Research Projects

Clonal hematopoiesis (CH) arises when hematopoietic stem cells acquire somatic mutations that give a growth advantage, leading to the expansion of distinct blood cell clones. Though often asymptomatic, CH is a biomarker of aging and a risk factor for myeloid malignancies, cardiovascular disease, and all-cause mortality. Mutations in key driver genes such as DNMT3A, TET2, ASXL1, JAK2, and TP53 with variant allele fractions (VAF) ≥2% define clonal hematopoiesis of indeterminate potential (CHIP). Despite its growing relevance, CH remains poorly studied in non-European populations. While large studies like the UK Biobank have profiled CH in Europeans, its prevalence, mutation spectrum, and genetic predisposition remain uncharacterized in India's genetically diverse population. We hypothesize that CH in India follows unique patterns driven by population-specific germline variation, environmental exposures, and aging trajectories. This study aims to generate the first CHIP variant catalog using high-depth WGS data from ~9,000 healthy individuals in the GenomeIndia initiative. Discovery: We will implement a robust somatic variant detection pipeline using GATK Mutect2 to identify putative CH mutations. Variants will be filtered based on VAF, sequencing depth, strand bias, and germline exclusion using gnomAD, dbSNP, and curated list of CH driver genes. Functional and clinical annotation will be done using VEP and ANNOVAR. We will assess CH burden, mutation spectrum, and subpopulation-specific patterns by integrating genomic and phenotypic data. Regression and exploratory models will evaluate associations between CH status and traits such as age, sex, hematological and biochemical markers. GWAS using REGENIE or BOLT-LMM will identify germline variants associated with CH, accounting for relevant covariates. Gene-level burden tests and network-based analyses will help identify causal genes and biological pathways. Comparative analyses with global cohorts (e.g., UK Biobank, 1000 Genomes) will reveal population-specific insights into CH biology. Validation: We will validate CH-associated variants using ~3,000 individuals aged 45+ from aging cohorts at the Centre for Brain Research (SANSCOG and TLSA). These cohorts provide deep phenotyping with longitudinal clinical, cognitive, and neuroimaging data, allowing replication of findings and assessment of CH-related clinical consequences. We will evaluate associations between CH status and traits such as cardiovascular risk, cognitive performance, and brain imaging metrics, exploring both deleterious and potentially protective effects of CH in aging. This project will provide critical insights into the evolutionary, clinical, and epidemiological implications of CH in a non-European population. The CH variant list will be made publicly available to enable broader research use, support cross-population analyses, and guide precision medicine and preventive strategies tailored to India’s unique demographic landscape.