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Genetic risk for schizophrenia is associated with substance use in emerging adulthood: an event-level polygenic prediction model.

ABSTRACT: BACKGROUND:Emerging adulthood is a peak period of risk for alcohol and illicit drug use. Recent advances in psychiatric genetics suggest that the co-occurrence of substance use and psychopathology arises, in part, from a shared genetic etiology. We sought to extend this research by investigating the influence of genetic risk for schizophrenia on trajectories of four substance use behaviors as they occurred across emerging adulthood. METHOD:Young adult participants of non-Hispanic European descent provided DNA samples and completed daily reports of substance use for 1 month per year across 4 years (N = 30 085 observations of N = 342 participants). A schizophrenia polygenic score was included in two-level hierarchical linear models designed to test associations between genetic risk for schizophrenia, participant age, and four substance use phenotypes. RESULTS:Participants with a greater schizophrenia polygenic score experienced greater age-related increases in the likelihood of using substances across emerging adulthood (p < 0.005). Additionally, our results suggest that the polygenic score was positively associated with participants' overall likelihood to engage in illicit drug use but not alcohol-related substance use. CONCLUSIONS:This study used a novel combination of polygenic prediction and intensive longitudinal methods to characterize the influence of genetic risk for schizophrenia on patterns of age-related change in substance use across emerging adulthood. Results suggest that genetic risk for schizophrenia has developmentally specific effects on substance use behaviors in a non-clinical population of young adults.

SUBMITTER: Mallard TT

PROVIDER: S-EPMC6711829 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Genetic risk for schizophrenia is associated with substance use in emerging adulthood: an event-level polygenic prediction model.

Mallard Travis T TT Harden K Paige KP Fromme Kim K

Psychological medicine 20181012 12

<h4>Background</h4>Emerging adulthood is a peak period of risk for alcohol and illicit drug use. Recent advances in psychiatric genetics suggest that the co-occurrence of substance use and psychopathology arises, in part, from a shared genetic etiology. We sought to extend this research by investigating the influence of genetic risk for schizophrenia on trajectories of four substance use behaviors as they occurred across emerging adulthood.<h4>Method</h4>Young adult participants of non-Hispanic ...[more]

PMID: 30309397

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Project description:BackgroundHeavy episodic drinking is developmentally normative among adolescents and young adults, but is linked to adverse consequences in later life, such as drug and alcohol dependence. Genetic and peer influences are robust predictors of heavy episodic drinking in youth, but little is known about the interplay between polygenic risk and peer influences as they impact developmental patterns of heavy episodic drinking.MethodsData were from a multisite prospective study of alcohol use among adolescents and young adults with genome-wide association data (n = 412). Generalized linear mixed models were used to characterize the initial status and slopes of heavy episodic drinking between age 15 and 28. Polygenic risk scores (PRS) were derived from a separate genome-wide association study for alcohol dependence and examined for their interaction with substance use among the adolescents' closest friends in predicting the initial status and slopes of heavy episodic drinking.ResultsClose friend substance use was a robust predictor of adolescent heavy episodic drinking, even after controlling for parental knowledge and peer substance use in the school. PRS were predictive of the initial status and early patterns of heavy episodic drinking in males, but not in females. No interaction was detected between PRS and close friend substance use for heavy episodic drinking trajectories in either males or females.ConclusionsAlthough substance use among close friends and genetic influences play an important role in predicting heavy episodic drinking trajectories, particularly during the late adolescent to early adult years, we found no evidence of interaction between these influences after controlling for other social processes, such as parental knowledge and broader substance use among other peers outside of close friends. The use of longitudinal models and accounting for multiple social influences may be crucial for future studies focused on uncovering gene-environment interplay. Clinical implications are also discussed.

Project description:Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome-wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow-up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome-wide single-nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta-analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC-SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation-based analysis revealed an excess of strongly associated loci among GWAS top-ranked signals for verbal working memory (WM) and antisaccade intra-subject reaction time variability (empirical P < 0.001), suggesting multiple true-positive single-SNP associations. Substantial heritability was observed for WM performance. Further, sustained attention/vigilance and WM were suggestively correlated with both COGENT and PGC-SZ derived polygenic scores. Overall, these results imply that common genetic variation explains some of the variability in neurocognitive functioning among young adults, particularly WM, and provide supportive evidence that increased SZ genetic risk predicts neurocognitive fluctuations in the general population.

Project description:BackgroundTo better characterize brain-based mechanisms of polygenic liability for psychopathology and psychological traits, we extended our previous report (Liu et al. Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci. Psychological Medicine, 2017), focused solely on schizophrenia, to test the association between multivariate psychophysiological candidate endophenotypes (including novel measures of θ/δ oscillatory activity) and a range of polygenic scores (PGSs), namely alcohol/cannabis/nicotine use, an updated schizophrenia PGS (containing 52 more genome-wide significant loci than the PGS used in our previous report) and educational attainment.MethodA large community-based twin/family sample (N = 4893) was genome-wide genotyped and imputed. PGSs were constructed for alcohol use, regular smoking initiation, lifetime cannabis use, schizophrenia, and educational attainment. Eleven endophenotypes were assessed: visual oddball task event-related electroencephalogram (EEG) measures (target-related parietal P3 amplitude, frontal θ, and parietal δ energy/inter-trial phase clustering), band-limited resting-state EEG power, antisaccade error rate. Principal component analysis exploited covariation among endophenotypes to extract a smaller number of meaningful dimensions/components for statistical analysis.ResultsEndophenotypes were heritable. PGSs showed expected intercorrelations (e.g. schizophrenia PGS correlated positively with alcohol/nicotine/cannabis PGSs). Schizophrenia PGS was negatively associated with an event-related P3/δ component [β = -0.032, nonparametric bootstrap 95% confidence interval (CI) -0.059 to -0.003]. A prefrontal control component (event-related θ/antisaccade errors) was negatively associated with alcohol (β = -0.034, 95% CI -0.063 to -0.006) and regular smoking PGSs (β = -0.032, 95% CI -0.061 to -0.005) and positively associated with educational attainment PGS (β = 0.031, 95% CI 0.003-0.058).ConclusionsEvidence suggests that multivariate endophenotypes of decision-making (P3/δ) and cognitive/attentional control (θ/antisaccade error) relate to alcohol/nicotine, schizophrenia, and educational attainment PGSs and represent promising targets for future research.

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Genetic risk for schizophrenia is associated with substance use in emerging adulthood: an event-level polygenic prediction model.

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Genetic risk for schizophrenia is associated with substance use in emerging adulthood: an event-level polygenic prediction model.

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