Predicting Genetic Risk for Impulsivity and Substance Use in Adolescence

Abstract Studying genetic contributions to substance initiation is crucial for identifying at-risk individuals and developing targeted prevention strategies. Investigating these factors during adolescence is vital, as this period is critical for brain development and represents an age of experimentation and initiation of substance use. Here we generate polygenic scores (PGSs), using data from the PGS catalog, across a range of substance use related traits to assess PGS in predicting i) measures of impulsivity taken from the UPPS-P questionnaire and ii) self-reported use of nicotine/tobacco, cannabis, alcohol and caffeine in early-mid adolescence. Repeat cross-sectional analyses across age bands (ages 9-10, 11-13, and 13-15) were conducted using the longitudinal Adolescent Brain Cognitive Development (ABCD) Study® (total N=8,753; 55% female). Due to the large contribution of European-like (EUR-like) individuals in discovery samples, we performed ancestry stratified analysis in EUR-like (n=5,225), African (AFR-like; n=637) and ad-mixed (MIX-like; n=2,891) groups reflecting genetic similarity to continental ancestry groups. In the EUR-like group, PGS related to nicotine/tobacco were associated with greater impulsivity across all subscales of the UPPS-P at all ages. Analyses across ages 9-15 years old revealed PGS-impulsivity associations that: a) grew as the sample aged (e.g. Smoking Status PGS with Lack of Perseverance: 9-10 years-old: β=0.065, 11-13 years-old: β=0.11, 13-15 years-old: β=0.12) and b) others that diminished as the sample aged (e.g. Alcohol Consumption PGS with Sensation Seeking: 9-10 years-old: β=0.070, 11-13 years-old: β=0.062, 13-15 years-old: β=0.03). Evaluating the performance of PGS against self-reported substance use, PGS of nicotine/tobacco traits were associated with regular consumption of caffeine across ages. At ages 13-15, PGS of smoking traits were associated with cannabis and tobacco exposure (e.g., Smoking Initiation PGS and self-reported cannabis use, ΔR2=0.0094), in addition to weekly caffeine consumption. Across ages, nicotine/tobacco and alcohol PGS and regular energy drink consumption associations grew over time (e.g., Smoking Status PGS: 9-10 years-old: β=0.088, 11-13 years-old: β=0.24, 13-15 years-old: β=0.29). As with impulsivity, some PGS associations decreased over time (Alcohol Consumption PGS and self-reported alcohol use: 9-10 years-old: β=0.12, 11-13 years-old: β=0.11, 13-15 years-old: β=0.083). Replication of our EUR-like results in AFR-like and MIX-like sub-samples revealed a significant attenuation of effects, underscoring the importance of collecting genetic studies in larger ancestrally diverse cohorts. Our results highlight the dynamic relationship between genetic risk factors of substance use, trait impulsivity, and self-reported substance initiation throughout adolescence. Further, evidence here indicates caffeine consumption represents an early risk factor for problematic substance use in later life. Results support PGSs, in conjunction with larger phenotypic profiles, for identification of prevention efforts. Competing Interest Statement The authors have declared no competing interest. Funding Statement N.E. Wade was supported by National Institute on Drug Abuse (DA050779; DA054980). This work was also supported by T32 AA013525 (PI: Riley/Spadoni to Szpak, Wallace, and Sullivan). C.C. Fan and R. Loughnan were supported by grants R01MH122688 and RF1MH120025 funded by the National Institute for Mental Health (NIMH). Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study (https://abcdstudy.org), held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit more than 10,000 children age 9-10 and follow them over 10 years into early adulthood. The ABCD Study® is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data that were originally located at http://dx.doi.org/10.15154/z563-zd24. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes N.E. Wade was supported by National Institute on Drug Abuse (DA050779; DA054980). This work was also supported by T32 AA013525 (PI: Riley/Spadoni to Szpak, Wallace, and Sullivan). C.C. Fan and R. Loughnan were supported by grants R01MH122688 and RF1MH120025 funded by the National Institute for Mental Health (NIMH). Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study (https://abcdstudy.org), held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit more than 10,000 children age 9-10 and follow them over 10 years into early adulthood. The ABCD Study® is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in the analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators. The ABCD data repository grows and changes over time. The ABCD data used in this report came from http://dx.doi.org/10.15154/z563-zd24. DOIs can be found at http://dx.doi.org/10.15154/z563-zd24. Data Availability The ABCD data repository grows and changes over time. The ABCD data used in this report came from http://dx.doi.org/10.15154/z563-zd24. DOIs can be found at http://dx.doi.org/10.15154/z563-zd24.