biostudies-literatureDeal MNIDDK NIH HHSNHLBI NIH HHS2542-2560https://www.ebi.ac.uk/biostudies/studies/S-EPMC11568758biostudies-literatureUnknown111(11)Mechanisms of abdominal obesity GWAS variants have remained largely unknown. To elucidate these mechanisms, we leveraged subcutaneous adipose tissue (SAT) single nucleus RNA-sequencing and genomics data. After discovering that heritability of abdominal obesity is enriched in adipocytes, we focused on a SAT unique adipocyte marker gene, the transcription factor TBX15, and its abdominal obesity-associated deleterious missense variant, rs10494217. The allele frequency of rs10494217 revealed a north-to-south decreasing gradient, with consistent significant F_ST values observed for 25 different populations when compared to Finns, a population with a history of genetic isolation. Given the role of Tbx15 in mouse thermogenesis, the frequency may have increased as an adaptation to cold iAmerican journal of human geneticsAn abdominal obesity missense variant in the adipocyte thermogenesis gene TBX15 is implicated in adaptation to cold in Finns.PMC11568758R01 DK132775R01 HL170604Pietilainen KHSaarinen TAlvarez MMannisto VHeinonen SPajukanta PSailakivi URajkumar SKaminska DArasu UTKar APihlajamaki JKaikkonen MULee SHTvan der Kolk BWJuuti ALaakso MDeal MfalseAn abdominal obesity missense variant in the adipocyte thermogenesis gene TBX15 is implicated in adaptation to cold in Finns.Mechanisms of abdominal obesity GWAS variants have remained largely unknown. To elucidate these mechanisms, we leveraged subcutaneous adipose tissue (SAT) single nucleus RNA-sequencing and genomics data. After discovering that heritability of abdominal obesity is enriched in adipocytes, we focused on a SAT unique adipocyte marker gene, the transcription factor TBX15, and its abdominal obesity-associated deleterious missense variant, rs10494217. The allele frequency of rs10494217 revealed a north-to-south decreasing gradient, with consistent significant F_ST values observed for 25 different populations when compared to Finns, a population with a history of genetic isolation. Given the role of Tbx15 in mouse thermogenesis, the frequency may have increased as an adaptation to cold i2024-01-01T00:00:00Z2024 Nov2026-06-02T03:36:28.227Z2025-04-04T12:01:29.662ZS-EPMC115687583951530010.1016/j.ajhg.2024.10.001