Sex Differences in the Etiology of Victimization in Adulthood.

Until relatively recently, the study of victimization has been largely outside the purview of behavioral geneticists and evolutionary psychologists. Recent victimology research, however, has shown that genetic and evolutionary forces are connected to the risk of victimization. The current study expands on these findings by examining whether genetic influences differentially explain victimization in males and females. To do so, we use a sample of sibling pairs drawn from the National Longitudinal Study of Adolescent to Adult Health (Add Health; N = 4,244). The analyses revealed no significant quantitative sex differences in the etiology of adult victimization. However, the results of this study do highlight the importance of accounting for genetic factors when studying the etiology of specific types of adult victimization. We conclude by discussing the implications of the current study for future research.

Partitioning the Genomic Components of Behavioral Disinhibition and Substance Use (Disorder) Using Genomic Structural Equation Modeling.

Externalizing behaviors encompass manifestations of risk-taking, self-regulation, aggression, sensation-/reward-seeking, and impulsivity. Externalizing research often includes substance use (SUB), substance use disorder (SUD), and other (non-SUB/SUD) "behavioral disinhibition" (BD) traits. Genome-wide and twin research have pointed to overlapping genetic architecture within and across SUB, SUD, and BD. We created single-factor measurement models-each describing SUB, SUD, or BD traits-based on mutually exclusive sets of European ancestry genome-wide association study (GWAS) statistics exploring externalizing variables. We then assessed the partitioning of genetic covariance among the three facets using correlated factors models and Cholesky decomposition. Even when the residuals for indicators relating to the same substance were correlated across the SUB and SUD factors, the two factors yielded a large correlation (rg = 0.803). BD correlated strongly with the SUD (rg = 0.774) and SUB (rg = 0.778) factors. In our initial decompositions, 33% of total BD variance remained after partialing out SUD and SUB. The majority of covariance between BD and SUB and between BD and SUD was shared across all factors, and, within these models, only a small fraction of the total variation in BD operated via an independent pathway with SUD or SUB outside of the other factor. When only nicotine/tobacco, cannabis, and alcohol were included for the SUB/SUD factors, their correlation increased to rg = 0.861; in corresponding decompositions, BD-specific variance decreased to 27%. Further research can better elucidate the properties of BD-specific variation by exploring its genetic/molecular correlates.

Non-Synonymous Substitutions in Cadherin 13, Solute Carrier Family 6 Member 4, and Monoamine Oxidase A Genes are Associated with Personality Traits in Thoroughbred Horses.

Retraining retired racehorses for various purposes can help correct behavioral issues. However, ensuring efficiency and preventing accidents present global challenges. Based on the hypothesis that a simple personality assessment could help address these challenges, the present study aimed to identify genetic markers associated with personality. Eight genes were selected from 18 personality-related candidate genes that are orthologs of human personality genes, and their association with personality was verified based on actual behavior. A total of 169 Thoroughbred horses were assessed for their tractability (questionnaire concerning tractability in 14 types of situations and 3 types of impressions) during the training process. Personality factors were extracted from the data using principal component analysis and analyzed for their association with single nucleotide variants as non-synonymous substitutions in the target genes. Three genes, CDH13, SLC6A4, and MAOA, demonstrated significant associations based on simple linear regression, marking the identification of these genes for the first time as contributors to temperament in Thoroughbred horses. All these genes, as well as the previously identified HTR1A, are involved in the serotonin neurotransmitter system, suggesting that the tractability of horses may be correlated with their social personality. Assessing the genotypes of these genes before retraining is expected to prevent problems in the development of a racehorse's second career and shorten the training period through individual customization of training methods, thereby improving racehorse welfare.

A Principal Components Analysis and Functional Annotation of Differentially Expressed Genes in Brain Regions of Gray Rats Selected for Tame or Aggressive Behavior.

The process of domestication, despite its short duration as it compared with the time scale of the natural evolutionary process, has caused rapid and substantial changes in the phenotype of domestic animal species. Nonetheless, the genetic mechanisms underlying these changes remain poorly understood. The present study deals with an analysis of the transcriptomes from four brain regions of gray rats (Rattus norvegicus), serving as an experimental model object of domestication. We compared gene expression profiles in the hypothalamus, hippocampus, periaqueductal gray matter, and the midbrain tegmental region between tame domesticated and aggressive gray rats and revealed subdivisions of differentially expressed genes by principal components analysis that explain the main part of differentially gene expression variance. Functional analysis (in the DAVID (Database for Annotation, Visualization and Integrated Discovery) Bioinformatics Resources database) of the differentially expressed genes allowed us to identify and describe the key biological processes that can participate in the formation of the different behavioral patterns seen in the two groups of gray rats. Using the STRING- DB (search tool for recurring instances of neighboring genes) web service, we built a gene association network. The genes engaged in broad network interactions have been identified. Our study offers data on the genes whose expression levels change in response to artificial selection for behavior during animal domestication.

Genetic background and sex influence somatosensory sensitivity and oxycodone analgesia in the Hybrid Rat Diversity Panel.

Opioid use disorder (OUD) is an ongoing public health concern in the United States, and relatively little work has addressed how genetic background contributes to OUD. Understanding the genetic contributions to oxycodone-induced analgesia could provide insight into the early stages of OUD development. Here, we present findings from a behavioral phenotyping protocol using several inbred strains from the Hybrid Rat Diversity Panel. Our behavioral protocol included a modified "up-down" von Frey procedure to measure inherent strain differences in the sensitivity to a mechanical stimulus on the hindpaw. We also performed the tail immersion assay, which measures the latency to display tail withdrawal in response to a hot water bath. Initial withdrawal thresholds were taken in drug-naïve animals to record baseline thermal sensitivity across the strains. Oxycodone-induced analgesia was measured after administration of oxycodone over the course of 2 h. Both mechanical and thermal sensitivity are shaped by genetic factors and display moderate heritability (h2 = 0.23-0.40). All strains displayed oxycodone-induced analgesia that peaked at 15-30 min and returned to baseline by 2 h. There were significant differences between the strains in the magnitude and duration of their analgesic response to oxycodone, although the heritability estimates were quite modest (h2 = 0.10-0.15). These data demonstrate that genetic background confers differences in mechanical sensitivity, thermal sensitivity, and oxycodone-induced analgesia.

The intergenerational transmission of risk and trust attitudes: Replicating and extending "Dohmen, Falk, Huffman and Sunde 2012" using genetically informed twin data.

This replication revisits an influential contribution on the intergenerational transmission of risk and trust attitudes, which, based on data from the German Socioeconomic Panel (GSOEP), reveals a positive correlation between parents' and children's attitudes. The authors of the original study argue that socialization in the family is important in the transmission process. The replication is motivated by mounting evidence indicating that within-family transmission has a considerable genetic component, which calls into question socialization as the main transmission pathway. To consider genetic transmission in addition to social transmission, the replication relies on the German twin family panel TwinLife. The findings reveal that, first, most of the variation in children's risk and social trust attitudes is attributable to differences in the non-shared environment, followed by genetic differences, whereas differences in the shared family environment - the main candidate for social transmission - do not matter. Second, correlations between parents' and children's attitudes essentially involve genetic similarity. Third, family conditions do not moderate these relationships. Thus, the findings do not support the socialization assumption.

Genes and gene networks underlying spatial cognition in food-caching chickadees.

Substantial progress has been made in understanding the genetic architecture of phenotypes involved in a variety of evolutionary processes. Behavioral genetics remains, however, among the least understood. We explore the genetic architecture of spatial cognitive abilities in a wild passerine bird, the mountain chickadee (Poecile gambeli). Mountain chickadees cache thousands of seeds in the fall and require specialized spatial memory to recover these caches throughout the winter. We previously showed that variation in spatial cognition has a direct effect on fitness and has a genetic basis. It remains unknown which specific genes and developmental pathways are particularly important for shaping spatial cognition. To further dissect the genetic basis of spatial cognitive abilities, we combine experimental quantification of spatial cognition in wild chickadees with whole-genome sequencing of 162 individuals, a new chromosome-scale reference genome, and species-specific gene annotation. We have identified a set of genes and developmental pathways that play a key role in creating variation in spatial cognition and found that the mechanism shaping cognitive variation is consistent with selection against mildly deleterious non-coding mutations. Although some candidate genes were organized into connected gene networks, about half do not have shared regulation, highlighting that multiple independent developmental or physiological mechanisms contribute to variation in spatial cognitive abilities. A large proportion of the candidate genes we found are associated with synaptic plasticity, an intriguing result that leads to the hypothesis that certain genetic variants create antagonism between behavioral plasticity and long-term memory, each providing distinct benefits depending on ecological context.

Partitioning the Genomic Components of Behavioral Disinhibition and Substance Use (Disorder) Using Genomic Structural Equation Modeling.

Externalizing behaviors encompass manifestations of risk-taking, self-regulation, aggression, sensation-/reward-seeking, and impulsivity. Externalizing research often includes substance use (SU), substance use disorder (SUD), and other (non-SU/SUD) "behavioral disinhibition" (BD) traits. Genome-wide and twin research have pointed to overlapping genetic architecture within and across SUB, SUD, and BD. We created single-factor measurement models-each describing SUB, SUD, or BD traits--based on mutually exclusive sets of European ancestry genome-wide association study (GWAS) statistics exploring externalizing variables. We then applied trivariate Cholesky decomposition to these factors in order to identify BD-specific genomic variation and assess the partitioning of BD's genetic covariance with each of the other facets. Even when the residuals for indicators relating to the same substance were correlated across the SUB and SUD factors, the two factors yielded a large zero-order correlation (rg=.803). BD correlated strongly with the SUD (rg=.774) and SUB factors (rg=.778). In our initial decompositions, 33% of total BD variance remained after removing variance associated with SUD and SUB. The majority of covariance between BD and SU and between BD and SUD was shared across all factors. When only nicotine/tobacco, cannabis, and alcohol were included for the SUB/SUD factors, their zero-order correlation increased to rg=.861; in corresponding decompositions, BD-specific variance decreased to 27%. In summary, BD, SU, and SUD were highly genetically correlated at the latent factor level, and a significant minority of genomic BD variation was not shared with SU and/or SUD. Further research can better elucidate the properties of BD-specific variation by exploring its genetic/molecular correlates.

Concurrent and longitudinal associations of developmental language disorder with peer victimization in adolescence: evidence from a co-twin study.

BACKGROUND: Children with developmental language disorder (DLD) experience higher levels of peer victimization than their peers. However, it is not known if such associations reflect genetic and environmental confounding. We used a co-twin control design to investigate the association of language difficulties (DLD and separately poor pragmatic language) with peer victimization and compare the developmental trajectories of peer victimization across adolescence for those with and without language difficulties. METHODS: Participants were 3,400 pairs of twins in the Twins Early Development Study (TEDS), a UK-based population birth cohort. Language abilities were assessed via online tests at age 11 and peer victimization was self-reported at ages 11, 14 and 16. Language difficulties were defined as language abilities at least -1.25 SD below the mean of the TEDS sample. We performed linear regressions and latent growth curve modeling at a population level and within monozygotic and same-sex dizygotic twin pairs. RESULTS: At population level, youth with DLD experienced higher levels of peer victimization at ages 11 (ß = 0.27, 95% Confidence Interval (CI) 0.20-0.35), 14 (ß = 0.15, 95% CI 0.03-0.27) and 16 (ß = 0.17, 95% CI 0.03-0.32) and a sharper decline in peer victimization between ages 11 and 16 compared to their peers without DLD. The associations between DLD and peer victimization were reduced in strength and not statistically significant in within-twin models. Moreover, there was no difference in the rate of change in peer victimization between twin pairs discordant for DLD. Results were similar for the association of poor pragmatic language with peer victimization. CONCLUSIONS: Associations between language difficulties (DLD and separately, poor pragmatic language) and peer victimization were confounded by genetic and shared environmental factors. Identifying specific factors underlying these associations is important for guiding future work to reduce peer victimization among adolescents with language difficulties.

[Genetic studies on forensic-psychiatric inpatients? : Clinical, ethical and legal considerations]. / Genetische Studien an forensisch Untergebrachten? : Klinische, ethische und juristische Überlegungen.

BACKGROUND: Research on people deprived of liberty raises serious questions, especially concerning behavioral genetic studies. QUESTION: Does including criminally detained patients with mental disorders in genetic studies lead to a gain of new knowledge and can this be ethically and legally justified? METHOD: Evaluation of existing literature and interdisciplinary reflection. RESULTS: After a review of research ethics and legal norms, we consider the benefits and risks of behavioral genetic research, taking the unique situation of test persons deprived of their liberty into account. The fundamental right to freedom of research also justifies foundational research in forensic psychiatry and psychotherapy. The possible future benefits of improving treatment plans must be weighed against the risks resulting from potential data leaks and inappropriate public reception of research results. Then we analyze possible threats to voluntary and informed consent to study participation in more detail by the ethical concept of vulnerability. Alongside problems with grasping complex issues, above all dependencies and power dynamics in the correctional system play a pivotal role. Recommendations on the ethical and legal inclusion of this study population are given. CONCLUSION: Including criminally detained study participants can be ethically and legally justified when autonomous consent is supported by specific organizational and legal procedures and measures, for example via a clear professional and organizational separation of correction and research.

Evaluation of the inheritance and dominance of behavioral resistance to imidacloprid in the house fly (Musca domestica L.) (Diptera: Muscidae).

The house fly, Musca domestica, is a cosmopolitan species known for its pestiferous nature and potential to mechanically vector numerous human and animal pathogens. Control of adult house flies often relies on insecticides formulated into food baits. However, due to the overuse of these baits, insecticide resistance has developed to all insecticide classes currently registered for use in the United States. Field populations of house flies have developed resistance to imidacloprid, the most widely used neonicotinoid insecticide for fly control, through both physiological and behavioral resistance mechanisms. In the current study, we conducted a comprehensive analysis of the inheritance and dominance of behavioral resistance to imidacloprid in a lab-selected behaviorally resistant house fly strain. Additionally, we conducted feeding preference assays to assess the feeding responses of genetic cross progeny to imidacloprid. Our results confirmed that behavioral resistance to imidacloprid is inherited as a polygenic trait, though it is inherited differently between male and female flies. We also demonstrated that feeding preference assays can be instrumental in future genetic inheritance studies as they provide direct insight into the behavior of different strains under controlled conditions that reveal, interactions between the organism and the insecticide. The findings of this study carry significant implications for pest management and underscore the need for integrated pest control approaches that consider genetic and ecological factors contributing to resistance.

Considerations, Caveats, and Suggestions for the Use of Polygenic Scores for Social and Behavioral Traits.

Polygenic scores (PGS) are increasingly being used for prediction of social and behavioral traits, but suffer from many methodological, theoretical, and ethical concerns that profoundly limit their value. Primarily, these scores are derived from statistical correlations, carrying no inherent biological meaning, and thus may capture indirect effects. Further, the performance of these scores depends upon the diversity of the reference populations and the genomic panels from which they were derived, which consistently underrepresent minoritized populations, leading to poor fit when applied to diverse groups. There is also inherent danger of eugenic applications for the information gained from these scores, and general risk of misunderstandings that could lead to stigmatization for underrepresented groups. We urge extreme caution in use of PGS particularly for social/behavioral outcomes fraught for misinterpretation, with potential harm for the minoritized groups least likely to benefit from their use.

The main genetic locus associated with the evolution of gamecocks is centered on ISPD.

Chickens were domesticated >4,000 years ago, probably first for fighting them and only later as a source of food. Fighting chickens, commonly known as gamecocks, continue to be bred throughout the world, but the genetic relationships among geographically diverse gamecocks and with nongame chickens are not known. Here, we sequenced the genomes of 44 geographically diverse gamecocks and 62 nongame chickens representing a variety of breeds. We combined these sequences with published genomes to generate the most diverse chicken genomes dataset yet assembled, with 307 samples. We found that gamecocks do not form a homogeneous group, yet they share genetic similarities that distinguish them from nongame chickens. Such similarities are likely the result of a common origin before their local diversification into, or mixing with nongame chickens. Particularly noteworthy is a variant in an intron of the isoprenoid synthase domain containing gene (ISPD), an extreme outlier present at a frequency of 89% in gamecocks but only 4% in nongame chickens. The ISPD locus has the strongest signal of selection in gamecocks, suggesting it is important for fighting performance. Because ISPD variants that are highly prevalent in gamecocks are still segregating in nongame chickens, selective breeding may help reduce its frequency in farm conditions in which aggression is not a desired trait. Altogether, our work provides genomic resources for agricultural genetics, uncovers a common origin for gamecocks from around the world and what distinguishes them genetically from chickens bred for purposes other than fighting, and points to ISPD as the most important locus related to fighting performance.

Opioid trail: Tracking contributions to opioid use disorder from host genetics to the gut microbiome.

Opioid use disorder (OUD) is a worldwide public health crisis with few effective treatment options. Traditional genetics and neuroscience approaches have provided knowledge about biological mechanisms that contribute to OUD-related phenotypes, but the complexity and magnitude of effects in the brain and body remain poorly understood. The gut-brain axis has emerged as a promising target for future therapeutics for several psychiatric conditions, so characterizing the relationship between host genetics and the gut microbiome in the context of OUD will be essential for development of novel treatments. In this review, we describe evidence that interactions between host genetics, the gut microbiome, and immune signaling likely play a key role in mediating opioid-related phenotypes. Studies in humans and model organisms consistently demonstrated that genetic background is a major determinant of gut microbiome composition. Furthermore, the gut microbiome is susceptible to environmental influences such as opioid exposure. Additional work focused on gene by microbiome interactions will be necessary to gain improved understanding of their effects on OUD-related behaviors.

Transposons in the Williams-Beuren Syndrome Critical Region are Associated with Social Behavior in Assistance Dogs.

A strong signature of selection in the domestic dog genome is found in a five-megabase region of chromosome six in which four structural variants derived from transposons have previously been associated with human-oriented social behavior, such as attentional bias to social stimuli and social interest in strangers. To explore these genetic associations in more phenotypic detail-as well as their role in training success in a specialized assistance dog program-we genotyped 1001 assistance dogs from Canine Companions for Independence®, including both successful graduates and dogs released from the training program for behaviors incompatible with their working role. We collected phenotypes on each dog using puppy-raiser questionnaires, trainer questionnaires, and both cognitive and behavioral tests. Using Bayesian mixed models, we found strong associations (95% credibility intervals excluding zero) between genotypes and certain behavioral measures, including separation-related problems, aggression when challenged or corrected, and reactivity to other dogs. Furthermore, we found moderate differences in the genotypes of dogs who graduated versus those who did not; insertions in GTF2I showed the strongest association with training success (ß = 0.23, CI95% = - 0.04, 0.49), translating to an odds-ratio of 1.25 for one insertion. Our results provide insight into the role of each of these four transposons in canine sociability and may inform breeding and training practices for working dog organizations. Furthermore, the observed importance of the gene GTF2I supports the emerging consensus that variation in GTF2I genotypes and expression have important consequences for social behavior broadly.

Endophenotyping social cognition in the broader autism phenotype.

Relatives of individuals with autism spectrum disorder (ASD) may display milder social traits of the broader autism phenotype (BAP) providing potential endophenotypic markers of genetic risk for ASD. We performed a case-control comparison to quantify social cognition and pragmatic language difficulties in the BAP (n = 25 cases; n = 33 controls) using the Faux Pas test (FPT) and the Goldman-Eisler Cartoon task. Using deep phenotyping we then examined patterns of inheritance of social cognition in two large multiplex families and the spectrum of performance in 32 additional families (159 members; n = 51 ASD, n = 87 BAP, n = 21 unaffected). BAP individuals showed significantly poorer FPT performance and reduced verbal fluency with the absence of a compression effect in social discourse compared to controls. In multiplex families, we observed reduced FPT performance in 89% of autistic family members, 63% of BAP relatives and 50% of unaffected relatives. Across all affected families, there was a graded spectrum of difficulties, with ASD individuals showing the most severe FPT difficulties, followed by the BAP and unaffected relatives compared to community controls. We conclude that relatives of probands show an inherited pattern of graded difficulties in social cognition with atypical faux pas detection in social discourse providing a novel candidate endophenotype for ASD.

The paradise fish, an advanced animal model for behavioral genetics and evolutionary developmental biology.

Paradise fish (Macropodus opercularis) is an air-breathing freshwater fish species with a signature labyrinth organ capable of extracting oxygen from the air that helps these fish to survive in hypoxic environments. The appearance of this evolutionary innovation in anabantoids resulted in a rewired circulatory system, but also in the emergence of species-specific behaviors, such as territorial display, courtship and parental care in the case of the paradise fish. Early zoologists were intrigued by the structure and function of the labyrinth apparatus and a series of detailed descriptive histological studies at the beginning of the 20th century revealed the ontogenesis and function of this specialized system. A few decades later, these fish became the subject of numerous ethological studies, and detailed ethograms of their behavior were constructed. These latter studies also demonstrated a strong genetic component underlying their behavior, but due to lack of adequate molecular tools, the fine genetic dissection of the behavior was not possible at the time. The technological breakthroughs that transformed developmental biology and behavioral genetics in the past decades, however, give us now a unique opportunity to revisit these old questions. Building on the classic descriptive studies, the new methodologies will allow us to follow the development of the labyrinth apparatus at a cellular resolution, reveal the genes involved in this process and also the genetic architecture behind the complex behaviors that we can observe in this species.

A pilot study examining the relationship between chronic heroin use and telomere length among individuals of African ancestry.

BACKGROUND: Prior research has suggested a possible link between heroin use and shortened telomere length (TL), a marker of cellular aging and genomic stability. We sought to replicate these findings by examining the relationship between TL and heroin use among individuals of African ancestry. METHODS: This cross-sectional study examined TL among 57 participants [17.5 % female; mean age 48.0 (±6.80) years] of African ancestry with Opioid Use Disorder (OUD) and a mean heroin use duration of 18.2 (±10.7) years. Quantitative polymerase chain reaction (qPCR) was used to calculate TL as the ratio between telomere repeat copy number (T) and a single-copy gene, copy number (S). The primary dependent variable was TL (T/S Ratio) measured in kilobase pairs. Covariates included heroin use years and personality traits. Using a hybrid approach, multiple linear regression and Bayesian linear regression examined the association of chronological age, heroin use years and personality traits with TL. RESULTS: The multiple linear regression model fit the data well, R2 = 0.265, F(7,49) = 2.53, p < .026. Chronological age (ß = -0.36, p = .017), neuroticism (ß = 0.46, p = .044), and conscientiousness (ß = 0.52, p = .040) were significant predictors of TL. Bayesian linear regression provided moderate support for the alternate hypothesis that chronological age and TL are associated, BF10 = 5.77, R2 = 0.120. The posterior summary of the coefficient was M = 0.719 (SD = 0.278, 95 % credible interval [-1.28, -0.163]). CONCLUSIONS: Contrary to prior studies, these findings suggest that heroin use duration may not be significantly associated with TL among individuals of African ancestry, highlighting the need for more rigorous research to elucidate the complexity of this relationship.

Brain Gene Expression of Foraging Behavior and Social Environment in Ceratina calcarata.

Rudimentary social systems have the potential to both advance our understanding of how complex sociality may have evolved and our understanding of how changes in social environment may influence gene expression and cooperation. Recently, studies of primitively social Hymenoptera have greatly expanded empirical evidence for the role of social environment in shaping behavior and gene expression. Here, we compare brain gene expression profiles of foragers across social contexts in the small carpenter bee, Ceratina calcarata. We conducted experimental manipulations of field colonies to examine gene expression profiles among social contexts including foraging mothers, regular daughters, and worker-like dwarf eldest daughters in the presence and absence of mother. Our analysis found significant differences in gene expression associated with female age, reproductive status, and social environment, including circadian clock gene dyw, hexamerin, and genes involved in the regulation of juvenile hormone and chemical communication. We also found that candidate genes differentially expressed in our study were also associated with division of labor, including foraging, in other primitively and advanced eusocial insects. Our results offer evidence for the role of the regulation of key developmental hormones and circadian rhythms in producing cooperative behavior in rudimentary insect societies.

Associations between polygenic risk of substance use and use disorder and alcohol, cannabis, and nicotine use in adolescence and young adulthood in a longitudinal twin study.

BACKGROUND: Recent well-powered genome-wide association studies have enhanced prediction of substance use outcomes via polygenic scores (PGSs). Here, we test (1) whether these scores contribute to prediction over-and-above family history, (2) the extent to which PGS prediction reflects inherited genetic variation v. demography (population stratification and assortative mating) and indirect genetic effects of parents (genetic nurture), and (3) whether PGS prediction is mediated by behavioral disinhibition prior to substance use onset. METHODS: PGSs for alcohol, cannabis, and nicotine use/use disorder were calculated for Minnesota Twin Family Study participants (N = 2483, 1565 monozygotic/918 dizygotic). Twins' parents were assessed for histories of substance use disorder. Twins were assessed for behavioral disinhibition at age 11 and substance use from ages 14 to 24. PGS prediction of substance use was examined using linear mixed-effects, within-twin pair, and structural equation models. RESULTS: Nearly all PGS measures were associated with multiple types of substance use independently of family history. However, most within-pair PGS prediction estimates were substantially smaller than the corresponding between-pair estimates, suggesting that prediction is driven in part by demography and indirect genetic effects of parents. Path analyses indicated the effects of both PGSs and family history on substance use were mediated via disinhibition in preadolescence. CONCLUSIONS: PGSs capturing risk of substance use and use disorder can be combined with family history measures to augment prediction of substance use outcomes. Results highlight indirect sources of genetic associations and preadolescent elevations in behavioral disinhibition as two routes through which these scores may relate to substance use.