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

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 and Tõnu Esko
Additional contact information
Erik Abner: University of Tartu
Kanwal Batool: University of Tartu
Nele Taba: University of Tartu
Tiit Nikopensius: University of Tartu
Kristi Läll: University of Tartu
Anastasiia Alekseienko: University of Tartu
Anders Eriksson: University of Tartu
Joel Rämö: University of Helsinki
Hele Haapaniemi: University of Helsinki
Hanna Maria Kariis: University of Tartu
Liis Haljasmägi: University of Tartu
Urmo Võsa: University of Tartu
Taavi Tillmann: University of Tartu
Uku Vainik: University of Tartu
Kelli Lehto: University of Tartu
Hanna M. Ollila: University of Helsinki
Kai Kisand: University of Tartu
Tõnu Esko: University of Tartu

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64006-9

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