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 FST 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 in Finns. Our selection analysis provided significant evidence of selection for the abdominal obesity risk allele T of rs10494217 in Finns, with a north-to-south decreasing trend in other populations, and demonstrated that latitude significantly predicts the allele frequency. We also discovered that the risk allele status significantly affects SAT adipocyte expression of multiple adipocyte marker genes in trans in two cohorts. Two of these trans genes have been connected to thermogenesis, supporting the thermogenic effect of the TBX15 missense variant as a possible cause of its selection. Adipose expression of one trans gene, a lncRNA, AC002066.1, was strongly associated with adipocyte size, implicating it in metabolically unhealthy adipocyte hypertrophy. In summary, the abdominal obesity variant rs10494217 was selected in Finns, and individuals with the risk allele have trans effects on adipocyte expression of genes relating to thermogenesis and adipocyte hypertrophy.

中文翻译：

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脂肪细胞产热基因 TBX15 中的腹部肥胖错义变异与芬兰人对寒冷的适应有关。


腹部肥胖 GWAS 变异的机制在很大程度上仍然未知。为了阐明这些机制，我们利用了皮下脂肪组织 （SAT） 单核 RNA 测序和基因组学数据。在发现脂肪细胞中富含腹部肥胖的遗传性后，我们专注于 SAT 独特的脂肪细胞标志基因，转录因子 TBX15 及其与腹部肥胖相关的有害错义变体 rs10494217。rs10494217 的等位基因频率揭示了从北到南的递减梯度，与具有遗传隔离历史的芬兰人相比，在 25 个不同人群中观察到一致的显着 FST 值。鉴于 Tbx15 在小鼠产热中的作用，芬兰人对寒冷的适应可能已经增加频率。我们的选择分析为芬兰人 rs10494217 的腹部肥胖风险等位基因 T 提供了选择的重要证据，在其他人群中呈从北到南下降的趋势，并表明纬度显着预测等位基因频率。我们还发现，在两个队列中，风险等位基因状态显着影响 SAT 脂肪细胞中多个脂肪细胞标志基因的表达。其中两个反基因与产热有关，支持 TBX15 错义变体的产热效应是其选择的可能原因。一个反基因 lncRNA AC002066.1 的脂肪表达与脂肪细胞大小密切相关，这暗示它与代谢不健康的脂肪细胞肥大有关。综上所述，在芬兰人中选择了腹部肥胖变异 rs10494217，具有风险等位基因的个体对脂肪细胞与产热和脂肪细胞肥大相关的基因表达具有反式影响。