Whole exome sequencing revealed new variants and haplotypes associated with monogenic obesity

Morteza Gholami; Armita Kakavand Hamidi; Zeinab Naghshband; Mojgan Asadi; Mahsa M Amoli

doi:10.1007/s40200-024-01507-2

Whole exome sequencing revealed new variants and haplotypes associated with monogenic obesity

J Diabetes Metab Disord. 2024 Dec 20;24(1):23. doi: 10.1007/s40200-024-01507-2. eCollection 2025 Jun.

Authors

Morteza Gholami¹, Armita Kakavand Hamidi², Zeinab Naghshband³, Mojgan Asadi⁴, Mahsa M Amoli¹

Affiliations

¹ Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
² Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
³ Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
⁴ Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

PMID: 39712340
PMCID: PMC11662120 (available on 2025-12-20)
DOI: 10.1007/s40200-024-01507-2

Abstract

Objectives: This study aims to identify new variants and haplotypes associated with monogenic obesity by analyzing known obesity genes in whole exome sequencing (WES) data.

Methods: The monogenic obesity-associated genes were identified by using the National Institutes of Health (NIH) Genetic Testing Registry (GTR) monogenic obesity panels. WES was performed on (n = 49) extremely obese (children under 5 with weight-for-height greater than 3 standard deviations (SD) above the World Health Organization (WHO) Child Growth Standards median) and (n = 50) control nonobese (25 > body mass index (BMI) < 30) subjects without a history of childhood obesity, and also Iranome WES data of healthy subjects (n = 800).

Results: Seventy-four genes were included in WES analyses. After Bonferroni correction, the T allele of rs2275155 on SDCCAG8 was significantly associated with the increased risk of obesity for allelic and co-dominant models (p˂0.05). Also, a significant association was observed for the T allele of rs116167439 on CEP19 and the T allele of rs201676524 a rare variant on ADCY3; for allelic, dominant, overdominant, and co-dominant models (p˂0.05). In the haplotype association study, TC (on CEP19), CATA (on SDCCAG8), CAA, CTA, CAAA, and TTGA (on ADCY3) haplotypes showed significant associations with monogenic obesity (p < 0.05).

Conclusions: This study suggested that the T allele of two common variants rs2275155 and rs116167439, also rare variant rs201676524 are associated with an increased risk of monogenic obesity. The significant haplotype associations indicate these variants may be in linkage with causative rare variants and should be considered in future studies.

Supplementary information: The online version contains supplementary material available at 10.1007/s40200-024-01507-2.

Keywords: Haplotype; Obesity; Variant; Whole exome sequencing.

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