A Phenome-Wide Association Study (PheWAS) of Genetic Risk for C-Reactive Protein in Children of European Ancestry: Results From the ABCD Study.

BACKGROUND: C-reactive protein (CRP) is a moderately heritable marker of systemic inflammation that is associated with adverse physical and mental health outcomes. Identifying factors associated with genetic liability to elevated CRP in childhood may inform our understanding of variability in CRP that could be targeted to prevent and/or delay the onset of related health outcomes. METHODS: We conducted a phenome-wide association study (PheWAS) of genetic risk for elevated CRP (i.e. CRP polygenic risk score [PRS]) among children genetically similar to European ancestry reference populations (median analytic n = 5,509) from the Adolescent Brain and Cognitive Development℠ (ABCD) Study. Associations between CRP PRS and 2,377 psychosocial and neuroimaging phenotypes were estimated using independent mixed effects models. Post hoc analyses examined whether: (1) covarying for measured body mass index (BMI) or removing the shared genetic architecture between CRP and BMI altered phenotypic associations, (2) sex moderated CRP PRS associations, and (3) associations are unconfounded by assortative mating or passive gene-environment correlations (using a within-family analyses). Multiple testing was adjusted for using Bonferroni and false discovery rate (FDR) correction. RESULTS: Nine phenotypes were positively associated with CRP PRS after multiple testing correction: five weight- and eating-related phenotypes (e.g. BMI, overeating), three phenotypes related to caregiver somatic problems (e.g. caregiver somatic complaints), as well as weekday video watching (all ps = 1.2 × 10-7 - 2.5 × 10-4, all p FDR s = 0.0002 - 0.05). No neuroimaging phenotypes were associated with CRP PRS (all ps = 0.0003 - 0.998; all p FDR s = 0.08 - 0.998) after correction for multiple testing. Eating and weight-related phenotypes remained associated with CRP PRS in within-family analyses. Covarying for BMI resulted in largely consistent results, and sex did not moderate any CRP PRS associations. Removing the shared genetic variance between CRP and BMI attenuated all relationships; associations with weekday video watching, caregiver somatic problems and caregiver report that the child is overweight remained significant while associations with waist circumference, weight, and caregiver report that child overeats did not. DISCUSSION: Genetic liability to elevated CRP is associated with higher weight, eating, and weekday video watching during childhood as well as caregiver somatic problems. These associations were consistent with direct genetic effects (i.e., not solely due to confounding factors like passive gene-environment correlations) and were independent of measured BMI. The majority of associations with weight and eating phenotypes were attributable to shared genetic architecture between BMI and inflammation. The relationship between genetics and heightened inflammation in later life may be partially attributable to modifiable behaviors (e.g. weight and activity levels) that are expressed as early as childhood.

Multivariate, Multi-omic Analysis in 799,429 Individuals Identifies 134 Loci Associated with Somatoform Traits.

Somatoform traits, which manifest as persistent physical symptoms without a clear medical cause, are prevalent and pose challenges to clinical practice. Understanding the genetic basis of these disorders could improve diagnostic and therapeutic approaches. With publicly available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multi-omic analysis of four somatoform traits-fatigue, irritable bowel syndrome, pain intensity, and health satisfaction-in 799,429 individuals genetically similar to Europeans. Using genomic structural equation modeling, GWAS identified 134 loci significantly associated with a somatoform common factor, including 44 loci not significant in the input GWAS and 8 novel loci for somatoform traits. Gene-property analyses highlighted an enrichment of genes involved in synaptic transmission and enriched gene expression in 12 brain tissues. Six genes, including members of the CD300 family, had putatively causal effects mediated by protein abundance. There was substantial polygenic overlap (76-83%) between the somatoform and externalizing, internalizing, and general psychopathology factors. Somatoform polygenic scores were associated most strongly with obesity, Type 2 diabetes, tobacco use disorder, and mood/anxiety disorders in independent biobanks. Drug repurposing analyses suggested potential therapeutic targets, including MEK inhibitors. Mendelian randomization indicated potentially protective effects of gut microbiota, including Ruminococcus bromii. These biological insights provide promising avenues for treatment development.

Generalized genetic liability to substance use disorders.

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs.

Combining Transdiagnostic and Disorder-Level GWAS Enhances Precision of Psychiatric Genetic Risk Profiles in a Multi-Ancestry Sample.

The etiology of substance use disorders (SUDs) and psychiatric disorders reflects a combination of both transdiagnostic (i.e., common) and disorder-level (i.e., independent) genetic risk factors. We applied genomic structural equation modeling to examine these genetic factors across SUDs, psychotic, mood, and anxiety disorders using genome-wide association studies (GWAS) of European- (EUR) and African-ancestry (AFR) individuals. In EUR individuals, transdiagnostic genetic factors represented SUDs (143 lead single nucleotide polymorphisms [SNPs]), psychotic (162 lead SNPs), and mood/anxiety disorders (112 lead SNPs). We identified two novel SNPs for mood/anxiety disorders that have probable regulatory roles on FOXP1, NECTIN3, and BTLA genes. In AFR individuals, genetic factors represented SUDs (1 lead SNP) and psychiatric disorders (no significant SNPs). The SUD factor lead SNP, although previously significant in EUR- and cross-ancestry GWAS, is a novel finding in AFR individuals. Shared genetic variance accounted for overlap between SUDs and their psychiatric comorbidities, with second-order GWAS identifying up to 12 SNPs not significantly associated with either first-order factor in EUR individuals. Finally, common and independent genetic effects showed different associations with psychiatric, sociodemographic, and medical phenotypes. For example, the independent components of schizophrenia and bipolar disorder had distinct associations with affective and risk-taking behaviors, and phenome-wide association studies identified medical conditions associated with tobacco use disorder independent of the broader SUDs factor. Thus, combining transdiagnostic and disorder-level genetic approaches can improve our understanding of co-occurring conditions and increase the specificity of genetic discovery, which is critical for psychiatric disorders that demonstrate considerable symptom and etiological overlap.

Candidate Genes from an FDA-Approved Algorithm Fail to Predict Opioid Use Disorder Risk in Over 450,000 Veterans.

Importance: Recently, the Food and Drug Administration gave pre-marketing approval to algorithm based on its purported ability to identify genetic risk for opioid use disorder. However, the clinical utility of the candidate genes comprising the algorithm has not been independently demonstrated. Objective: To assess the utility of 15 variants in candidate genes from an algorithm intended to predict opioid use disorder risk. Design: This case-control study examined the association of 15 candidate genetic variants with risk of opioid use disorder using available electronic health record data from December 20, 1992 to September 30, 2022. Setting: Electronic health record data, including pharmacy records, from Million Veteran Program participants across the United States. Participants: Participants were opioid-exposed individuals enrolled in the Million Veteran Program (n = 452,664). Opioid use disorder cases were identified using International Classification of Disease diagnostic codes, and controls were individuals with no opioid use disorder diagnosis. Exposures: Number of risk alleles present across 15 candidate genetic variants. Main Outcome and Measures: Predictive performance of 15 genetic variants for opioid use disorder risk assessed via logistic regression and machine learning models. Results: Opioid exposed individuals (n=33,669 cases) were on average 61.15 (SD = 13.37) years old, 90.46% male, and had varied genetic similarity to global reference panels. Collectively, the 15 candidate genetic variants accounted for 0.4% of variation in opioid use disorder risk. The accuracy of the ensemble machine learning model using the 15 genes as predictors was 52.8% (95% CI = 52.1 - 53.6%) in an independent testing sample. Conclusions and Relevance: Candidate genes that comprise the approved algorithm do not meet reasonable standards of efficacy in predicting opioid use disorder risk. Given the algorithm's limited predictive accuracy, its use in clinical care would lead to high rates of false positive and negative findings. More clinically useful models are needed to identify individuals at risk of developing opioid use disorder.

Alcohol milestones and internalizing, externalizing, and executive function: longitudinal and polygenic score associations.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Two common and distinct forms of variation in human functional brain networks.

The cortex has a characteristic layout with specialized functional areas forming distributed large-scale networks. However, substantial work shows striking variation in this organization across people, which relates to differences in behavior. While most previous work treats individual differences as linked to boundary shifts between the borders of regions, here we show that cortical 'variants' also occur at a distance from their typical position, forming ectopic intrusions. Both 'border' and 'ectopic' variants are common across individuals, but differ in their location, network associations, properties of subgroups of individuals, activations during tasks, and prediction of behavioral phenotypes. Border variants also track significantly more with shared genetics than ectopic variants, suggesting a closer link between ectopic variants and environmental influences. This work argues that these two dissociable forms of variation-border shifts and ectopic intrusions-must be separately accounted for in the analysis of individual differences in cortical systems across people.

A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals.

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. FINDINGS: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. INTERPRETATION: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine. FUNDING: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).

Pleiotropy and genetically inferred causality linking multisite chronic pain to substance use disorders.

Individuals suffering from chronic pain develop substance use disorders (SUDs) more often than others. Understanding the shared genetic influences underlying the comorbidity between chronic pain and SUDs will lead to a greater understanding of their biology. Genome-wide association statistics were obtained from the UK Biobank for multisite chronic pain (MCP, Neffective = 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, Neffective = 296,974), cannabis use disorder (CanUD, Neffective = 161,053), opioid use disorder (OUD, Neffective = 57,120), and problematic tobacco use (PTU, Neffective = 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (rg) analyses were performed to assess MCP-SUD pleiotropy. Bidirectional Mendelian Randomization analyses evaluated possible causal relationships. Finally, to identify and characterize individual loci, we performed a genome-wide pleiotropy analysis and a brain-wide analysis using imaging phenotypes available from the UK Biobank. MCP was positively genetically correlated with AUD (rg = 0.26, p = 7.55 × 10-18), CanUD (rg = 0.37, p = 8.21 × 10-37), OUD (rg = 0.20, p = 1.50 × 10-3), and PTU (rg = 0.29, p = 8.53 × 10-12). Although the MR analyses supported bi-directional relationships, MCP had larger effects on AUD (pain-exposure: beta = 0.18, p = 8.21 × 10-4; pain-outcome: beta = 0.07, p = 0.018), CanUD (pain-exposure: beta = 0.58, p = 2.70 × 10-6; pain-outcome: beta = 0.05, p = 0.014) and PTU (pain-exposure: beta = 0.43, p = 4.16 × 10-8; pain-outcome: beta = 0.09, p = 3.05 × 10-6) than the reverse. The genome-wide analysis identified two SNPs pleiotropic between MCP and all SUD investigated: IHO1 rs7652746 (ppleiotropy = 2.69 × 10-8), and CADM2 rs1248857 (ppleiotropy = 1.98 × 10-5). In the brain-wide analysis, rs7652746 was associated with multiple cerebellum and amygdala imaging phenotypes. When analyzing MCP pleiotropy with each SUD separately, we found 25, 22, and 4 pleiotropic variants for AUD, CanUD, and OUD, respectively. To our knowledge, this is the first large-scale study to provide evidence of potential causal relationships and shared genetic mechanisms underlying MCP-SUD comorbidity.

Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders.

We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff = 51,568), cannabis use disorder (CanUD, Neff = 161,053), opioid use disorder (OUD, Neff = 57,120), problematic alcohol use (PAU, Neff = 502,272), and problematic tobacco use (PTU, Neff = 97,836). ADHD, CanUD, and OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAS combined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated a multi-trait analysis including information regarding Fagerström Test for Nicotine Dependence and cigarettes per day. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD, PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to two latent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. The evidence of a causal effect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomization analysis. Conversely, similar strength of evidence was found between ADHD and CanUD. CADM2 rs62250713 was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variants between ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associated with increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms to the comorbidity between ADHD and SUDs.

GenomeMUSter mouse genetic variation service enables multitrait, multipopulation data integration and analysis.

Hundreds of inbred mouse strains and intercross populations have been used to characterize the function of genetic variants that contribute to disease. Thousands of disease-relevant traits have been characterized in mice and made publicly available. New strains and populations including consomics, the collaborative cross, expanded BXD, and inbred wild-derived strains add to existing complex disease mouse models, mapping populations, and sensitized backgrounds for engineered mutations. The genome sequences of inbred strains, along with dense genotypes from others, enable integrated analysis of trait-variant associations across populations, but these analyses are hampered by the sparsity of genotypes available. Moreover, the data are not readily interoperable with other resources. To address these limitations, we created a uniformly dense variant resource by harmonizing multiple data sets. Missing genotypes were imputed using the Viterbi algorithm with a data-driven technique that incorporates local phylogenetic information, an approach that is extendable to other model organisms. The result is a web- and programmatically accessible data service called GenomeMUSter, comprising single-nucleotide variants covering 657 strains at 106.8 million segregating sites. Interoperation with phenotype databases, analytic tools, and other resources enable a wealth of applications, including multitrait, multipopulation meta-analysis. We show this in cross-species comparisons of type 2 diabetes and substance use disorder meta-analyses, leveraging mouse data to characterize the likely role of human variant effects in disease. Other applications include refinement of mapped loci and prioritization of strain backgrounds for disease modeling to further unlock extant mouse diversity for genetic and genomic studies in health and disease.

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.

Associations Between Polygenic Scores for Cognitive and Non-cognitive Factors of Educational Attainment and Measures of Behavior, Psychopathology, and Neuroimaging in the Adolescent Brain Cognitive Development Study.

Background: Both cognitive and non-cognitive (e.g., traits like curiosity) factors are critical for social and emotional functioning and independently predict educational attainment. These factors are heritable and genetically correlated with a range of health-relevant traits and behaviors in adulthood (e.g., risk-taking, psychopathology). However, whether these associations are present during adolescence, and to what extent these relationships diverge, could have implications for adolescent health and well-being. Methods: Using data from 5,517 youth of European ancestry from the ongoing Adolescent Brain Cognitive DevelopmentSM Study, we examined associations between polygenic scores (PGS) for cognitive and non-cognitive factors and outcomes related to cognition, socioeconomic status, risk tolerance and decision-making, substance initiation, psychopathology, and brain structure. Results: Cognitive and non-cognitive PGSs were both positively associated with cognitive performance and family income, and negatively associated with ADHD and severity of psychotic-like experiences. The cognitive PGS was also associated with greater risk-taking, delayed discounting, and anorexia, as well as lower likelihood of nicotine initiation. The cognitive PGS was further associated with cognition scores and anorexia in within-sibling analyses, suggesting these results do not solely reflect the effects of assortative mating or passive gene-environment correlations. The cognitive PGS showed significantly stronger associations with cortical volumes than the non-cognitive PGS and was associated with right hemisphere caudal anterior cingulate and pars-orbitalis in within-sibling analyses, while the non-cognitive PGS showed stronger associations with white matter fractional anisotropy and a significant within-sibling association for right superior corticostriate-frontal cortex. Conclusions: Our findings suggest that PGSs for cognitive and non-cognitive factors show similar associations with cognition and socioeconomic status as well as other psychosocial outcomes, but distinct associations with regional neural phenotypes in this adolescent sample.

Prenatal cannabis exposure is associated with localized brain differences that partially mediate associations with increased adolescent psychopathology.

Prenatal cannabis exposure (PCE) is associated with mental health problems, but the neurobiological mechanisms remain unknown. We find that PCE is associated with localized differences across neuroimaging metrics that longitudinally mediate associations with mental health in adolescence (n=9,322-10,186). Differences in brain development may contribute to PCE-related variability in adolescent mental health.

Alcohol use and grey matter structure: Disentangling predispositional and causal contributions in human studies.

Alcohol use is a growing global health concern and economic burden. Alcohol involvement (i.e., initiation, use, problematic use, alcohol use disorder) has been reliably associated with broad spectrum grey matter differences in cross-sectional studies. These findings have been largely interpreted as reflecting alcohol-induced atrophy. However, emerging data suggest that brain structure differences also represent pre-existing vulnerability factors for alcohol involvement. Here, we review evidence from human studies with designs (i.e., family-based, genomic, longitudinal) that allow them to assess the plausibility that these correlates reflect predispositional risk factors and/or causal consequences of alcohol involvement. These studies provide convergent evidence that grey matter correlates of alcohol involvement largely reflect predisposing risk factors, with some evidence for potential alcohol-induced atrophy. These conclusions highlight the importance of study designs that can provide causal clues to cross-sectional observations. An integrative model may best account for these data, in which predisposition to alcohol use affects brain development, effects which may then be compounded by the neurotoxic consequences of heavy alcohol use.

A multivariate approach to understanding the genetic overlap between externalizing phenotypes and substance use disorders.

Substance use disorders (SUDs) are phenotypically and genetically correlated with each other and with other psychological traits characterized by behavioural under-control, termed externalizing phenotypes. In this study, we used genomic structural equation modelling to explore the shared genetic architecture among six externalizing phenotypes and four SUDs used in two previous multivariate genome-wide association studies of an externalizing and an addiction risk factor, respectively. We first evaluated five confirmatory factor analytic models, including a common factor model, alternative parameterizations of two-factor structures and a bifactor model. We next explored the genetic correlations between factors identified in these models and other relevant psychological traits. Finally, we quantified the degree of polygenic overlap between externalizing and addiction risk using MiXeR. We found that the common and two-factor structures provided the best fit to the data, evidenced by high factor loadings, good factor reliability and no evidence of concerning model characteristics. The two-factor models yielded high genetic correlations between factors (rg s ≥ 0.87), and between the effect sizes of genetic correlations with external traits (rg  ≥ 0.95). Nevertheless, 21 of the 84 correlations with external criteria showed small, significant differences between externalizing and addiction risk factors. MiXer results showed that approximately 81% of influential externalizing variants were shared with addiction risk, whereas addiction risk shared 56% of its influential variants with externalizing. These results suggest that externalizing and addiction genetic risk are largely shared, though both constructs also retain meaningful unshared genetic variance. These results can inform future efforts to identify specific genetic influences on externalizing and SUDs.

GenomeMUSter mouse genetic variation service enables multi-trait, multi-population data integration and analyses.

Hundreds of inbred laboratory mouse strains and intercross populations have been used to functionalize genetic variants that contribute to disease. Thousands of disease relevant traits have been characterized in mice and made publicly available. New strains and populations including the Collaborative Cross, expanded BXD and inbred wild-derived strains add to set of complex disease mouse models, genetic mapping resources and sensitized backgrounds against which to evaluate engineered mutations. The genome sequences of many inbred strains, along with dense genotypes from others could allow integrated analysis of trait - variant associations across populations, but these analyses are not feasible due to the sparsity of genotypes available. Moreover, the data are not readily interoperable with other resources. To address these limitations, we created a uniformly dense data resource by harmonizing multiple variant datasets. Missing genotypes were imputed using the Viterbi algorithm with a data-driven technique that incorporates local phylogenetic information, an approach that is extensible to other model organism species. The result is a web- and programmatically-accessible data service called GenomeMUSter ( https://muster.jax.org ), comprising allelic data covering 657 strains at 106.8M segregating sites. Interoperation with phenotype databases, analytic tools and other resources enable a wealth of applications including multi-trait, multi-population meta-analysis. We demonstrate this in a cross-species comparison of the meta-analysis of Type 2 Diabetes and of substance use disorders, resulting in the more specific characterization of the role of human variant effects in light of mouse phenotype data. Other applications include refinement of mapped loci and prioritization of strain backgrounds for disease modeling to further unlock extant mouse diversity for genetic and genomic studies in health and disease.

Characteristics Associated With Cannabis Use Initiation by Late Childhood and Early Adolescence in the Adolescent Brain Cognitive Development (ABCD) Study.

This cohort study evaluates characteristics associated with early-onset cannabis use.