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Longitudinal characterization of impulsivity phenotypes boosts signal for genomic correlates and heritability

Molecular Psychiatry volume 30, pages 608–618 (2025)Cite this article

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Abstract

Genomic correlates of impulsivity have been identified in several genome-wide association studies (GWAS) using cross-sectional designs, but no studies have investigated the molecular genetic correlates of impulsivity phenotypes using longitudinally constructed traits. In 3860 unrelated European participants in the Avon Longitudinal Study of Parents and Children (ALSPAC), we constructed longitudinal phenotypes for delay discounting and impulsive personality traits (as measured by the UPPS-P impulsive behavior scales) via assessment at ages 24, 26, and 28. We conducted GWASs of impulsivity using both cross-sectional and longitudinal phenotypes, estimated heritability and their phenotypic and genetic correlations, and evaluated their association with recently-developed polygenic risk scores (PRSs) for the impulsivity indicators themselves and also related psychiatric conditions. Latent growth curve modeling revealed a stable intercept over time for all impulsivity phenotypes. High genetic correlation of cross-sectional measures over time suggested a stable genetic component for delay discounting (rg = 0.53–0.99) and sensation seeking (rg = 0.99). Heritability estimates of the stable longitudinal phenotypes substantively improved as compared to their cross-sectional counterparts, revealing a significant SNP-heritability for delay discounting (0.22; p = 0.03) and sensation seeking (0.35; p = 0.0007). Consistent with previous reports, GWAS and gene-based analyses revealed associations between specific longitudinal impulsivity indicators and CADM2 and NCAM1 genes. The PRSs for the impulsivity indicators and disorders related to self-regulation were also significantly associated with longitudinal impulsivity traits. Finally, we validated the associations between longitudinal impulsivity phenotypes and their PRSs in an independent 13-wave longitudinal study (n = 1019) and the benefit of longitudinal phenotypes in simulation studies. In this first longitudinal genetic study of impulsivity traits, the results revealed stable genomic correlates of delay discounting and sensation seeking over time and further validated the utility of recently-developed PRSs, both in relation to the observed traits and in connecting them to psychiatric disorders. More generally, these findings support using latent intercepts as novel longitudinal phenotypes to boost signal for heritability and genomic correlates of mechanisms contributing to psychiatric disease liability.

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Fig. 1: Heatmap of phenotypic and genetic correlation of cross-sectional and longitudinal impulsivity intercepts.
Fig. 2: SNP-based heritability of cross-sectional and longitudinal impulsivity intercept phenotypes estimated using LDscore.
Fig. 3: PRSs association with cross-sectional and longitudinal impulsivity intercept phenotypes.

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Data availability

Genotype and phenotype data are available through the ALSPAC data team pending a successful application. Access to the ALSPAC data was granted under project # B3136. Summary statistics generated in the current study, including a total of 6 LGC GWASs and 18 cross-sectional GWASs, will be made available on GWAS catalog (https://www.ebi.ac.uk/gwas).

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Acknowledgements

We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. We are especially thankful to all the staff and participants of the Population Assessment for Tomorrow’s Health registry conducted at St. Joseph’s Healthcare Hamilton/McMaster University. This research was enabled in part by support provided by SHARCNET (https://www.sharcnet.ca/) and the Digital Research Alliance of Canada (alliance can .ca). The PRS analyses included summary statistics from published GWASs made available by the Psychiatric Genomics Consortium (PGC), the Million Veterans Program (MVP), the GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN), and 23andMe.

Funding

The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Genomewide genotyping data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding is available on the ALSPAC website. This research was specifically funded by the Peter Boris Center for Addictions Research. JM is supported by the Peter Boris Chair in Addictions Research and a Canada Research Chair in Translational Addiction Research (JM; CRC-2020-00179). MRM is a member of the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00032/07). This publication is the work of the authors and WQD will serve as guarantor for the contents of this paper.

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Authors and Affiliations

  1. Peter Boris Centre for Addictions Research, St. Joseph’s Healthcare Hamilton, Hamilton, ON, Canada

    Wei Q. Deng, Kyla Belisario & James MacKillop

  2. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada

    Wei Q. Deng, Kyla Belisario & James MacKillop

  3. School of Psychological Science, University of Bristol, Bristol, UK

    Marcus R. Munafò

  4. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK

    Marcus R. Munafò

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  1. Wei Q. Deng
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  2. Kyla Belisario
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Contributions

JM conceived, designed the study, and acquired funding; WQD and KB designed the statistical models, analyzed data, and produced visualizations; WQD designed and carried out the genomic analyses; KB carried out phenotypic analyses; JM and MRM acquired data; WQD, KB, and JM drafted the manuscript. All authors discussed results, critically reviewed the content, provided revisions of the manuscript for important intellectual content, and approved the final version.

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Correspondence to Wei Q. Deng or James MacKillop.

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Competing interests

JM is a principal in Beam Diagnostics, Inc. and a consultant to Clairvoyant Therapeutics, Inc. No other authors have disclosures.

Ethics statement

Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. All PATH CANN participants underwent informed consent, and the registry was approved by the Hamilton Integrated Review Ethics Board (#1074).

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Deng, W.Q., Belisario, K., Munafò, M.R. et al. Longitudinal characterization of impulsivity phenotypes boosts signal for genomic correlates and heritability. Mol Psychiatry 30, 608–618 (2025). https://doi.org/10.1038/s41380-024-02704-4

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