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<p>Obesity is a major risk factor for type 2 diabetes, a disease affecting approximately 10% of the global population. Obesity is a heterogeneous condition, with different components exerting distinct, and sometimes opposing, effects on type 2 diabetes risk. Here, we aim to identify molecular mechanisms through which distinct components of obesity influence risk for type 2 diabetes by integrating multi-omics data. We identify SNPs associated with body mass index in males and females and cluster them based on their Mendelian randomisation estimates on type 2 diabetes risk. This analysis reveals four SNP clusters with distinct effects on type 2 diabetes ranging from strongly harmful to protective. We perform cluster-specific two-sample Mendelian randomisation analyses across over&#xa0;3000 molecular traits to delineate metabolic, lipid, endocrine and glycaemic pathways mediating the harmful and protective effects of distinct obesity components on type 2 diabetes risk.</p>

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Genetic and molecular signatures highlight diverse pathways linking obesity to type 2 diabetes

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月8日

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  • Pascal M. Mutie,
  • Tijana Stojanovic,
  • Valeria Lo Faro,
  • Torgny Karlsson,
  • Åsa Johansson

摘要

Obesity is a major risk factor for type 2 diabetes, a disease affecting approximately 10% of the global population. Obesity is a heterogeneous condition, with different components exerting distinct, and sometimes opposing, effects on type 2 diabetes risk. Here, we aim to identify molecular mechanisms through which distinct components of obesity influence risk for type 2 diabetes by integrating multi-omics data. We identify SNPs associated with body mass index in males and females and cluster them based on their Mendelian randomisation estimates on type 2 diabetes risk. This analysis reveals four SNP clusters with distinct effects on type 2 diabetes ranging from strongly harmful to protective. We perform cluster-specific two-sample Mendelian randomisation analyses across over 3000 molecular traits to delineate metabolic, lipid, endocrine and glycaemic pathways mediating the harmful and protective effects of distinct obesity components on type 2 diabetes risk.