Symptoms of problematic alcohol use differ in their genetic associations with comorbid internalizing, externalizing, and neurodevelopmental psychiatric disorders

Background and Aims Certain symptoms of problematic alcohol use (PAU) show associations with comorbid internalizing and externalizing disorders even after controlling for their common PAU factor. Outsized associations between PAU indicators and comorbid psychopathology may reflect distinct etiologic pathways or measurement characteristics that, if unaccounted for, could bias comorbidity estimates with PAU. Although these issues could represent a source of bias in estimates of genetic correlation with PAU, no studies have yet extended this work using genomic data. Design Genomic structural equation modeling and the Qtrait function identified PAU indicators that showed appreciable residual genetic correlations with eleven comorbid psychiatric disorders and whose associations did not operate strictly through the latent PAU factor. Setting Genome-wide association studies (GWAS) were conducted in a variety of international locations. Participants GWAS used in this study were conducted on 86,979 to 425,166 individuals of European ancestry. Measurements The primary measurements were GWAS summary statistics for various forms of internalizing, externalizing, and neurodevelopmental psychiatric disorders and nine indicators from the Alcohol Use Disorder Identification Test. Findings PAU indicators assessing alcohol-related consequences (i.e., Injuries, Failed expectations, Guilt/Remorse) each showed appreciable and positive residual genetic associations with multiple comorbid psychiatric conditions spanning various disorder spectra. Alcohol Quantity, 6+ Frequency, Blackouts, and Others concerned did not show direct genetic relationships with comorbid disorders.

Alcohol-related consequences share unique genetic underpinnings with multiple psychiatric conditions apart from what is shared with their latent problematic alcohol use factor. Thus, alcohol-related consequences may unduly reflect dysfunction from comorbid psychiatric conditions or related third variables. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by National Institutes of Health (NIH) grants K01 AA027757 (Wang), K01 AA028058 (Bountress), and R34 DA061267 (Bountress). 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 University of Pittsburgh Institutional Review Board Committee gave ethical approval for this work 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 Data Availability All data produced are available online at the psychiatric genetics consortium, CTG Lab website, University of Minnestoa site, and the Gelertner Lab site. https://medicine.yale.edu/lab/gelernter/stats/ https://conservancy.umn.edu/items/91f6a003-6af2-4809-9785-53dc579dc788