Novel genetic associations with childhood adipocytokines in Indian adolescents

Adipocytokines, including leptin, adiponectin, and resistin, are key mediators linking adiposity, insulin resistance, and inflammation. We present the first genome-wide association study (GWAS; N = 5258) and exome-wide association study (ExWAS; N = 4578) on leptin, adiponectin, and resistin in South Asian population. We identified novel associations in genes ZNF467, and LEPREL2 for leptin; ZNF467, LEPREL2, CRLF3, ZNF732, SOX30, XIRP1, ATP8B3, SPATA2L, TMCO4, TLN2, ABCA12, and SHB for adiponectin; and D2HGDH for resistin. Additionally, we confirmed known associations of FTO, MC4R, and HOXB3 with leptin and ADIPOQ with adiponectin. Notably, ADIPOQ variants were consistently significant across GWAS, ExWAS, and gene-based analyses, reinforcing their central role in regulating adiponectin levels. Most of these novel associations identified were population-specific, highlighting the importance of studying diverse populations to uncover unique genetic signals. After adjusting for BMI, the associations with adiponectin and resistin remained significant, whereas most associations for leptin weakened in both effect size and significance. Functional annotation revealed that the identified variants were enriched for expression in adipose tissue, the brain (cerebellar hemisphere and cerebral cortex), and the pituitary gland. These variants act as eQTLs and splice-QTLs in adipose, brain, and pancreas, suggesting cross-tissue regulatory mechanisms. ExWAS further implicated rare variant burden in genes such as LONP1, ZNF335, and TTC16 for adiponectin and resistin. These findings enhance our understanding of adipocytokine biology, emphasises the need for population-specific genetic research, and lays foundation for future functional studies.