for the eye as it comprises tissue types derived from all three germinal layers. We attempted to deconstruct genetic eye diseases (GEDs) into primary phenotypic features, to understand the complex genome-phenome relationship in GEDs. Our work imparts a structure in dissecting GEDs into unique phenotypes to study the relationship between genes and diseases involving the eye.
Disease-Phenotype Deconvolution in Genetic Eye Diseases Using Online Mendelian Inheritance in Man. Pandey P, ACHARYA M (2016) Investigative Ophthalmology & Visual ScienceMay 1; 57(6):2567-76.
A complex regulatory network of transcription factors critical for ocular development and disease. ACHARYA M*, Huang L, Fleisch VF, Allison WT, Walter MA (2011) Hum. Mol. Genet. Apr 15; 20(8):1610-24 *corresponding author
Human PRKC apoptosis WT1 regulator is a novel PITX2-interacting protein that regulates PITX2 transcriptional activity in ocular cells. ACHARYA M, Lingenfelter DJ, Huang L, Gage PJ, Walter MA (2009) J. Biol. Chem. Dec 11; 284(50): 34829-38
Molecular basis for involvement of CYP1B1 in MYOC upregulation and its potential implication in glaucoma pathogenesis. Mookherjee S, ACHARYA M, Banerjee D, Bhattacharjee A, Ray K (2012) PLOS ONE. 7(9): e45077 doi:10.1371/journal.pone.0045077
Analysis of mutations of the PITX2 transcription factor found in Axenfeld-Rieger Syndrome patients. Footz T, Idrees F, ACHARYA M, Kozlowski K, Walter MA (2009) Invest. Ophthalmol. Vis. Sci Jun; 50(6): 2599-606.