A multivariate genome-wide association study of psycho-cardiometabolic multimorbidity

Vilte Baltramonaityte; Jean Baptiste Pingault; the EarlyCause Consortium; Charlotte A.M. Cecil; Priyanka Choudhary; Marjo Riitta Järvelin; Brenda W.J.H. Penninx; Janine Felix; Sylvain Sebert; Yuri Milaneschi; Esther Walton

doi:10.1371/journal.pgen.1010508

A multivariate genome-wide association study of psycho-cardiometabolic multimorbidity

Vilte Baltramonaityte, Jean Baptiste Pingault, the EarlyCause Consortium, Charlotte A.M. Cecil, Priyanka Choudhary, Marjo Riitta Järvelin, Brenda W.J.H. Penninx, Janine Felix, Sylvain Sebert, Yuri Milaneschi, Esther Walton^*

^*Corresponding author for this work

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Abstract

Coronary artery disease (CAD), type 2 diabetes (T2D) and depression are among the leading causes of chronic morbidity and mortality worldwide. Epidemiological studies indicate a substantial degree of multimorbidity, which may be explained by shared genetic influences. However, research exploring the presence of pleiotropic variants and genes common to CAD, T2D and depression is lacking. The present study aimed to identify genetic variants with effects on cross-trait liability to psycho-cardiometabolic diseases. We used genomic structural equation modelling to perform a multivariate genome-wide association study of multimorbidity (N_effective = 562,507), using summary statistics from univariate genome-wide association studies for CAD, T2D and major depression. CAD was moderately genetically correlated with T2D (r_g = 0.39, P = 2e-34) and weakly correlated with depression (r_g = 0.13, P = 3e-6). Depression was weakly correlated with T2D (r_g = 0.15, P = 4e-15). The latent multimorbidity factor explained the largest proportion of variance in T2D (45%), followed by CAD (35%) and depression (5%). We identified 11 independent SNPs associated with multimorbidity and 18 putative multimorbidity-associated genes. We observed enrichment in immune and inflammatory pathways. A greater polygenic risk score for multimorbidity in the UK Biobank (N = 306,734) was associated with the co-occurrence of CAD, T2D and depression (OR per standard deviation = 1.91, 95% CI = 1.74–2.10, relative to the healthy group), validating this latent multimorbidity factor. Mendelian randomization analyses suggested potentially causal effects of BMI, body fat percentage, LDL cholesterol, total cholesterol, fasting insulin, income, insomnia, and childhood maltreatment. These findings advance our understanding of multimorbidity suggesting common genetic pathways.

Original language	English
Article number	e1010508
Number of pages	22
Journal	PLoS Genetics
Volume	19
Issue number	6 June
DOIs	https://doi.org/10.1371/journal.pgen.1010508
Publication status	Published - 30 Jun 2023

Bibliographical note

Funding Information:
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No 848158 (EarlyCause). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are grateful to the UK Biobank and all its voluntary participants. We also thank all 23andMe research participants who made this study possible.

Publisher Copyright:
© 2023 Baltramonaityte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Baltramonaityte, V., Pingault, J. B., the EarlyCause Consortium, Cecil, C. A. M., Choudhary, P., Järvelin, M. R., Penninx, B. W. J. H., Felix, J., Sebert, S., Milaneschi, Y., & Walton, E. (2023). A multivariate genome-wide association study of psycho-cardiometabolic multimorbidity. PLoS Genetics, 19(6 June), Article e1010508. https://doi.org/10.1371/journal.pgen.1010508

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abstract = "Coronary artery disease (CAD), type 2 diabetes (T2D) and depression are among the leading causes of chronic morbidity and mortality worldwide. Epidemiological studies indicate a substantial degree of multimorbidity, which may be explained by shared genetic influences. However, research exploring the presence of pleiotropic variants and genes common to CAD, T2D and depression is lacking. The present study aimed to identify genetic variants with effects on cross-trait liability to psycho-cardiometabolic diseases. We used genomic structural equation modelling to perform a multivariate genome-wide association study of multimorbidity (Neffective = 562,507), using summary statistics from univariate genome-wide association studies for CAD, T2D and major depression. CAD was moderately genetically correlated with T2D (rg = 0.39, P = 2e-34) and weakly correlated with depression (rg = 0.13, P = 3e-6). Depression was weakly correlated with T2D (rg = 0.15, P = 4e-15). The latent multimorbidity factor explained the largest proportion of variance in T2D (45%), followed by CAD (35%) and depression (5%). We identified 11 independent SNPs associated with multimorbidity and 18 putative multimorbidity-associated genes. We observed enrichment in immune and inflammatory pathways. A greater polygenic risk score for multimorbidity in the UK Biobank (N = 306,734) was associated with the co-occurrence of CAD, T2D and depression (OR per standard deviation = 1.91, 95% CI = 1.74–2.10, relative to the healthy group), validating this latent multimorbidity factor. Mendelian randomization analyses suggested potentially causal effects of BMI, body fat percentage, LDL cholesterol, total cholesterol, fasting insulin, income, insomnia, and childhood maltreatment. These findings advance our understanding of multimorbidity suggesting common genetic pathways.",

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note = "Funding Information: This project has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under Grant Agreement No 848158 (EarlyCause). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are grateful to the UK Biobank and all its voluntary participants. We also thank all 23andMe research participants who made this study possible. Publisher Copyright: {\textcopyright} 2023 Baltramonaityte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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AU - Järvelin, Marjo Riitta

AU - Penninx, Brenda W.J.H.

AU - Felix, Janine

AU - Sebert, Sylvain

AU - Milaneschi, Yuri

AU - Walton, Esther

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PY - 2023/6/30

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N2 - Coronary artery disease (CAD), type 2 diabetes (T2D) and depression are among the leading causes of chronic morbidity and mortality worldwide. Epidemiological studies indicate a substantial degree of multimorbidity, which may be explained by shared genetic influences. However, research exploring the presence of pleiotropic variants and genes common to CAD, T2D and depression is lacking. The present study aimed to identify genetic variants with effects on cross-trait liability to psycho-cardiometabolic diseases. We used genomic structural equation modelling to perform a multivariate genome-wide association study of multimorbidity (Neffective = 562,507), using summary statistics from univariate genome-wide association studies for CAD, T2D and major depression. CAD was moderately genetically correlated with T2D (rg = 0.39, P = 2e-34) and weakly correlated with depression (rg = 0.13, P = 3e-6). Depression was weakly correlated with T2D (rg = 0.15, P = 4e-15). The latent multimorbidity factor explained the largest proportion of variance in T2D (45%), followed by CAD (35%) and depression (5%). We identified 11 independent SNPs associated with multimorbidity and 18 putative multimorbidity-associated genes. We observed enrichment in immune and inflammatory pathways. A greater polygenic risk score for multimorbidity in the UK Biobank (N = 306,734) was associated with the co-occurrence of CAD, T2D and depression (OR per standard deviation = 1.91, 95% CI = 1.74–2.10, relative to the healthy group), validating this latent multimorbidity factor. Mendelian randomization analyses suggested potentially causal effects of BMI, body fat percentage, LDL cholesterol, total cholesterol, fasting insulin, income, insomnia, and childhood maltreatment. These findings advance our understanding of multimorbidity suggesting common genetic pathways.

AB - Coronary artery disease (CAD), type 2 diabetes (T2D) and depression are among the leading causes of chronic morbidity and mortality worldwide. Epidemiological studies indicate a substantial degree of multimorbidity, which may be explained by shared genetic influences. However, research exploring the presence of pleiotropic variants and genes common to CAD, T2D and depression is lacking. The present study aimed to identify genetic variants with effects on cross-trait liability to psycho-cardiometabolic diseases. We used genomic structural equation modelling to perform a multivariate genome-wide association study of multimorbidity (Neffective = 562,507), using summary statistics from univariate genome-wide association studies for CAD, T2D and major depression. CAD was moderately genetically correlated with T2D (rg = 0.39, P = 2e-34) and weakly correlated with depression (rg = 0.13, P = 3e-6). Depression was weakly correlated with T2D (rg = 0.15, P = 4e-15). The latent multimorbidity factor explained the largest proportion of variance in T2D (45%), followed by CAD (35%) and depression (5%). We identified 11 independent SNPs associated with multimorbidity and 18 putative multimorbidity-associated genes. We observed enrichment in immune and inflammatory pathways. A greater polygenic risk score for multimorbidity in the UK Biobank (N = 306,734) was associated with the co-occurrence of CAD, T2D and depression (OR per standard deviation = 1.91, 95% CI = 1.74–2.10, relative to the healthy group), validating this latent multimorbidity factor. Mendelian randomization analyses suggested potentially causal effects of BMI, body fat percentage, LDL cholesterol, total cholesterol, fasting insulin, income, insomnia, and childhood maltreatment. These findings advance our understanding of multimorbidity suggesting common genetic pathways.

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A multivariate genome-wide association study of psycho-cardiometabolic multimorbidity

Abstract

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