Genetic burden of rare leptin-melanocortin variants in pediatric nonsyndromic obesity: Evidence from a Taiwanese cohort

Yu-Ming Chang; Daw-Yang Hwang; Yen-Yin Chou; Yu-Wen Pan; Yun-Han Weng; Meng-Che Tsai

doi:10.1016/j.orcp.2026.07.003

Genetic burden of rare leptin-melanocortin variants in pediatric nonsyndromic obesity: Evidence from a Taiwanese cohort

Obes Res Clin Pract. 2026 Aug 3:S1871-403X(26)00073-6. doi: 10.1016/j.orcp.2026.07.003. Online ahead of print.

Authors

Yu-Ming Chang¹, Daw-Yang Hwang², Yen-Yin Chou¹, Yu-Wen Pan³, Yun-Han Weng³, Meng-Che Tsai⁴

Affiliations

¹ Department of Genomic Medicine, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan; Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan.
² National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
³ Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan.
⁴ Department of Genomic Medicine, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan; Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan; Department of Medical Humanities and Social Medicine, School of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: mengchets@gs.ncku.edu.tw.

PMID: 42547334
DOI: 10.1016/j.orcp.2026.07.003

Abstract

Background: Rare and deleterious variants in the leptin-melanocortin pathway can underlie severe childhood obesity, but data from East Asian populations remain limited.

Methods: We conducted a single-center prospective observational cohort study of 188 Taiwanese children (4-18 years) with nonsyndromic obesity recruited between Jan 2017 and Dec 2024 for targeted sequencing of 12 leptin-melanocortin genes and compared them with two cohorts from the Taiwan Biobank: 527 normal‑weight adults presumed to have normal weight in childhood and 213 obese adults. We compared carrier proportions and mean variant counts and applied the Optimal Sequence Kernel Association Test (SKAT-O) across groups at the pathway and gene levels for three variant sets: all exonic variants, rare variants, and potentially influential variants (PIVs, defined as rare protein-truncating variants or missense variants with high deleteriousness scores). We also analyzed questionnaire-derived eating behavior scores using SKAT-O within the childhood obesity cohort.

Results: Children with obesity carried a higher PIV burden than both normal-weight adults (41.0% vs. 24.1%; p < 0.0001) and obese adults (41.0% vs. 25.8%; p = 0.001); mean PIV counts were also higher. Pathway-level SKAT-O supported enrichment driven by rare variants and PIVs. Gene-level enrichment for LEPR and MAGEL2, and variant-level enrichment for two missense variants, MAGEL2 p.Gly285Arg and LEPR p.Asn128Lys, were observed in the childhood obesity group. Analyses of eating‑behavior scores showed nominal signals for exonic variants in MAGEL2 and PIVs in SIM1, but neither met the Bonferroni‑corrected threshold.

Conclusions: Rare, putatively deleterious leptin-melanocortin variants, particularly in LEPR and MAGEL2, are enriched in Taiwanese children with nonsyndromic obesity, underscoring the value of pathway-focused genetic evaluation in pediatric obesity.

Keywords: Leptin-melanocortin pathway; Pathway analysis; Pediatric obesity; Rare variant.