Patterns and predictors of alcohol misuse trajectories from adolescence through early midlife.

We took a multilevel developmental contextual approach and characterized trajectories of alcohol misuse from adolescence through early midlife, examined genetic and environmental contributions to individual differences in those trajectories, and identified adolescent and young adult factors associated with change in alcohol misuse. Data were from two longitudinal population-based studies. FinnTwin16 is a study of Finnish twins assessed at 16, 17, 18, 25, and 35 years (N = 5659; 52% female; 32% monozygotic). The National Longitudinal Study of Adolescent to Adult Health (Add Health) is a study of adolescents from the United States, who were assessed at five time points from 1994 to 2018 (N = 18026; 50% female; 64% White, 21% Black, 4% Native American, 7% Asian, 9% Other race/ethnicity). Alcohol misuse was measured as frequency of intoxication in FinnTwin16 and frequency of binge drinking in Add Health. In both samples, trajectories of alcohol misuse were best described by a quadratic growth curve: Alcohol misuse increased across adolescence, peaked in young adulthood, and declined into early midlife. Individual differences in these trajectories were primarily explained by environmental factors. Several adolescent and young adult correlates were related to the course of alcohol misuse, including other substance use, physical and mental health, and parenthood.

A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency.

Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.

Association of parental divorce, discord, and polygenic risk with children's alcohol initiation and lifetime risk for alcohol use disorder.

BACKGROUND: Parental divorce and discord are associated with poorer alcohol-related outcomes for offspring. However, not all children exposed to these stressors develop alcohol problems. Our objective was to test gene-by-environment interaction effects whereby children's genetic risk for alcohol problems modifies the effects of parental divorce and discord to predict alcohol outcomes. METHODS: The sample included European (EA; N = 5608, 47% male, Mage ~ 36 years) and African (AA; N = 1714, 46% female, Mage ~ 33 years) ancestry participants from the Collaborative Study on the Genetics of Alcoholism. Outcomes included age at initiation of regular drinking and lifetime DSM-5 alcohol use disorder (AUD). Predictors included parental divorce, parental relationship discord, and offspring alcohol problems polygenic risk scores (PRSALC ). Mixed effects Cox proportional hazard models were used to examine alcohol initiation and generalized linear mixed effects models were used to examine lifetime AUD. Tests of PRS moderation of the effects of parental divorce/relationship discord on alcohol outcomes were examined on multiplicative and additive scales. RESULTS: Among EA participants, parental divorce, parental discord, and higher PRSALC were associated with earlier alcohol initiation and greater lifetime AUD risk. Among AA participants, parental divorce was associated with earlier alcohol initiation and discord was associated with earlier initiation and AUD. PRSALC was not associated with either. Parental divorce/discord and PRSALC interacted on an additive scale in the EA sample, but no interactions were found in AA participants. CONCLUSIONS: Children's genetic risk for alcohol problems modifies the impact of parental divorce/discord, consistent with an additive model of diathesis-stress interaction, with some differences across ancestry.

A longitudinal study examining the associations between interpersonal trauma and romantic relationships among college students.

We examined the associations between the developmental timing of interpersonal trauma exposure (IPT) and three indicators of involvement in and quality of romantic relationships in emerging adulthood: relationship status, relationship satisfaction, and partner alcohol use. We further examined whether these associations varied in a sex-specific manner. In a sample of emerging adult college students (N = 12,358; 61.5% female) assessed longitudinally across the college years, we found precollege IPT increased the likelihood of being in a relationship, while college-onset IPT decreased the likelihood. Precollege and college-onset IPT predicted lower relationship satisfaction, and college-onset IPT predicted higher partner alcohol use. There was no evidence that associations between IPT and relationship characteristics varied in a sex-specific manner. Findings indicate that IPT exposure, and the developmental timing of IPT, may affect college students' relationship status. Findings also suggest that IPT affects their ability to form satisfying relationships with prosocial partners.

Genetic nurture effects for alcohol use disorder.

We tested whether aspects of the childhood/adolescent home environment mediate genetic risk for alcohol problems within families across generations. Parental relationship discord and parental divorce were the focal environments examined. The sample included participants of European ancestry (N = 4806, 51% female) and African ancestry (N = 1960, 52% female) from the high-risk Collaborative Study on the Genetics of Alcoholism. Alcohol outcomes in the child generation included lifetime criterion counts for DSM-5 Alcohol Use Disorder (AUD), lifetime maximum drinks in 24 h, age at initiation of regular drinking, and age at first alcohol intoxication. Predictors in the parent generation included relationship discord, divorce, alcohol measures parallel to those in the child generation, and polygenic scores for alcohol problems. Parental polygenic scores were partitioned into alleles that were transmitted and non-transmitted to the child. The results from structural equation models were consistent with genetic nurture effects in European ancestry families. Exposure to parental relationship discord and parental divorce mediated, in part, the transmission of genetic risk for alcohol problems from parents to children to predict earlier ages regular drinking (ßindirect = -0.018 [-0.026, -0.011]) and intoxication (ßindirect = -0.015 [-0.023, -0.008]), greater lifetime maximum drinks (ßindirect = 0.006 [0.002, 0.01]) and more lifetime AUD criteria (ßindirect = 0.011 [0.006, 0.016]). In contrast, there was no evidence that parental alleles had indirect effects on offspring alcohol outcomes via parental relationship discord or divorce in the smaller number of families of African ancestry. In conclusion, parents transmit genetic risk for alcohol problems to their children not only directly, but also indirectly via genetically influenced aspects of the home environment. Further investigation of genetic nurture in non-European samples is needed.

Principal Component Analysis Reduces Collider Bias in Polygenic Score Effect Size Estimation.

In this study, we test principal component analysis (PCA) of measured confounders as a method to reduce collider bias in polygenic association models. We present results from simulations and application of the method in the Collaborative Study of the Genetics of Alcoholism (COGA) sample with a polygenic score for alcohol problems, DSM-5 alcohol use disorder as the target phenotype, and two collider variables: tobacco use and educational attainment. Simulation results suggest that assumptions regarding the correlation structure and availability of measured confounders are complementary, such that meeting one assumption relaxes the other. Application of the method in COGA shows that PC covariates reduce collider bias when tobacco use is used as the collider variable. Application of this method may improve PRS effect size estimation in some cases by reducing the effect of collider bias, making efficient use of data resources that are available in many studies.

Alcohol use disorder, psychiatric comorbidities, marriage and divorce in a high-risk sample.

OBJECTIVE: To examine associations between alcohol use disorder (AUD), its psychiatric comorbidities, and their interactions, with marital outcomes in a diverse high-risk, genetically informative sample. METHOD: Participants included European ancestry (EA; n = 4,045) and African ancestry (AA; n = 1,550) individuals from the multigenerational Collaborative Study on the Genetics of Alcoholism (COGA) sample (56% female, Mage ∼ 41 years). Outcomes were lifetime marriage and divorce. Predictors included lifetime AUD, an alcohol problems polygenic score (PRS), and AUD comorbidities, including conduct or antisocial personality disorder (ASP), cannabis dependence/abuse (CAN), frequent tobacco use (TOB), and major depressive disorder (MDD). Mixed effect Cox models and generalized linear mixed effects models were fit. RESULTS: Among EA participants, those with AUD and CAN were less likely to marry (hazard ratios [HRs] 0.70-0.83, ps < 0.01). Among AA participants, those with AUD and TOB were less likely to marry (HRs 0.66-0.82, ps < 0.05) and those with MDD were more likely to marry (HR = 1.34, ps < 0.01). Among EA participants, AUD, CAN, TOB, and MDD were associated with higher odds of divorce (odds ratios [ORs] 1.59-2.21, ps < 0.01). Among AA participants, no predictors were significantly associated with divorce. Significant random effects indicated genetic and environmental influences on marriage, but only environmental factors on divorce. CONCLUSIONS: In a high-risk sample, AUD was associated with reduced likelihood of marriage in EA and AA individuals and increased risk of divorce in EA individuals. These associations were largely independent of comorbidities. Genetic and environmental background factors contributed to marriage, while only environmental background factors contributed to divorce. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A longitudinal study of the moderating effects of romantic relationships on the associations between alcohol use and trauma in college students.

BACKGROUND AND AIMS: College students report high levels of alcohol use, which can be exacerbated by interpersonal trauma exposure (IPT). Romantic relationships may represent salient contexts for moderating associations between IPT and alcohol use. We examined whether relationship status, partner alcohol use and relationship satisfaction moderated associations between IPT and alcohol use, and whether these associations varied in a sex-specific manner. DESIGN: University-wide longitudinal survey of college students. SETTING: Large, urban public university in mid-Atlantic United States. PARTICIPANTS: We used two subsets of participants (n = 5673 and 3195) from the Spit for Science project, a longitudinal study of college students. Participants completed baseline assessments during the autumn of their freshman year and were invited to complete follow-up assessments every spring thereafter. Participants were included in the present study if they completed surveys at baseline and at least one follow-up assessment (meanfollow-ups  = 1.70, range = 1-4). MEASUREMENTS: Predictors included precollege and college-onset IPT, relationship status, partner alcohol use, relationship satisfaction and sex. Alcohol consumption was the primary outcome of interest. Pre-college IPT was measured at baseline and all other measures were assessed at each follow-up. FINDINGS: Individuals with pre-college IPT consumed more alcohol than those without IPT, but this was mitigated for those in relationships (ß = -0.15, P = 0.046, 95% confidence interval (CI) = -0.29, 0.00). Individuals with college-onset IPT consumed more alcohol than those without IPT, and this was more pronounced for those with higher partner alcohol use (ß = -0.18, P = 0.001, 95% CI = -0.29, -0.07). Relationship satisfaction was not a significant moderator of the associations between IPT and alcohol use (Ps > 0.05 and 95% CIs include 0). CONCLUSIONS: Involvement in relationships, but not relationship satisfaction, appears to reduce the effects of interpersonal trauma exposure (IPT) on alcohol use among US college students, while high partner alcohol use appears to exacerbate it. The moderating effects of relationship characteristics depend on the developmental timing of IPT.

Associations between the CADM2 gene, substance use, risky sexual behavior, and self-control: A phenome-wide association study.

Risky behaviors, such as substance use and unprotected sex, are associated with various physical and mental health problems. Recent genome-wide association studies indicated that variation in the cell adhesion molecule 2 (CADM2) gene plays a role in risky behaviors and self-control. In this phenome-wide scan for risky behavior, it was tested if underlying common vulnerability could be (partly) explained by pleiotropic effects of this gene and how large the effects were. Single nucleotide polymorphism (SNP)-level and gene-level association tests within four samples (25 and Up, Spit for Science, Netherlands Twin Register, and UK Biobank and meta-analyses over all samples (combined sample of 362,018 participants) were conducted to test associations between CADM2, substance- and sex-related risk behaviors, and various measures related to self-control. We found significant associations between the CADM2 gene, various risky behaviors, and different measures of self-control. The largest effect sizes were found for cannabis use, sensation seeking, and disinhibition. Effect sizes ranged from 0.01% to 0.26% for single top SNPs and from 0.07% to 3.02% for independent top SNPs together, with sufficient power observed only in the larger samples and meta-analyses. In the largest cohort, we found indications that risk-taking proneness mediated the association between CADM2 and latent factors for lifetime smoking and regular alcohol use. This study extends earlier findings that CADM2 plays a role in risky behaviors and self-control. It also provides insight into gene-level effect sizes and demonstrates the feasibility of testing mediation. These findings present a good starting point for investigating biological etiological pathways underlying risky behaviors.

Cannabis use in college: Genetic predispositions, peers, and activity participation.

BACKGROUND: Among adult college students in the US, cannabis use is common and associated with considerable negative consequences to health, cognition, and academic functioning, underscoring the importance of identifying risk and protective factors. Cannabis use is influenced by genetic factors, but genetic risk is not determinative. Accordingly, it is critical to identify environments that reduce risk among those who are at elevated genetic risk. This study examined the impact of polygenic scores for cannabis initiation, various forms of social activity participation, and peer deviance on recent cannabis use. Our aim was to test whether these environments moderate genetic risk for cannabis use. METHODS: Data came from a longitudinal sample of undergraduate college students of European American (EA; NEA = 750) and African American (AA; NAA = 405) ancestry. Generalized estimating equations with a logit link function were used to examine main effects and two-way interactions. RESULTS: Engagement with church activities was associated with lower probability of cannabis use. Peer deviance was associated with higher probability of cannabis use. Engagement with community activities moderated the influence of the polygenic risk score in the EA sample, such that PRS was associated with recent cannabis use among those who never engaged in community activities. This effect did not replicate in AAs, which may have been due to the portability of PRS based on EA discovery samples. CONCLUSIONS: Results suggest that community activities may limit the influence of genetic risk, as associations between PRS and cannabis use were only observed among individuals who never engaged in community activities.

Hierarchical, rotation-equivariant neural networks to select structural models of protein complexes.

Predicting the structure of multi-protein complexes is a grand challenge in biochemistry, with major implications for basic science and drug discovery. Computational structure prediction methods generally leverage predefined structural features to distinguish accurate structural models from less accurate ones. This raises the question of whether it is possible to learn characteristics of accurate models directly from atomic coordinates of protein complexes, with no prior assumptions. Here we introduce a machine learning method that learns directly from the 3D positions of all atoms to identify accurate models of protein complexes, without using any precomputed physics-inspired or statistical terms. Our neural network architecture combines multiple ingredients that together enable end-to-end learning from molecular structures containing tens of thousands of atoms: a point-based representation of atoms, equivariance with respect to rotation and translation, local convolutions, and hierarchical subsampling operations. When used in combination with previously developed scoring functions, our network substantially improves the identification of accurate structural models among a large set of possible models. Our network can also be used to predict the accuracy of a given structural model in absolute terms. The architecture we present is readily applicable to other tasks involving learning on 3D structures of large atomic systems.

E-cigarette use is prospectively associated with initiation of cannabis among college students.

E-cigarettes have dramatically increased in popularity among youth. Coincident with expanded legalization, young adults' use of cannabis (marijuana) has also steadily increased in recent years. Use of tobacco products can increase the chances of later cannabis initiation among youth. However, most longitudinal investigations of tobacco and cannabis use patterns have focused on tobacco cigarettes, included adolescents as opposed to young adults, and have only employed two timepoints. The current study examined prospective associations between e-cigarette and cannabis use in a large, diverse college sample assessed over four timepoints (freshman - senior year; N = 4,670). E-cigarette use and cannabis use were modelled in a four-wave cross-lagged model. The results showed significant bidirectional associations between both substances, even after controlling for time-varying levels of depressive symptoms, alcohol use, and polysubstance use, sensation seeking, demographic variables, concurrent associations and previous levels of use. Moreover, the significance of the predictive path from e-cigarette use to later cannabis use remained unchanged when we ran the same model, but restricted the sample to e-cigarette-only users (i.e., never cigarette smokers), whereas only one prospective path from cannabis to e-cigarette use was significant in this subsample. The current findings suggest that the association of e-cigarette use and cannabis use is likely bidirectional, with stronger support for the link from e-cigarette use to later cannabis use, above and beyond cigarette use. As e-cigarettes gain further hold of the tobacco product market share and cannabis legalization continues to expand, data such as these will be critical for informing regulatory decisions for e-cigarettes and cannabis, particularly involving their accessibility to youth and young adults.

But they move! Vicariance and dispersal in southern South America: Using two methods to reconstruct the biogeography of a clade of lizards endemic to South America.

This study aims to identify events that modeled the historical biogeography of Phymaturus, using three methodologies: Spatial Analysis of Vicariance (VIP), Statistical Dispersal-Vicariance Analysis (S-DIVA), and Bayesian Binary Method MCMC (BBM). In order to assign areas for the Dispersal-Vicariance and the BBM analyses, we preferred not to use predefined areas, but to identify areas defined via an endemism analysis of Phymaturus species. The analyses were conducted using the same basic topology, which we obtained by constructing a metatree with two recent phylogenies, both morphology and molecular-based. This topology was also used to obtain time divergence estimates in BEAST, using more outgroups than for the metatree in order to get more accurate estimates. The S-DIVA analysis based on the metatree found 25 vicariance events, 20 dispersals and two extinctions; the S-DIVA analysis based on the BEAST tree yielded 30 vicariance events, 42 dispersal events and five extinctions, and the BBM analysis yielded 63 dispersal events, 28 vicariance events and 1 extinction event. According to the metatree analysis, the ancestral area for Phymaturus covers northern Payunia and southern Central Monte. A vicariant event fragmented the ancestral distribution of the genus, resulting in northern Payunia and southern Central Monte as ancestral area for the P. palluma group, and southern Payunia for the P. patagonicus group. The analysis based on the BEAST tree showed a more complex reconstruction, with several dispersal and extinction events in the ancestral node. The Spatial Analysis of Vicariance identified 41 disjunct sister nodes and removed 10 nodes. The barrier that separates the P. palluma group from the P. patagonicus group is roughly congruent with the southern limit of the P. palluma group. The ancestral range for the genus occupies a central position relative to the distribution of the group, which implies that the species must have migrated to the north (P. palluma group) and to the south (P. patagonicus group). To answer questions related to the specific timing of the events, a molecular clock for Phymaturus was obtained, using a Liolaemus fossil for calibration. The present contribution provides a hypothetical framework for the events that modeled the distribution of Phymaturus.

Alcohol Metabolizing Polygenic Risk for Alcohol Consumption in European American College Students.

OBJECTIVE: Evidence suggests that the nature and magnitude of some genetic effects on alcohol use vary by age. We tested for moderation in the effect of an alcohol metabolizing polygenic score by time across the college years. METHOD: Participants (total n = 2,214) were drawn from three cohorts of undergraduate college students, who were assessed annually for up to 4 years starting in their freshman year. Polygenic risk scores (PRSs) were calculated from genes involved in the metabolism of alcohol, as many of these markers are among the best replicated in association studies examining alcohol use phenotypes. Linear mixed effects models were fit by maximum likelihood to test the main effects of time and the PRS on alcohol consumption, as well as moderation of the PRS effect on alcohol consumption by time. RESULTS: In the main effects model, the fixed effects for time and the PRS were positively associated with alcohol consumption. The interaction term testing moderation of the PRS effect by time reached statistical significance and remained statistically significant after other relevant interaction effects were controlled for. The main effect of the PRS accounted for 0.2% of the variance in alcohol consumption, whereas the interaction of PRS effect and time accounted for 0.05%. CONCLUSIONS: Alcohol metabolizing genetic effects on alcohol use appear to be more influential in later years of college than in earlier years. Shifting environmental contexts, such as increased access to alcohol as individuals approach the legal age to purchase alcohol, may account for this association.

ALDH2*2 and peer drinking in East Asian college students.

BACKGROUND: The ALDH2*2 allele (A-allele) at rs671 is more commonly carried by Asians and is associated with alcohol-related flushing, a strong adverse reaction to alcohol that is protective against drinking. Social factors, such as having friends who binge drink, also contribute to drinking in Asian youth. OBJECTIVES: This study examined the interplay between ALDH2*2, peer drinking, and alcohol consumption in college students. We hypothesized that the relationship between ALDH2*2 and standard grams of ethanol per month would vary based on the level of peer drinking. METHODS: Subjects (N = 318, 63.25% female) were East Asian college students in the United States who reported drinking alcohol. Data were from the freshman year of a university survey that included a saliva DNA sample. ALDH2*2 status was coded ALDH2*2(+) (A/G and A/A genotypes) and ALDH2*2(-) (G/G genotype). Peer drinking was students' perception of how many of their friends "got drunk". RESULTS: Main effects of ALDH2*2(-) and having more friends who got drunk were associated with greater alcohol consumption. The ALDH2*2 × peer drunkenness interaction showed a stronger positive association with alcohol consumption for ALDH2*2(-) versus ALDH2*2(+) at increasing levels of peer drunkenness. Follow-up comparisons within each peer drunkenness level identified significantly higher alcohol consumption for ALDH2*2(-) compared to ALDH2*2(+) at the all friends got drunk level. CONCLUSION: There was evidence of a stronger effect for ALDH2*2(-) compared to ALDH2*2(+) with greater alcohol use when students were more exposed to peer drinking. Findings contribute to a growing literature on the interrelationships between genetic influences and more permissive environments for alcohol consumption.

The role of romantic relationship status in pathways of risk for emerging adult alcohol use.

Dating several people in emerging adulthood has been associated with higher alcohol use compared with being single or being in an exclusive relationship. As a follow-up to that report, we examined whether romantic relationship status is part of a pathway of risk between antecedent alcohol use risk factors and subsequent alcohol outcomes. Participants were 4,410 emerging adults assessed at 2 time-points during their first year of college. We found that a parental history of alcohol problems was indirectly related to dating several people via 2 modestly correlated pathways. The first pathway was through conduct problems. The second pathway was through positive urgency (i.e., a positive emotion-based predisposition to rash action). In turn, dating several people was associated with higher alcohol use. Our results suggest that these familial and individual-level alcohol risk factors are related to emerging adults' selection into subsequent romantic relationship experiences that are associated with higher alcohol use. These findings have implications for how romantic relationship experiences may fit into developmental models of the etiology of alcohol use. (PsycINFO Database Record

Stroke incidence and case fatality rate in an urban population.

BACKGROUND: The epidemiology of stroke in sub-Saharan African populations and variation of subtypes between communities are not well understood. Our aim was to ascertain prospectively the incidence of first-ever stroke and ischemic stroke subtypes in an urban city population of Southwestern Nigeria. METHODS: A community-based stroke registry was set up to enroll hospitalized and nonhospitalized first-ever stroke cases at all health care facilities located in the assigned community. The study was conducted between November 1, 2010, and October 31, 2011, in Akure North and South Local Government Areas of Ondo State, Southwestern Nigeria. RESULTS: We identified 298 incidents of strokes in patients presenting for the first time ever. Pathologic diagnosis was confirmed in 75% of the cases. Adjusted age-standardized incidence rate was 60.67 per 100,000 per year after adjustment to the World Health Organization World Population. Incidence of cerebral infarction and intracerebral hemorrhage increased with age in both men and women. CONCLUSIONS: The incidence of stroke in our population-based study ranks low compared with high-income countries. However, when incidence rates were compared by pathologic type, our rates for intracerebral hemorrhage and that of subarachnoid hemorrhage are comparable with those of high-income countries.

Maternal separation alters social odor preference development in infant mice (Mus musculus).

This study examined whether daily periods of maternal separation during the first two weeks of life would decrease attraction to familiar nest odors in CD-1 mice 10 and 14 days old. We also investigated whether placing a group of mice (Mus musculus) in nest shavings during the 180-min separation period would mitigate possible separation-induced deficits. The maternal separation procedure has been widely used as a rodent model for the effects of inconsistent or inadequate early caretaking on human development. From postnatal day (PND) 1 to 14, litters were separated from the dam, but not littermates for either 15 or 180 min, or were facility-reared controls. Control, facility-reared mice preferred home-cage nest to clean familiar shaving odors on PND 10, but not PND 14. In contrast, home-cage nest odors attracted maternally separated mice on both test days. Our results suggest that maternal separation maintains the olfactory tether to the nest in a period when the attraction normally begins to weaken.