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<p>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 <i>ADGRL3</i> gene (−0.18 kg/m²; <i>P</i> = 3.21 × 10⁻⁹). Moreover, the missense rare variant <i>PTPRT</i>:p.Arg1384His associated with lower BMI (−0.44 kg/m²; <i>P</i> = 2.51 × 10⁻¹⁰), while the protein-truncating variant <i>POMC</i>:p.Glu206* was associated with considerably higher BMI (+ 0.81 kg/m²; <i>P</i> = 1.48 × 10<sup>−12</sup>), both likely affecting the functioning of the leptin-melanocortin pathway. <i>POMC</i>:p.Glu206* was observed in different North-European populations, suggesting a broader, yet elusive, distribution of this damaging variant. These observations indicate the previously unrecognized roles of the <i>ADGRL3</i> and <i>PTPRT</i> genes in body weight regulation and suggest an increased prevalence of the <i>POMC</i>:p.Glu206* variant in European populations, offering avenues for developing interventions in obesity management.</p>

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Characterization of prevalent genetic variants in the Estonian Biobank body-mass index GWAS

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月8日

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  • Erik Abner,
  • Kanwal Batool,
  • Nele Taba,
  • Tiit Nikopensius,
  • Kristi Läll,
  • Anastasiia Alekseienko,
  • Anders Eriksson,
  • Joel Rämö,
  • Hele Haapaniemi,
  • Hanna Maria Kariis,
  • Liis Haljasmägi,
  • Urmo Võsa,
  • Taavi Tillmann,
  • Uku Vainik,
  • Kelli Lehto,
  • Hanna M. Ollila,
  • Kai Kisand,
  • Andres Metspalu,
  • Mait Metspalu,
  • Lili Milani,
  • Reedik Mägi,
  • Tõnu Esko,
  • Mari Nelis,
  • Georgi Hudjashov,
  • Tõnu Esko

摘要

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 = 3.21 × 10⁻⁹). Moreover, the missense rare variant PTPRT:p.Arg1384His associated with lower BMI (−0.44 kg/m²; P = 2.51 × 10⁻¹⁰), while the protein-truncating variant POMC:p.Glu206* was associated with considerably higher BMI (+ 0.81 kg/m²; P = 1.48 × 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 previously unrecognized 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.