Polygenic Risk for Aggression Predicts Adult Substance Use Disorder Diagnoses via Substance Use Offending in Emerging Adulthood and is Moderated by a Family-Centered Intervention

A substance use offense reflects an encounter with law enforcement and the court system in response to breaking the law which may increase risk for substance use problems later in life. Individuals may also be at risk for substance use offending and substance use problems based on genetic predisposition. We examined a mediation model in which polygenic risk for aggression predicted adult substance use disorder diagnoses (SUD) via substance use offending in emerging adulthood. In addition, we explored for potential attenuation of genetic influences on these outcomes by a family-based intervention, the Family Check-Up (FCU). Secondary data analyses based upon the Project Alliance 1 sample was conducted among those with genetic data (n?=?631; 322 from control and 309 from FCU intervention). The sample was ethnically diverse (30% African American, 44% European American, 6% Latinx, 4% Asian American, 3% Native American, and 13% Other). Greater polygenic risk for aggression was found to increase risk for substance use violations (age 19–23), which in turn was associated with greater likelihood of being diagnosed with SUD at age 27. A gene-by-intervention effect was found in which individuals in the control group had greater risk for SUD with increasing polygenic risk for aggression. Some convergence in results was found when replicating analyses in African American and European American subgroups. Results imply that genetic predisposition may increase risk for problematic substance use later in life via antisocial behavior, such as substance use offending, and that this can be attenuated by a family-centered intervention.

     

Ancestry effects on type 2 diabetes genetic risk inference in Hispanic/Latino populations

Background

Hispanic/Latino (HL) populations bear a disproportionately high burden of type 2 diabetes (T2D). The ability to predict T2D genetic risk using polygenic risk scores (PRS) offers great promise for improved screening and prevention. However, there are a number of complications related to the accurate inference of genetic risk across HL populations with distinct ancestry profiles. We investigated how ancestry affects the inference of T2D genetic risk using PRS in diverse HL populations from Colombia and the United States (US). In Colombia, we compared T2D genetic risk for the Mestizo population of Antioquia to the Afro-Colombian population of Chocó, and in the US, we compared European-American versus Mexican-American populations.

Methods

Whole genome sequences and genotypes from the 1000 Genomes Project and the ChocoGen Research Project were used for genetic ancestry inference and for T2D polygenic risk score (PRS) calculation. Continental ancestry fractions for HL genomes were inferred via comparison with African, European, and Native American reference genomes, and PRS were calculated using T2D risk variants taken from multiple genome-wide association studies (GWAS) conducted on cohorts with diverse ancestries. A correction for ancestry bias in T2D risk inference based on the frequencies of ancestral versus derived alleles was developed and applied to PRS calculations in the HL populations studied here.

Results

T2D genetic risk in Colombian and US HL populations is positively correlated with African and Native American ancestry and negatively correlated with European ancestry. The Afro-Colombian population of Chocó has higher predicted T2D risk than Antioquia, and the Mexican-American population has higher predicted risk than the European-American population. The inferred relative risk of T2D is robust to differences in the ancestry of the GWAS cohorts used for variant discovery. For trans-ethnic GWAS, population-specific variants and variants with same direction effects across populations yield consistent results. Nevertheless, the control for bias in T2D risk prediction confirms that explicit consideration of genetic ancestry can yield more reliable cross-population genetic risk inferences.

Conclusions

T2D associations that replicate across populations provide for more reliable risk inference, and modeling population-specific frequencies of ancestral and derived risk alleles can help control for biases in PRS estimation.

     

Genetic and environmental influences underlying externalizing behaviors, cigarette smoking and illicit drug use across adolescence

We investigated genetic and environmental influences common to adolescent externalizing behavior (at age 12), smoking (at age 14) and initiation of drug use (at age 17) using the FinnTwin12 cohort data. Multivariate Cholesky models were fit to data from 737 monozygotic and 722 dizygotic twin pairs. Heritability of externalizing behavior was 56%, that of smoking initiation/amount 20/32%, and initiation of drug use 27%. In the best-fitting model common environmental influences explained most of the covariance between externalizing behavior and smoking initiation (69%) and amount (77%). Covariance between smoking initiation/amount and drug use was due to additive genetic (42/22%) and common environmental (58/78%) influences. Half of the covariance between externalizing behavior and drug use was due to shared genetic and half due to the environments shared by co-twins. Using a longitudinal, prospective design, our results indicate that early observed externalizing behavior provides significant underlying genetic and environmental influences common to later substance use, here manifested as initiation of drug use in late adolescence.     

Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank

PurposeGenome-wide association studies have identified hundreds of single nucleotide variations (formerly single nucleotide polymorphisms) associated with several cancers, but the predictive ability of polygenic risk scores (PRSs) is unclear, especially among non-Whites.MethodsPRSs were derived from genome-wide significant single-nucleotide variations for 15 cancers in 20,079 individuals in an academic biobank. We evaluated the improvement in discriminatory accuracy by including cancer-specific PRS in patients of genetically-determined African and European ancestry.ResultsAmong the individuals of European genetic ancestry, PRSs for breast, colon, melanoma, and prostate were significantly associated with their respective cancers. Among the individuals of African genetic ancestry, PRSs for breast, colon, prostate, and thyroid were significantly associated with their respective cancers. The area under the curve of the model consisting of age, sex, and principal components was 0.621 to 0.710, and it increased by 1% to 4% with the inclusion of PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, area under the curve was overall higher in the model without the PRS (0.723-0.810) but increased by <1% with the inclusion of PRS for most cancers.ConclusionPRS moderately increased the ability to discriminate the cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.     

Observed Externalizing Behavior: A Developmental Comparison of Genetic and Environmental Influences Across Three Samples

Estimates of genetic and environmental influences on externalizing behavior are markedly inconsistent. In an attempt to refine and extend our knowledge of externalizing behavior, the current study examined the etiology of externalizing behavior using observational data in middle childhood and adolescence from three twin and sibling samples. Observational ratings offer a unique perspective on externalizing behavior rarely examined within behavioral genetic designs. Shared environmental influences were significant and moderate to large in magnitude across all three samples (i.e., 44, 77, and 38%), while genetic influences (31%) were significant only for the adolescent sample. All three samples showed greater shared environmental influences and less genetic influence than is typically found when examining self-, parent-, and teacher-reports of externalizing behavior. These findings are consistent with other reports that have found evidence for shared environmental influences on measures of child externalizing behavior—in direct contrast to a commonly held perception that shared environmental factors do not have significant influences on behavior beyond early childhood.     

Genetic Innovation and Stability in Externalizing Problem Behavior Across Development: A Multi-Informant Twin Study

The use of cross-informant ratings in previous longitudinal studies on externalizing behavior may have obscured the presence of continuity of genetic risk. The current study included latent factors representing the latent estimates of externalizing behavior based on both parent and self-report which eliminated rater-specific effects from these latent estimates. Symptoms of externalizing behavior of 1,480 Swedish twin pairs were obtained at ages 8–9, 13–14, 16–17 and 19–20 both by parent and self-report. Mx modeling was used to estimate additive genetic, shared and specific environmental influences. Genetic continuity was found over the entire developmental period as well as additional sources of genetic influence emerging around early and late adolescence. New unique environmental effects (E) on externalizing behavior arose early in adolescence. The results support both the presence of genetic continuity and change in externalizing behavior during adolescence due to newly emerging genetic and environmental risk factors.     

Preference on Cash-Choice Task Predicts Externalizing Outcomes in 17-Year-Olds

Delay-discounting, the tendency to prefer a smaller-sooner reward to a larger-later reward, has been associated with a range of externalizing behaviors. Laboratory delay-discounting tasks have emerged as a useful measure to index impulsivity and a proclivity towards externalizing pyschopathology. While many studies demonstrate the existence of a latent externalizing factor that is heritable, there have been few genetic studies of delay-discounting. Further, the increased vulnerability for risky behavior in adolescence makes adolescent samples an attractive target for future research, and expeditious, ecologically-valid delay-discounting measures are helpful in this regard. The primary goal of this study was to help validate the utility of a “cash-choice” measure for use in a sample of older adolescents. We used a sample of 17-year-old twins (n = 791) from the Minnesota Twin Family Enrichment study. Individuals who chose the smaller-sooner reward were more likely to have used a range of addictive substances, engaged in sexual intercourse, and earned lower GPAs. Best fitting biometric models from univariate analyses supported the heritability of cash-choice and externalizing, but bivariate modeling results indicated that the correlation between cash-choice and externalizing was determined largely by shared environmental influences, thus failing to support cash-choice as a possible endophenotype for externalizing in this age group. Our findings lend further support to the utility of cash-choice as a measure of individual differences in decision making and suggest that, by late adolescence, this task indexes shared environmental risk for externalizing behavior.     

Nicotine dependence and problem behaviors among urban South African adolescents

Tobacco use and its concomitant, nicotine dependence, are increasing in African countries and other parts of the developing world. However, little research has assessed nicotine dependence in South Africa or other parts of the African continent. Previous research has found that adolescent problem behaviors, including tobacco use, tend to cluster. This study examined the relationship between nicotine dependence and adolescent problem behaviors in an ethnically diverse sample of urban South African adolescents. A community sample (N = 731) consisting of “Black,” “White,” “Coloured,” and “Indian” youths aged 12–17 years was drawn from the Johannesburg metropolitan area. Structured interviews were administered by trained interviewers. Nicotine dependence was assessed by the Fagerström Test of Nicotine Dependence. Logistic regression analyses showed that higher levels of nicotine dependence significantly predicted elevated levels of violent behavior, deviant behavior, marijuana and other illegal drug use, binge drinking, early sexual intercourse, multiple sexual partners, and inconsistent condom use, despite control on the adolescents’ demographic characteristics, peer smoking, conflict with parents, peer deviance, and the availability of legal and illegal substances. These relationships were robust across ethnicity and gender. The findings indicate the need for policy makers and prevention and intervention programs in South Africa to consider adolescent nicotine dependence in conjunction with comorbid problem behaviors, including other substance use, sexual risk behaviors, and deviant behaviors.     

Childhood peer rejection and aggression as predictors of adolescent girls' externalizing and health risk behaviors: a 6-year longitudinal study

This 6-year longitudinal study examined girls' peer-nominated social preference and aggression in childhood as predictors of self- and parent-reported externalizing symptoms, substance use (i.e. cigarette, alcohol, and marijuana use), and sexual risk behavior in adolescence. Participants were 148 girls from diverse ethnic backgrounds, who were initially assessed in Grades 4-6 and again in Grades 10-12. Results supported a moderator model, indicating that social preference changed the nature of the association between childhood aggression and adolescent outcomes. When accompanied by peer rejection, aggressive behavior was moderately stable over time and significantly associated with adolescent girls' substance use and sexual risk behavior. However, under conditions of peer acceptance, no significant association between childhood aggression and adolescent outcomes emerged.     

Externalizing Behaviors are Associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster

There is strong evidence for shared genetic factors contributing to childhood externalizing disorders and substance abuse. Externalizing disorders often precede early substance experimentation, leading to the idea that individuals inherit a genetic vulnerability to generalized disinhibitory psychopathology. Genetic variation in the CHRNA5/CHRNA3/CHRNB4 gene cluster has been associated with early substance experimentation, nicotine dependence, and other drug behaviors. This study examines whether the CHRNA5/CHRNA3/CHRNB4 locus is correlated also with externalizing behaviors in three independent longitudinally assessed adolescent samples. We developed a common externalizing behavior phenotype from the available measures in the three samples, and tested for association with 10 SNPs in the gene cluster. Significant results were detected in two of the samples, including rs8040868, which remained significant after controlling for smoking quantity. These results expand on previous work focused mainly on drug behaviors, and support the hypothesis that variation in the CHRNA5/CHRNA3/CHRNB4 locus is associated with early externalizing behaviors.     

Estimation of Parental Effects Using Polygenic Scores

Offspring resemble their parents for both genetic and environmental reasons. Understanding the relative magnitude of these alternatives has long been a core interest in behavioral genetics research, but traditional designs, which compare phenotypic covariances to make inferences about unmeasured genetic and environmental factors, have struggled to disentangle them. Recently, Kong et al. (2018) showed that by correlating offspring phenotypic values with the measured polygenic score of parents’ nontransmitted alleles, one can estimate the effect of “genetic nurture”—a type of passive gene–environment covariation that arises when heritable parental traits directly influence offspring traits. Here, we instantiate this basic idea in a set of causal models that provide novel insights into the estimation of parental influences on offspring. Most importantly, we show how jointly modeling the parental polygenic scores and the offspring phenotypes can provide an unbiased estimate of the variation attributable to the environmental influence of parents on offspring, even when the polygenic score accounts for a small fraction of trait heritability. This model can be further extended to (a) account for the influence of different types of assortative mating, (b) estimate the total variation due to additive genetic effects and their covariance with the familial environment (i.e., the full genetic nurture effect), and (c) model situations where a parental trait influences a different offspring trait. By utilizing structural equation modeling techniques developed for extended twin family designs, our approach provides a general framework for modeling polygenic scores in family studies and allows for various model extensions that can be used to answer old questions about familial influences in new ways.

     

THE RELATION BETWEEN RISK AND PROTECTIVE FACTORS FOR PROBLEM BEHAVIORS AND DEPRESSIVE SYMPTOMS,ANTISOCIAL BEHAVIOR,AND ALCOHOL USE IN ADOLESCENCE

Both externalizing and internalizing psychopathology increase throughout adolescence and a similar set of risk and protective factors may underlie depressive symptoms, antisocial behavior, and alcohol use. Analyses test how risk and protective factors for externalizing behavior in community, school, family, peer, and individual domains are related to depressive symptoms, antisocial behavior, and alcohol use concurrently and longitudinally in a sample of 2,002 students assessed in 8^th and 10^th grades (52% male; 58% Caucasian). Findings indicate that risk and protective factors for antisocial behavior and alcohol use are also associated with depressive symptoms, both concurrently and longitudinally. Prevention approaches that target risk and protective factors for externalizing problems may have crossover effects on depressive symptoms during adolescence.     

Continuity of Genetic Risk for Aggressive Behavior Across the Life-Course

We test whether genetic influences that explain individual differences in aggression in early life also explain individual differences across the life-course. In two cohorts from The Netherlands (N?=?13,471) and Australia (N?=?5628), polygenic scores (PGSs) were computed based on a genome-wide meta-analysis of childhood/adolescence aggression. In a novel analytic approach, we ran a mixed effects model for each age (Netherlands: 12–70 years, Australia: 16–73 years), with observations at the focus age weighted as 1, and decaying weights for ages further away. We call this approach a ‘rolling weights’ model. In The Netherlands, the estimated effect of the PGS was relatively similar from age 12 to age 41, and decreased from age 41–70. In Australia, there was a peak in the effect of the PGS around age 40 years. These results are a first indication from a molecular genetics perspective that genetic influences on aggressive behavior that are expressed in childhood continue to play a role later in life.

     

The impact of receiving polygenic risk scores for alcohol use disorder on psychological distress,risk perception,and intentions to reduce drinking

For the return of polygenic risk scores to become an acceptable clinical practice in psychiatry, receipt of polygenic risk scores must be associated with minimal harm and changes in behavior that decrease one's risk for developing a psychiatric outcome. Data from a randomized controlled trial was used to assess the impact of different levels of hypothetical polygenic risk scores for alcohol use disorder on psychological distress, risk perception, and intentions to change drinking behaviors. The analytic sample consisted of 325 participants recruited from an urban, public university. Results demonstrated that there were significant increases in psychological distress as the level of genetic risk for alcohol use disorder increased. In addition, the perceived chance of developing alcohol use disorder significantly increased as the level of genetic risk increased. Promisingly, a greater proportion of participants indicated that they would intend to engage in follow-up behaviors, such as seeking additional information, talking to a healthcare provider about risk, and reducing drinking behaviors, as the level of genetic risk increased. Returning polygenic risk scores for alcohol use disorder in a clinical setting has the potential to promote risk-reducing behavior change, especially with increasing levels of genetic risk. The study was registered on ClinicalTrials.gov (Identifier: NCT05143073).     

Polygenic risk score as a possible tool for identifying familial monogenic causes of complex diseases

PurposeThe study aimed to evaluate whether polygenic risk scores could be helpful in addition to family history for triaging individuals to undergo deep-depth diagnostic sequencing for identifying monogenic causes of complex diseases.MethodsAmong 44,550 exome-sequenced European ancestry UK Biobank participants, we identified individuals with a clinically reported or computationally predicted monogenic pathogenic variant for breast cancer, bowel cancer, heart disease, diabetes, or Alzheimer disease. We derived polygenic risk scores for these diseases. We tested whether a polygenic risk score could identify rare pathogenic variant heterozygotes among individuals with a parental disease history.ResultsMonogenic causes of complex diseases were more prevalent among individuals with a parental disease history than in the rest of the population. Polygenic risk scores showed moderate discriminative power to identify familial monogenic causes. For instance, we showed that prescreening the patients with a polygenic risk score for type 2 diabetes can prioritize individuals to undergo diagnostic sequencing for monogenic diabetes variants and reduce needs for such sequencing by up to 37%.ConclusionAmong individuals with a family history of complex diseases, those with a low polygenic risk score are more likely to have monogenic causes of the disease and could be prioritized to undergo genetic testing.     

Etiology of Stability and Growth of Internalizing and Externalizing Behavior Problems Across Childhood and Adolescence

Internalizing and externalizing behaviors are heritable, and show genetic stability during childhood and adolescence. Less work has explored how genes influence individual differences in developmental trajectories. We estimated ACE biometrical latent growth curve models for the Teacher Report Form (TRF) and parent Child Behavior Checklist (CBCL) internalizing and externalizing scales from ages 7 to 16 years in 408 twin pairs from the Colorado Longitudinal Twin Study. We found that Intercept factors were highly heritable for both internalizing and externalizing behaviors (a2 = .61–.92), with small and nonsignificant environmental influences for teacher-rated data but significant nonshared environmental influences for parent-rated data. There was some evidence of heritability of decline in internalizing behavior (Slopes for teacher and parent ratings), but the Slope genetic variance was almost entirely shared with that for the Intercept when different than zero. These results suggest that genetic effects on these developmental trajectories operate primarily on initial levels and stability, with no significant unique genetic influences for change. Finally, cross-rater analyses of the growth factor scores revealed moderate to large genetic and environmental associations between growth factors derived from parents' and teachers' ratings, particularly the Intercepts.     

African American ancestry contribution to asthma and atopic dermatitis

ObjectiveAsthma and atopic dermatitis (AD) are complex diseases with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. Here we summarize current knowledge from asthma and AD genome-wide association studies (GWAS) and pharmacogenetic studies in African ancestry populations.Data SourcesGWAS catalog; PUBMed.Study SelectionsGWAS catalog studies with trait annotations “asthma” and “atopic eczema” and African ancestry individuals in the discovery dataset; the recent CAAPA asthma GWAS; reports on pharmacogenetic studies in asthma and AD.ResultsAlthough GWASs have revolutionized gene discovery for multiple complex traits, African Americans continue to be severely underrepresented in sufficiently powered genetics studies. Indeed, of the 16 asthma and 21 AD loci that reached genomewide significance in Europeans, very few have replicated in African ancestry populations. Challenges in comparing results from European vs African ancestry cohorts include modest sample size, differences in risk allele frequency, effect size, correlation between genetic variants, and environmental exposure in evolutionary history. African Americans also constitute a small percentage of dermatological and respiratory-focused clinical trials. Pharmacogenetic studies have similarly been focused largely on non-Hispanic whites, despite compelling evidence that genetic variation from different ancestral backgrounds may alter therapeutic efficacy of asthma and AD drugs.ConclusionLarge-scale genetic studies of asthma and AD in African Americans are essential to reduce research and health disparities and empower scientific discoveries.     

Predictors of risky sexual behavior in African American adolescent girls: implications for prevention interventions

OBJECTIVE: To describe empirically the risky sexual behavior of an at-risk sample of adolescent girls, to assess psychosocial correlates of risky behavior, and to examine the utility of applying a risk and protective model to predicting teens' risky sexual behavior. METHOD: Participants included 158 African American girls, ages 12 to 19, who were receiving medical care in an adolescent primary care clinic. Teens completed measures of depression, conduct problems, substance use, peer norms, social support, HIV knowledge, sexual self-efficacy, and sexual behavior. RESULTS: Teens in this sample reported high rates of risky sexual behaviors, including early sexual debuts and frequent unprotected sexual encounters with multiple partners. African American girls who reported high rates of substance use and who reported that their peers engaged in risky behaviors also reported engaging in high rates of risky sexual behaviors. Little support was obtained for protective factors (HIV knowledge, social support, sexual self-efficacy) moderating the relations between risk factors and adolescents' risky sexual behavior in this sample. CONCLUSIONS: Teens presenting in primary care settings in urban environments seem to be at high risk for HIV, STDs, and substance abuse, and risk reduction strategies should be introduced during the preteen years. An interdisciplinary model of care in primary care settings serving adolescents is clearly indicated, and prevention-oriented interventions aimed at reducing risky behaviors and preventing the development of more significant health, mental health, or substance abuse disorders are needed.     

Gene-Environment Correlation and Interaction in Peer Effects on Adolescent Alcohol and Tobacco Use

Peer relationships are commonly thought to be critical for adolescent socialization, including the development of negative health behaviors such as alcohol and tobacco use. The interplay between genetic liability and peer influences on the development of adolescent alcohol and tobacco use was examined using a nationally-representative sample of adolescent sibling pairs and their best friends. Genetic factors, some of them related to an adolescent's own substance use and some of them independent of use, were associated with increased exposure to best friends with heavy substance use--a gene-environment correlation. Moreover, adolescents who were genetically liable to substance use were more vulnerable to the adverse influences of their best friends--a gene-environment interaction.     

Peer rejection in childhood, involvement with antisocial peers in early adolescence, and the development of externalizing behavior problems

A longitudinal, prospective design was used to examine the roles of peer rejection in middle childhood and antisocial peer involvement in early adolescence in the development of adolescent externalizing behavior problems. Both early starter and late starter pathways were considered. Classroom sociometric interviews from ages 6 through 9 years, adolescent reports of peers' behavior at age 13 years, and parent, teacher, and adolescent self-reports of externalizing behavior problems from age 5 through 14 years were available for 400 adolescents. Results indicate that experiencing peer rejection in elementary school and greater involvement with antisocial peers in early adolescence are correlated but that these peer relationship experiences may represent two different pathways to adolescent externalizing behavior problems. Peer rejection experiences, but not involvement with antisocial peers. predict later externalizing behavior problems when controlling for stability in externalizing behavior. Externalizing problems were most common when rejection was experienced repeatedly. Early externalizing problems did not appear to moderate the relation between peer rejection and later problem behavior. Discussion highlights multiple pathways connecting externalizing behavior problems from early childhood through adolescence with peer relationship experiences in middle childhood and early adolescence.