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Parsing genetically influenced risk pathways: genetic loci impact problematic alcohol use via externalizing and specific risk.

ABSTRACT: Genome-wide association studies (GWAS) identify genetic variants associated with a trait, regardless of how those variants are associated with the outcome. Characterizing whether variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk. In the current analysis, we used multivariate GWAS to tease apart variants associated with problematic alcohol use (ALCP-total) through either a shared risk for externalizing (EXT) or a problematic alcohol use-specific risk (ALCP-specific). SNPs associated with ALCP-specific were primarily related to alcohol metabolism. Genetic correlations showed ALCP-specific was predominantly associated with alcohol use and other forms of psychopathology, but not other forms of substance use. Polygenic scores for ALCP-total were associated with multiple forms of substance use, but polygenic scores for ALCP-specific were only associated with alcohol phenotypes. Polygenic scores for both ALCP-specific and EXT show different patterns of associations with alcohol misuse across development. Our results demonstrate that focusing on both shared and specific risk can better characterize pathways of risk for substance use disorders. Parsing risk pathways will become increasingly relevant as genetic information is incorporated into clinical practice.

SUBMITTER: Barr PB

PROVIDER: S-EPMC9525649 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Parsing genetically influenced risk pathways: genetic loci impact problematic alcohol use via externalizing and specific risk.

Barr Peter B PB Mallard Travis T TT Sanchez-Roige Sandra S Poore Holly E HE Linnér Richard Karlsson RK Waldman Irwin D ID Palmer Abraham A AA Harden K Paige KP Dick Danielle M DM

Translational psychiatry 20220930 1

Genome-wide association studies (GWAS) identify genetic variants associated with a trait, regardless of how those variants are associated with the outcome. Characterizing whether variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk. In the current analysis, we used multivariate GWAS to tease apart variants associated with problematic alcohol use (ALCP-total) through either a shared risk for externalizing (EXT) or a prob ...[more]

PMID: 36180423

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Project description:Genome wide association studies (GWAS) have associated thousands of loci with quantitative human blood trait variation. Loci and related genes that impact blood trait variation may regulate blood cell-intrinsic biological processes, or alternatively impact blood cell development and function via systemic factors. Clinical observations have linked tobacco or alcohol use with altered blood traits, but these trait relationships have not been systematically explored at the genetic level. Applying a Mendelian randomization (MR) framework to GWAS summary statistics, we explore relationships between smoking and drinking behaviors with 15 quantitative blood traits. We find that the effects of smoking and drinking are confined to red blood cell traits. An instrumental variable (IV) comprised of 113 single nucleotide polymorphisms (SNPs) associated with smoking initiation is associated with decreased hemoglobin (HGB: Effect = -0.07 standard deviation units [95% confidence interval = -0.03 to -0.10 SD units], P = 1x10-4), hematocrit (HCT: Effect = -0.06 [-0.03 - -0.09] SD units, P = 4x10-4), and red blood cell count (RBC: Effect = -0.05 [-0.02 - -0.09] SD units, P = 5x10-3) without impacting platelet count (P = 0.9) or white blood cell count (P = 0.6). Similarly, an IV associated with an increased number of alcoholic drinks consumed per week is associated with decreased HGB (Effect = -0.22 [-0.42 - -0.02] SD units, P = 3x10-2) and RBC (Effect = -0.27 [-0.51 - -0.03] SD units, P = 3x10-2). Using multivariable MR and causal mediation analyses, we find that an increased genetic predisposition to smoking initiation is associated with increased alcohol intake, and that alcohol use mediates the genetic effect of smoking initiation on red blood cell traits. These findings demonstrate a novel role for genetically influenced behaviors on human blood traits, revealing opportunities to dissect related pathways and mechanisms that influence hematopoiesis and blood cell biology.

Project description:Risk for substance use disorder (SUD) is associated with poor response inhibition and heightened reward sensitivity. During adolescence, incentives improve performance on response inhibition tasks and increase recruitment of cortical control areas (Geier et al., 2010) associated with SUD (Chung et al., 2011). However, it is unknown whether incentives moderate the relationship between response inhibition and trait-level psychopathology and personality features of substance use risk. We examined these associations in the current project using a rewarded antisaccade (AS) task (Geier et al., 2010) in youth at risk for substance use. Participants were 116 adolescents and young adults (ages 12-21) from the University of Pittsburgh site of the National Consortium on Adolescent Neurodevelopment and Alcohol [NCANDA] study, with neuroimaging data collected at baseline and 1 year follow up visits. Building upon previous work using this task in normative developmental samples (Geier et al., 2010) and adolescents with SUD (Chung et al., 2011), we examined both trial-wise BOLD responses and those associated with individual task-epochs (cue presentation, response preparation, and response) and associated them with multiple substance use risk factors (externalizing and internalizing psychopathology, family history of substance use, and trait impulsivity). Results showed that externalizing psychopathology and high levels of trait impulsivity (positive urgency, SUPPS-P) were associated with general decreases in antisaccade performance. Accompanying this main effect of poor performance, positive urgency was associated with reduced recruitment of the frontal eye fields (FEF) and inferior frontal gyrus (IFG) in both a priori regions of interest and at the voxelwise level. Consistent with previous work, monetary incentive improved antisaccade behavioral performance and was associated with increased activation in the striatum and cortical control areas. However, incentives did not moderate the association between response inhibition behavioral performance and any trait-level psychopathology and personality factor of substance use risk. Reward interactions were observed for BOLD responses at the task-epoch level, however, they were inconsistent across substance use risk types. The results from this study may suggest poor response inhibition and heightened reward sensitivity are not overlapping neurocognitive features of substance use risk. Alternatively, more subtle, common longitudinal processes might jointly explain reward sensitivity and response inhibition deficits in substance use risk.

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Project description:ImportanceProblematic alcohol use in physicians poses a serious concern to physicians' health and their ability to provide care. Understanding the extent and characteristics of physicians with problematic alcohol use will help inform interventions.ObjectiveTo estimate the extent of problematic alcohol use in physicians and how it differs by physician sex, age, medical specialty, and career stage (eg, residency vs practicing physician).Evidence reviewPreferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020-compliant systematic review, searching Medline, Embase, and PsychInfo from January 2006 to March 2020. Search terms included Medical Subject Headings terms and keywords related to physicians as the population and problematic alcohol use as the primary outcome. The quality of studies was assessed using the Newcastle-Ottawa Scale. We included articles where problematic alcohol use was measured by a validated tool (ie, Alcohol Use Disorders Identification Test [AUDIT], AUDIT Version C [AUDIT-C], or CAGE [Cut down, Annoyed, Guilty, and Eye-opener] questionnaire) in practicing physicians (ie, residents, fellows, or staff physicians).FindingsThirty-one studies involving 51 680 participants in 17 countries published between January 2006 and March 2020 were included. All study designs were cross-sectional, self-reported surveys. Problematic alcohol use varied widely regardless of measurement method (0 to 34% with AUDIT; 9% to 35% with AUDIT-C; 4% to 22% with CAGE). Reported problematic alcohol use increased over time from 16.3% in 2006 to 2010 to 26.8% in 2017 to 2020. The extent of problematic use by sex was examined in 19 studies, by age in 12 studies, by specialty in 7 studies, and by career stage in 5 studies. Seven of 19 studies (37%) identified that problematic alcohol use was more common in males than females. Based on the wide heterogeneity of methods for included studies, limited conclusions can be made on how problematic alcohol use varies based on physician age, sex, specialty, and career stage.Conclusions and relevanceStudies about problematic alcohol use in physicians demonstrate a high degree of heterogeneity in terms of methods of measurement, definitions for problematic alcohol use, and cohorts assessed. Most studies are primarily self-reported, precluding the ability to determine the true prevalence among the profession. Few studies provide relevant comparisons to aid in identifying key risk groups for targeted interventions.

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Parsing genetically influenced risk pathways: genetic loci impact problematic alcohol use via externalizing and specific risk.

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Parsing genetically influenced risk pathways: genetic loci impact problematic alcohol use via externalizing and specific risk.

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