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Background <p>Multimorbidity, the co-occurrence of multiple long-term conditions (LTCs), is an increasingly important clinical problem, but little is known about the underlying causes. We investigate the role of a critical multimorbidity risk factor, obesity, as measured by body mass index (BMI), in explaining shared genetics amongst 71 common LTCs.</p> Methods <p>In a population of northern Europeans, we estimated genetic correlation, between LTCs and partial genetic correlations after adjustment for the genetics of BMI. We used multiple causal inference methods to confirm that BMI causally affects individual LTCs, and their co-occurrence. Finally, we quantified the population-level impact of intervening and lowering BMI on the prevalence of 15 key common multimorbid LTC pairs.</p> Results <p>BMI partially explains some of the shared genetics for 740 LTC pairs (30% of all pairs considered). For a further 161 LTC pairs, the genetic similarity between the LTCs was entirely accounted for by BMI genetics. This list included diabetes and osteoarthritis and gout and osteoarthritis: Causal inference methods confirmed that higher BMI acts as a common risk factor for a subset of these pairs, and therefore BMI-lowering interventions would likely reduce their prevalence. For example, we estimated that a 1 standard deviation or 4.5 unit decrease in BMI would result in 17 fewer people with both chronic kidney disease and osteoarthritis per 1000 who currently have both LTCs.</p> Conclusions <p>Our genetics-centred approach quantifies the contribution of obesity to multi-morbidity. Our method for calculating full and partial genetic correlations is published as an R package <i>{partialLDSC}</i>.</p>

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Genetics identifies obesity as a shared risk factor for co-occurring multiple long-term conditions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月4日

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  • Ninon Mounier,
  • Bethany Voller,
  • Jane A. H. Masoli,
  • João Delgado,
  • Frank Dudbridge,
  • Luke C. Pilling,
  • Timothy M. Frayling,
  • Jack Bowden,
  • Jane AH Masoli,
  • Olivia Murrin,
  • Linus Tata,
  • Carlos Gallego-Moll,
  • Albert Roso-Llorach,
  • Lucía A. Carrasco-Ribelles,
  • Chris Fox,
  • Louise M. Allan,
  • Ruby M. Woodward,
  • Xiaoran Liang,
  • Jose M. Valderas,
  • Sara M. Khalid,
  • Sally E. Lamb,
  • Mary Mancini,
  • Leon Farmer,
  • Kate Boddy,
  • David Melzer,
  • Concepción Violán

摘要

Background

Multimorbidity, the co-occurrence of multiple long-term conditions (LTCs), is an increasingly important clinical problem, but little is known about the underlying causes. We investigate the role of a critical multimorbidity risk factor, obesity, as measured by body mass index (BMI), in explaining shared genetics amongst 71 common LTCs.

Methods

In a population of northern Europeans, we estimated genetic correlation, between LTCs and partial genetic correlations after adjustment for the genetics of BMI. We used multiple causal inference methods to confirm that BMI causally affects individual LTCs, and their co-occurrence. Finally, we quantified the population-level impact of intervening and lowering BMI on the prevalence of 15 key common multimorbid LTC pairs.

Results

BMI partially explains some of the shared genetics for 740 LTC pairs (30% of all pairs considered). For a further 161 LTC pairs, the genetic similarity between the LTCs was entirely accounted for by BMI genetics. This list included diabetes and osteoarthritis and gout and osteoarthritis: Causal inference methods confirmed that higher BMI acts as a common risk factor for a subset of these pairs, and therefore BMI-lowering interventions would likely reduce their prevalence. For example, we estimated that a 1 standard deviation or 4.5 unit decrease in BMI would result in 17 fewer people with both chronic kidney disease and osteoarthritis per 1000 who currently have both LTCs.

Conclusions

Our genetics-centred approach quantifies the contribution of obesity to multi-morbidity. Our method for calculating full and partial genetic correlations is published as an R package {partialLDSC}.