Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity

Zuccaro, Michael V.; LeDuc, Charles A.; Thaker, Vidhu V.

doi:10.1007/s13679-024-00567-y

Cited by 1 publication

(1 citation statement)

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“…Obesity is a highly heritable trait 1 , resulting from the combined effects of genetic factors and environmental influences. Variants in genes associated with appetite and metabolism can cause obesity 2 , and changes in leptin signaling and adipocyte genes are primary contributors to monogenic obesity 3 . Monogenic and polygenic forms of obesity share common biological pathways 4 , particularly involving the leptin-melanocortin pathway 5 .…”

Section: Introductionmentioning

confidence: 99%

Prevalence and impact of a protein-truncating POMC variant on obesity in the Estonian Biobank

Abner,

Batool,

Taba

et al. 2024

Preprint

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Population-specific genome-wide association studies can reveal high-impact genomic variants that influence traits like body-mass index (BMI). Using the Estonian Biobank BMI dataset (n=204,747 participants) we identified 214 genome-wide significant loci. Among those hits, we identified a common non-coding variant within the newly associated ADGRL3 gene (-0.18 kg/m²; P = 3.06 × 10⁻⁹). Moreover, the missense rare variant PTPRT:p.Arg1384His associated with lower BMI (-0.44 kg/m²; P = 2.5 × 10⁻¹⁰), while the protein-truncating variant POMC:p.Glu206* was associated with considerably higher BMI (+0.81 kg/m²; P = 1.5 × 10-12), both likely affecting the functioning of the leptin-melanocortin pathway. POMC:p.Glu206* was observed in different North-European populations, suggesting a broader, yet elusive, distribution of this damaging variant. These observations indicate the novel roles of the ADGRL3 and PTPRT genes in body weight regulation and suggest an increased prevalence of the POMC:p.Glu206* variant in European populations, offering avenues for developing interventions in obesity management.

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