The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities

Ana Luiza Arruda; Ozvan Bocher; Henry J. Taylor; Davis Cammann; Satoshi Yoshiji; Xianyong Yin; Chi Zhao; Jingchun Chen; Alexis C. Wood; Ken Suzuki; Josep M. Mercader; Cassandra N. Spracklen; James B. Meigs; Marijana Vujkovic; George Davey Smith; Jerome I. Rotter; Benjamin F. Voight; Andrew P. Morris; Eleftheria Zeggini

doi:10.1038/s41467-025-64927-5

The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities

Ana Luiza Arruda^*, Ozvan Bocher, Henry J. Taylor, Davis Cammann, Satoshi Yoshiji, Xianyong Yin, Chi Zhao, Jingchun Chen, Alexis C. Wood, Ken Suzuki, Josep M. Mercader, Cassandra N. Spracklen, James B. Meigs, Marijana Vujkovic, George Davey Smith, Jerome I. Rotter, Benjamin F. Voight, Andrew P. Morris, Eleftheria Zeggini^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

Type 2 diabetes is associated with a range of non-cardiovascular non-oncologic comorbidities. To move beyond associations and evaluate causal effects between type 2 diabetes genetic predisposition and 21 comorbidities, we apply Mendelian randomization analysis using genome-wide association studies across multiple genetic ancestries. Additionally, leveraging eight mechanistic clusters of type 2 diabetes genetic profiles, each representing distinct biological pathways, we investigate causal links between cluster-stratified type 2 diabetes genetic predisposition and comorbidity risk. We identify causal effects of type 2 diabetes genetic predisposition driven by distinct genetic clusters. For example, the risk-increasing effects of type 2 diabetes genetic predisposition on cataracts and erectile dysfunction are primarily attributed to adiposity and glucose regulation mechanisms, respectively. We observe opposing effect directions across different genetic ancestries for depression, asthma and chronic obstructive pulmonary disease. Our findings leverage the heterogeneity underpinning type 2 diabetes genetic predisposition to prioritize biological mechanisms underlying causal relationships with comorbidities.

Original language	English
Article number	9042
Number of pages	14
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-64927-5
Publication status	Published - 10 Oct 2025

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Publisher Copyright:
© The Author(s) 2025.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Bristol Population Health Science Institute

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10.1038/s41467-025-64927-5Licence: CC BY

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Integrative Epidemiology Unit
Davey Smith, G. (Principal Investigator)
1/04/23 → 31/03/28
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Arruda, A. L., Bocher, O., Taylor, H. J., Cammann, D., Yoshiji, S., Yin, X., Zhao, C., Chen, J., Wood, A. C., Suzuki, K., Mercader, J. M., Spracklen, C. N., Meigs, J. B., Vujkovic, M., Smith, G. D., Rotter, J. I., Voight, B. F., Morris, A. P., & Zeggini, E. (2025). The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities. Nature Communications, 16(1), Article 9042 . https://doi.org/10.1038/s41467-025-64927-5

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title = "The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities",

abstract = "Type 2 diabetes is associated with a range of non-cardiovascular non-oncologic comorbidities. To move beyond associations and evaluate causal effects between type 2 diabetes genetic predisposition and 21 comorbidities, we apply Mendelian randomization analysis using genome-wide association studies across multiple genetic ancestries. Additionally, leveraging eight mechanistic clusters of type 2 diabetes genetic profiles, each representing distinct biological pathways, we investigate causal links between cluster-stratified type 2 diabetes genetic predisposition and comorbidity risk. We identify causal effects of type 2 diabetes genetic predisposition driven by distinct genetic clusters. For example, the risk-increasing effects of type 2 diabetes genetic predisposition on cataracts and erectile dysfunction are primarily attributed to adiposity and glucose regulation mechanisms, respectively. We observe opposing effect directions across different genetic ancestries for depression, asthma and chronic obstructive pulmonary disease. Our findings leverage the heterogeneity underpinning type 2 diabetes genetic predisposition to prioritize biological mechanisms underlying causal relationships with comorbidities.",

author = "Arruda, \{Ana Luiza\} and Ozvan Bocher and Taylor, \{Henry J.\} and Davis Cammann and Satoshi Yoshiji and Xianyong Yin and Chi Zhao and Jingchun Chen and Wood, \{Alexis C.\} and Ken Suzuki and Mercader, \{Josep M.\} and Spracklen, \{Cassandra N.\} and Meigs, \{James B.\} and Marijana Vujkovic and Smith, \{George Davey\} and Rotter, \{Jerome I.\} and Voight, \{Benjamin F.\} and Morris, \{Andrew P.\} and Eleftheria Zeggini",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

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doi = "10.1038/s41467-025-64927-5",

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Arruda, AL, Bocher, O, Taylor, HJ, Cammann, D, Yoshiji, S, Yin, X, Zhao, C, Chen, J, Wood, AC, Suzuki, K, Mercader, JM, Spracklen, CN, Meigs, JB, Vujkovic, M, Smith, GD, Rotter, JI, Voight, BF, Morris, AP & Zeggini, E 2025, 'The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities', Nature Communications, vol. 16, no. 1, 9042 . https://doi.org/10.1038/s41467-025-64927-5

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T1 - The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities

AU - Arruda, Ana Luiza

AU - Bocher, Ozvan

AU - Taylor, Henry J.

AU - Cammann, Davis

AU - Yoshiji, Satoshi

AU - Yin, Xianyong

AU - Zhao, Chi

AU - Chen, Jingchun

AU - Wood, Alexis C.

AU - Suzuki, Ken

AU - Mercader, Josep M.

AU - Spracklen, Cassandra N.

AU - Meigs, James B.

AU - Vujkovic, Marijana

AU - Smith, George Davey

AU - Rotter, Jerome I.

AU - Voight, Benjamin F.

AU - Morris, Andrew P.

AU - Zeggini, Eleftheria

PY - 2025/10/10

Y1 - 2025/10/10

N2 - Type 2 diabetes is associated with a range of non-cardiovascular non-oncologic comorbidities. To move beyond associations and evaluate causal effects between type 2 diabetes genetic predisposition and 21 comorbidities, we apply Mendelian randomization analysis using genome-wide association studies across multiple genetic ancestries. Additionally, leveraging eight mechanistic clusters of type 2 diabetes genetic profiles, each representing distinct biological pathways, we investigate causal links between cluster-stratified type 2 diabetes genetic predisposition and comorbidity risk. We identify causal effects of type 2 diabetes genetic predisposition driven by distinct genetic clusters. For example, the risk-increasing effects of type 2 diabetes genetic predisposition on cataracts and erectile dysfunction are primarily attributed to adiposity and glucose regulation mechanisms, respectively. We observe opposing effect directions across different genetic ancestries for depression, asthma and chronic obstructive pulmonary disease. Our findings leverage the heterogeneity underpinning type 2 diabetes genetic predisposition to prioritize biological mechanisms underlying causal relationships with comorbidities.

AB - Type 2 diabetes is associated with a range of non-cardiovascular non-oncologic comorbidities. To move beyond associations and evaluate causal effects between type 2 diabetes genetic predisposition and 21 comorbidities, we apply Mendelian randomization analysis using genome-wide association studies across multiple genetic ancestries. Additionally, leveraging eight mechanistic clusters of type 2 diabetes genetic profiles, each representing distinct biological pathways, we investigate causal links between cluster-stratified type 2 diabetes genetic predisposition and comorbidity risk. We identify causal effects of type 2 diabetes genetic predisposition driven by distinct genetic clusters. For example, the risk-increasing effects of type 2 diabetes genetic predisposition on cataracts and erectile dysfunction are primarily attributed to adiposity and glucose regulation mechanisms, respectively. We observe opposing effect directions across different genetic ancestries for depression, asthma and chronic obstructive pulmonary disease. Our findings leverage the heterogeneity underpinning type 2 diabetes genetic predisposition to prioritize biological mechanisms underlying causal relationships with comorbidities.

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SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

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The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities

Abstract

Bibliographical note

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Integrative Epidemiology Unit

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