Abstract
Obesity, a risk factor for various human diseases originates through complex interactions between genes and prevailing environment that varies across populations. Indians exhibit a unique obesity phenotype likely attributed by specific gene pool and environmental factors. Here, we present genome-wide association study (GWAS) of 7,259 Indians to understand the genetic architecture of body mass index (BMI) in the population. Our study revealed novel association of variants in BAI3 (rs6913677) and SLC22A11 (rs2078267) at GWAS significance, and of ZNF45 (rs8100011) with near GWAS significance. As genetic loci may dictate the phenotype through modulation of epigenetic processes, we overlapped discovered genetic signatures with DNA methylation patterns of 236 Indian individuals, and analyzed expression of the candidate genes using publicly available data. The variants in BAI3 and SLC22A11 were found to dictate methylation patterns at unique CpGs harboring critical cis- regulatory elements. Further, BAI3, SLC22A11 and ZNF45 variants were found to overlie repressive chromatin, active enhancer, and active chromatin regions, in that order, in human subcutaneous adipose tissue in ENCODE database. Besides, the identified genomic regions represented potential binding sites for key transcription factors implicated in obesity and/or metabolic disorders. Interestingly, rs8100011 (ZNF45) acted as a robust cis-expression quantitative trait locus (cis-eQTL) in subcutaneous adipose tissue in GTEx portal, and ZNF45 gene expression showed an inverse correlation with BMI in skeletal muscle of Indian subjects. Further, gene-based GWAS analysis revealed CPS1 and UPP2 as additional leads regulating BMI in Indians. Our study decodes potential genomic mechanisms underlying obesity phenotype in Indians.
Footnotes
↵& Membership of INDICO consortium has been listed in acknowledgements section
Conflicts of interest There was no conflict of interest between authors
Financial support This work was supported by Council of Scientific and Industrial Research [CSIR], Government of India through Centre for Cardiovascular and Metabolic Disease Research [CARDIOMED] project [Grant No: BSC0122-(12)] & Department of Biotechnology (DBT), Government of India through BIOCHILD grant given to CSIR-Institute of Genomics and Integrative Biology, New Delhi, India. This study was also partially funded by Department of Science & Technology, Government of India through PURSE II CDST/SR/PURSE PHASE II/11 provided to Jawaharlal Nehru University, New Delhi, India. Part of this work was conducted using the UK Biobank Resource under Application Number 9161.