Associations between the CADM2 gene, substance use, risky sexual behavior, and self‐control: A phenome‐wide association study

Rachel M. Arends; Joëlle A. Pasman; Karin J.H. Verweij; Eske M. Derks; Scott D. Gordon; Ian Hickie; Nathaniel S. Thomas; Fazil Aliev; Brendan P. Zietsch; Matthijs D. van der Zee; Brittany L. Mitchell; Nicholas G. Martin; Danielle M. Dick; Nathan A. Gillespie; Eco J.C. de Geus; Dorret I. Boomsma; Arnt F.A. Schellekens; Jacqueline M. Vink

doi:10.1111/adb.13015

Associations between the CADM2 gene, substance use, risky sexual behavior, and self‐control: A phenome‐wide association study

Rachel M. Arends^*, Joëlle A. Pasman, Karin J.H. Verweij, Eske M. Derks, Scott D. Gordon, Ian Hickie, Nathaniel S. Thomas, Fazil Aliev, Brendan P. Zietsch, Matthijs D. van der Zee, Brittany L. Mitchell, Nicholas G. Martin, Danielle M. Dick, Nathan A. Gillespie, Eco J.C. de Geus, Dorret I. Boomsma, Arnt F.A. Schellekens, Jacqueline M. Vink

^*Corresponding author for this work

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

Abstract

Risky behaviors, such as substance use and unprotected sex, are associated with various physical and mental health problems. Recent genome-wide association studies indicated that variation in the cell adhesion molecule 2 (CADM2) gene plays a role in risky behaviors and self-control. In this phenome-wide scan for risky behavior, it was tested if underlying common vulnerability could be (partly) explained by pleiotropic effects of this gene and how large the effects were. Single nucleotide polymorphism (SNP)-level and gene-level association tests within four samples (25 and Up, Spit for Science, Netherlands Twin Register, and UK Biobank and meta-analyses over all samples (combined sample of 362,018 participants) were conducted to test associations between CADM2, substance- and sex-related risk behaviors, and various measures related to self-control. We found significant associations between the CADM2 gene, various risky behaviors, and different measures of self-control. The largest effect sizes were found for cannabis use, sensation seeking, and disinhibition. Effect sizes ranged from 0.01% to 0.26% for single top SNPs and from 0.07% to 3.02% for independent top SNPs together, with sufficient power observed only in the larger samples and meta-analyses. In the largest cohort, we found indications that risk-taking proneness mediated the association between CADM2 and latent factors for lifetime smoking and regular alcohol use. This study extends earlier findings that CADM2 plays a role in risky behaviors and self-control. It also provides insight into gene-level effect sizes and demonstrates the feasibility of testing mediation. These findings present a good starting point for investigating biological etiological pathways underlying risky behaviors.

Original language	English
Article number	e13015
Pages (from-to)	1-13
Number of pages	13
Journal	Addiction Biology
Volume	26
Issue number	6
Early online date	18 Feb 2021
DOIs	https://doi.org/10.1111/adb.13015
Publication status	Published - Nov 2021

Bibliographical note

Funding Information:
This study has been conducted using four databases including the 25 and Up, Spit for Science, Netherlands Twin Register, and the UK Biobank. We want to thank all participants and the individuals who contributed to the inclusion, data collection, and data distribution. A special thanks to Ward de Witte, Nina Moth‐Rota, and Barbara Franke for helping with requesting and providing the UK Biobank data. Tissue‐specific gene expression results mentioned in the discussion and Figure S2C were obtained from the Genotype‐Tissue Expression (GTEx) Project (retrieved on 12/05/2019). This project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. K.J.H.V. is supported by the Foundation Volksbond Rotterdam and by a grant from Amsterdam Neuroscience. Spit for Science has been supported by Virginia Commonwealth University, P20 AA017828, R37AA011408, K02AA018755, P50 AA022537; K01AA024152 from the National Institute on Alcohol Abuse and Alcoholism; and UL1RR031990 from the National Center for Research Resources and National Institutes of Health Roadmap for Medical Research. This research was also supported by the National Institute on Drug Abuse of the National Institutes of Health (NIH) under Award U54DA036105 and the Center for Tobacco Products of the U.S. Food and Drug Administration (FDA). The 25up study was funded by the National Health and Medical Research Council Project Grant APP1069141 to IBH and NGM.

Funding Information:
This study has been conducted using four databases including the 25 and Up, Spit for Science, Netherlands Twin Register, and the UK Biobank. We want to thank all participants and the individuals who contributed to the inclusion, data collection, and data distribution. A special thanks to Ward de Witte, Nina Moth-Rota, and Barbara Franke for helping with requesting and providing the UK Biobank data. Tissue-specific gene expression results mentioned in the discussion and Figure?S2C were obtained from the Genotype-Tissue Expression (GTEx) Project (retrieved on 12/05/2019). This project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. K.J.H.V. is supported by the Foundation Volksbond Rotterdam and by a grant from Amsterdam Neuroscience. Spit for Science has been supported by Virginia Commonwealth University, P20 AA017828, R37AA011408, K02AA018755, P50 AA022537; K01AA024152 from the National Institute on Alcohol Abuse and Alcoholism; and UL1RR031990 from the National Center for Research Resources and National Institutes of Health Roadmap for Medical Research. This research was also supported by the National Institute on Drug Abuse of the National Institutes of Health (NIH) under Award U54DA036105 and the Center for Tobacco Products of the U.S. Food and Drug Administration (FDA). The 25up study was funded by the National Health and Medical Research Council Project Grant APP1069141 to IBH and NGM.

Publisher Copyright:
© 2021 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

Keywords

CADM2
multi-cohort
phenome-wide
risky behavior
self-control
substance use

UN SDGs

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

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Arends, R. M., Pasman, J. A., Verweij, K. J. H., Derks, E. M., Gordon, S. D., Hickie, I., Thomas, N. S., Aliev, F., Zietsch, B. P., van der Zee, M. D., Mitchell, B. L., Martin, N. G., Dick, D. M., Gillespie, N. A., de Geus, E. J. C., Boomsma, D. I., Schellekens, A. F. A., & Vink, J. M. (2021). Associations between the CADM2 gene, substance use, risky sexual behavior, and self‐control: A phenome‐wide association study. Addiction Biology, 26(6), 1-13. [e13015]. https://doi.org/10.1111/adb.13015

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title = "Associations between the CADM2 gene, substance use, risky sexual behavior, and self‐control: A phenome‐wide association study",

abstract = "Risky behaviors, such as substance use and unprotected sex, are associated with various physical and mental health problems. Recent genome-wide association studies indicated that variation in the cell adhesion molecule 2 (CADM2) gene plays a role in risky behaviors and self-control. In this phenome-wide scan for risky behavior, it was tested if underlying common vulnerability could be (partly) explained by pleiotropic effects of this gene and how large the effects were. Single nucleotide polymorphism (SNP)-level and gene-level association tests within four samples (25 and Up, Spit for Science, Netherlands Twin Register, and UK Biobank and meta-analyses over all samples (combined sample of 362,018 participants) were conducted to test associations between CADM2, substance- and sex-related risk behaviors, and various measures related to self-control. We found significant associations between the CADM2 gene, various risky behaviors, and different measures of self-control. The largest effect sizes were found for cannabis use, sensation seeking, and disinhibition. Effect sizes ranged from 0.01% to 0.26% for single top SNPs and from 0.07% to 3.02% for independent top SNPs together, with sufficient power observed only in the larger samples and meta-analyses. In the largest cohort, we found indications that risk-taking proneness mediated the association between CADM2 and latent factors for lifetime smoking and regular alcohol use. This study extends earlier findings that CADM2 plays a role in risky behaviors and self-control. It also provides insight into gene-level effect sizes and demonstrates the feasibility of testing mediation. These findings present a good starting point for investigating biological etiological pathways underlying risky behaviors.",

keywords = "CADM2, multi-cohort, phenome-wide, risky behavior, self-control, substance use",

author = "Arends, {Rachel M.} and Pasman, {Jo{\"e}lle A.} and Verweij, {Karin J.H.} and Derks, {Eske M.} and Gordon, {Scott D.} and Ian Hickie and Thomas, {Nathaniel S.} and Fazil Aliev and Zietsch, {Brendan P.} and {van der Zee}, {Matthijs D.} and Mitchell, {Brittany L.} and Martin, {Nicholas G.} and Dick, {Danielle M.} and Gillespie, {Nathan A.} and {de Geus}, {Eco J.C.} and Boomsma, {Dorret I.} and Schellekens, {Arnt F.A.} and Vink, {Jacqueline M.}",

note = "Funding Information: This study has been conducted using four databases including the 25 and Up, Spit for Science, Netherlands Twin Register, and the UK Biobank. We want to thank all participants and the individuals who contributed to the inclusion, data collection, and data distribution. A special thanks to Ward de Witte, Nina Moth‐Rota, and Barbara Franke for helping with requesting and providing the UK Biobank data. Tissue‐specific gene expression results mentioned in the discussion and Figure S2C were obtained from the Genotype‐Tissue Expression (GTEx) Project (retrieved on 12/05/2019). This project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. K.J.H.V. is supported by the Foundation Volksbond Rotterdam and by a grant from Amsterdam Neuroscience. Spit for Science has been supported by Virginia Commonwealth University, P20 AA017828, R37AA011408, K02AA018755, P50 AA022537; K01AA024152 from the National Institute on Alcohol Abuse and Alcoholism; and UL1RR031990 from the National Center for Research Resources and National Institutes of Health Roadmap for Medical Research. This research was also supported by the National Institute on Drug Abuse of the National Institutes of Health (NIH) under Award U54DA036105 and the Center for Tobacco Products of the U.S. Food and Drug Administration (FDA). The 25up study was funded by the National Health and Medical Research Council Project Grant APP1069141 to IBH and NGM. Funding Information: This study has been conducted using four databases including the 25 and Up, Spit for Science, Netherlands Twin Register, and the UK Biobank. We want to thank all participants and the individuals who contributed to the inclusion, data collection, and data distribution. A special thanks to Ward de Witte, Nina Moth-Rota, and Barbara Franke for helping with requesting and providing the UK Biobank data. Tissue-specific gene expression results mentioned in the discussion and Figure?S2C were obtained from the Genotype-Tissue Expression (GTEx) Project (retrieved on 12/05/2019). This project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. K.J.H.V. is supported by the Foundation Volksbond Rotterdam and by a grant from Amsterdam Neuroscience. Spit for Science has been supported by Virginia Commonwealth University, P20 AA017828, R37AA011408, K02AA018755, P50 AA022537; K01AA024152 from the National Institute on Alcohol Abuse and Alcoholism; and UL1RR031990 from the National Center for Research Resources and National Institutes of Health Roadmap for Medical Research. This research was also supported by the National Institute on Drug Abuse of the National Institutes of Health (NIH) under Award U54DA036105 and the Center for Tobacco Products of the U.S. Food and Drug Administration (FDA). The 25up study was funded by the National Health and Medical Research Council Project Grant APP1069141 to IBH and NGM. Publisher Copyright: {\textcopyright} 2021 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.",

year = "2021",

month = nov,

doi = "10.1111/adb.13015",

language = "English",

volume = "26",

pages = "1--13",

journal = "Addiction Biology",

issn = "1355-6215",

publisher = "Wiley-Blackwell",

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Arends, RM, Pasman, JA, Verweij, KJH, Derks, EM, Gordon, SD, Hickie, I, Thomas, NS, Aliev, F, Zietsch, BP, van der Zee, MD, Mitchell, BL, Martin, NG, Dick, DM, Gillespie, NA, de Geus, EJC, Boomsma, DI, Schellekens, AFA & Vink, JM 2021, 'Associations between the CADM2 gene, substance use, risky sexual behavior, and self‐control: A phenome‐wide association study', Addiction Biology, vol. 26, no. 6, e13015, pp. 1-13. https://doi.org/10.1111/adb.13015

TY - JOUR

T1 - Associations between the CADM2 gene, substance use, risky sexual behavior, and self‐control

T2 - A phenome‐wide association study

AU - Arends, Rachel M.

AU - Pasman, Joëlle A.

AU - Verweij, Karin J.H.

AU - Derks, Eske M.

AU - Gordon, Scott D.

AU - Hickie, Ian

AU - Thomas, Nathaniel S.

AU - Aliev, Fazil

AU - Zietsch, Brendan P.

AU - van der Zee, Matthijs D.

AU - Mitchell, Brittany L.

AU - Martin, Nicholas G.

AU - Dick, Danielle M.

AU - Gillespie, Nathan A.

AU - de Geus, Eco J.C.

AU - Boomsma, Dorret I.

AU - Schellekens, Arnt F.A.

AU - Vink, Jacqueline M.

N1 - Funding Information: This study has been conducted using four databases including the 25 and Up, Spit for Science, Netherlands Twin Register, and the UK Biobank. We want to thank all participants and the individuals who contributed to the inclusion, data collection, and data distribution. A special thanks to Ward de Witte, Nina Moth‐Rota, and Barbara Franke for helping with requesting and providing the UK Biobank data. Tissue‐specific gene expression results mentioned in the discussion and Figure S2C were obtained from the Genotype‐Tissue Expression (GTEx) Project (retrieved on 12/05/2019). This project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. K.J.H.V. is supported by the Foundation Volksbond Rotterdam and by a grant from Amsterdam Neuroscience. Spit for Science has been supported by Virginia Commonwealth University, P20 AA017828, R37AA011408, K02AA018755, P50 AA022537; K01AA024152 from the National Institute on Alcohol Abuse and Alcoholism; and UL1RR031990 from the National Center for Research Resources and National Institutes of Health Roadmap for Medical Research. This research was also supported by the National Institute on Drug Abuse of the National Institutes of Health (NIH) under Award U54DA036105 and the Center for Tobacco Products of the U.S. Food and Drug Administration (FDA). The 25up study was funded by the National Health and Medical Research Council Project Grant APP1069141 to IBH and NGM. Funding Information: This study has been conducted using four databases including the 25 and Up, Spit for Science, Netherlands Twin Register, and the UK Biobank. We want to thank all participants and the individuals who contributed to the inclusion, data collection, and data distribution. A special thanks to Ward de Witte, Nina Moth-Rota, and Barbara Franke for helping with requesting and providing the UK Biobank data. Tissue-specific gene expression results mentioned in the discussion and Figure?S2C were obtained from the Genotype-Tissue Expression (GTEx) Project (retrieved on 12/05/2019). This project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. K.J.H.V. is supported by the Foundation Volksbond Rotterdam and by a grant from Amsterdam Neuroscience. Spit for Science has been supported by Virginia Commonwealth University, P20 AA017828, R37AA011408, K02AA018755, P50 AA022537; K01AA024152 from the National Institute on Alcohol Abuse and Alcoholism; and UL1RR031990 from the National Center for Research Resources and National Institutes of Health Roadmap for Medical Research. This research was also supported by the National Institute on Drug Abuse of the National Institutes of Health (NIH) under Award U54DA036105 and the Center for Tobacco Products of the U.S. Food and Drug Administration (FDA). The 25up study was funded by the National Health and Medical Research Council Project Grant APP1069141 to IBH and NGM. Publisher Copyright: © 2021 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

PY - 2021/11

Y1 - 2021/11

N2 - Risky behaviors, such as substance use and unprotected sex, are associated with various physical and mental health problems. Recent genome-wide association studies indicated that variation in the cell adhesion molecule 2 (CADM2) gene plays a role in risky behaviors and self-control. In this phenome-wide scan for risky behavior, it was tested if underlying common vulnerability could be (partly) explained by pleiotropic effects of this gene and how large the effects were. Single nucleotide polymorphism (SNP)-level and gene-level association tests within four samples (25 and Up, Spit for Science, Netherlands Twin Register, and UK Biobank and meta-analyses over all samples (combined sample of 362,018 participants) were conducted to test associations between CADM2, substance- and sex-related risk behaviors, and various measures related to self-control. We found significant associations between the CADM2 gene, various risky behaviors, and different measures of self-control. The largest effect sizes were found for cannabis use, sensation seeking, and disinhibition. Effect sizes ranged from 0.01% to 0.26% for single top SNPs and from 0.07% to 3.02% for independent top SNPs together, with sufficient power observed only in the larger samples and meta-analyses. In the largest cohort, we found indications that risk-taking proneness mediated the association between CADM2 and latent factors for lifetime smoking and regular alcohol use. This study extends earlier findings that CADM2 plays a role in risky behaviors and self-control. It also provides insight into gene-level effect sizes and demonstrates the feasibility of testing mediation. These findings present a good starting point for investigating biological etiological pathways underlying risky behaviors.

AB - Risky behaviors, such as substance use and unprotected sex, are associated with various physical and mental health problems. Recent genome-wide association studies indicated that variation in the cell adhesion molecule 2 (CADM2) gene plays a role in risky behaviors and self-control. In this phenome-wide scan for risky behavior, it was tested if underlying common vulnerability could be (partly) explained by pleiotropic effects of this gene and how large the effects were. Single nucleotide polymorphism (SNP)-level and gene-level association tests within four samples (25 and Up, Spit for Science, Netherlands Twin Register, and UK Biobank and meta-analyses over all samples (combined sample of 362,018 participants) were conducted to test associations between CADM2, substance- and sex-related risk behaviors, and various measures related to self-control. We found significant associations between the CADM2 gene, various risky behaviors, and different measures of self-control. The largest effect sizes were found for cannabis use, sensation seeking, and disinhibition. Effect sizes ranged from 0.01% to 0.26% for single top SNPs and from 0.07% to 3.02% for independent top SNPs together, with sufficient power observed only in the larger samples and meta-analyses. In the largest cohort, we found indications that risk-taking proneness mediated the association between CADM2 and latent factors for lifetime smoking and regular alcohol use. This study extends earlier findings that CADM2 plays a role in risky behaviors and self-control. It also provides insight into gene-level effect sizes and demonstrates the feasibility of testing mediation. These findings present a good starting point for investigating biological etiological pathways underlying risky behaviors.

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KW - multi-cohort

KW - phenome-wide

KW - risky behavior

KW - self-control

KW - substance use

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Associations between the CADM2 gene, substance use, risky sexual behavior, and self‐control: A phenome‐wide association study

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Bibliographical note

Keywords

UN SDGs

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