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Rare Variant Analysis of Obesity-Associated Genes in Young Adults With Severe Obesity From a Consanguineous Population of Pakistan

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posted on 21.01.2022, 16:22 authored by Sadia Saeed, Qasim M Janjua, Attiya Haseeb, Roohia Khanam, Emmanuelle Durand, Emmanuel Vaillant, Lijiao Ning, Alaa Badreddine, Lionel Berberian, Mathilde Boissel, Souhila Amanzougarene, Mickaël Canouil, Mehdi Derhourhi, Amélie Bonnefond, Muhammad Arslan, Philippe Froguel
Recent advances in genetic analysis have significantly helped in progressively attenuating the heritability gap of obesity and have brought into focus monogenic variants that disrupt the melanocortin signalling. In a previous study, next generation sequencing has revealed a monogenic aetiology in ~50% of the children with severe obesity from a consanguineous population in Pakistan. Here we assess rare variants in obesity causing genes in young adults with severe obesity from the same region. Genomic DNA from randomly selected 128 young adult obese subjects (BMI=37.2 ± 0.3; age=18.4 ± 0.3 years) was screened by conventional or augmented whole exome analysis for point mutations and copy number variants (CNVs). Leptin, insulin and cortisol levels were measured by ELISA. We identified thirteen subjects carrying 13 different pathogenic or likely pathogenic variants in LEPR, PCSK1, MC4R, NTRK2, POMC, SH2B1 and SIM1. We also identified for the first time in the human, two homozygous stop-gain mutations in ASNSD1 and IFI16 genes. Inactivation of these genes in mouse models has been shown to result in obesity. Additionally, we describe 9 homozygous mutations (7 missense, 1 stop-gain and 1 stop-loss) and 4 copy-loss CNVs in genes or genomic regions previously linked to obesity-associated traits by genome-wide association studies (GWAS). Unexpectedly, in contrast to obese children, pathogenic mutations in LEP and LEPR were either absent or rare, in this cohort of young adults. High morbidity and mortality risks and social disadvantage of children with LEP or LEPR deficiency may in part explain this difference between the two cohorts.


This work was supported by funding from the Medical Research Council (MRC) MR/S026193/1(PF) and the Pakistan Academy of Sciences (MA). The work related to association analysis has been conducted using the UK Biobank Application #67575. The work was also funded by grants from the French National Research Agency (ANR-10-LABX-46 [European Genomics Institute for Diabetes] and ANR-10-EQPX-07-01 [LIGAN-PM]), from the European Research Council (ERC GEPIDIAB – 294785, to PF; ERC Reg-Seq 7155575, to AB), from the National Center for Precision Diabetic Medicine – PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council and by the European Metropolis of Lille (MEL).