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

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.

Fig. 1

Study flowchart

Fig. 2

Results of haplotype analysis for ADCY3, CEP19, and SDCCAG8 genes’ variants. Linkage disequilibrium (LD) plots and haplotypic structures of CEP19 are based on solid and four-gamete rule methods. A shows the LD plots based on the haplotypic methods. B shows haplotypes based on the haplotypic method. LD plots and haplotypic structures of the SDCCAG8 gene, A1 and A2 show the LD plots based on the four-gamete rule and solid methods, respectively. B1 and B2 show the haplotypic blocks based on the four-gamete rule and solid methods, respectively. LD plots and haplotypic structures of ADCY3 gene, A shows the LD plots based on the solid method. The plots for the confidence interval and four-gamete rule methods are shown in Online Resource 3. B1, B2, and B3 show the haplotypic blocks based on the confidence interval, solid, and four-gamete rule methods, respectively. The horizontal bars in the upper LD plots show the location of each SNP. The boxes without any number correspond to a D′=1. Haplotype frequencies are shown at the bottom right of haplotypes. SNP numbers on haplotypes correspond to numbers in LD plots. Thick connection lines represent haplotypes with a frequency > 10%, while thin lines represent > 1% haplotype frequency