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Matt Mcgue - One of the best experts on this subject based on the ideXlab platform.

  • polygenic risk score for smoking is associated with externalizing psychopathology and disinhibited personality traits but not internalizing psychopathology in adolescence
    bioRxiv, 2020
    Co-Authors: Brian M Hicks, William G Iacono, Matt Mcgue, Emily C Durbin, Angus D Clark, Joseph D Deak, Mengzhen Liu, Jonathan D Schaefer, Sylia Wilson, Scott I. Vrieze
    Abstract:

    ImportanceLarge consortia of genome wide association studies have yielded more accurate polygenic risk scores (PRS) that aggregate the small effects of many genetic variants to characterize the genetic architecture of disorders and provide a personalized measure of genetic risk. ObjectiveWe examined whether a PRS for smoking measured genetic risk for general Behavioral Disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits. We examined these associations at multiple time points in adolescence using more refined phenotypes defined by stable characteristics across time and at young ages, which reduced potential confounds associated with cumulative exposure to substances and reverse causality. MethodsRandom intercept panel models were fit to symptoms of conduct disorder, oppositional defiant disorder, major depressive disorder (MDD), and teacher ratings of externalizing and internalizing problems and personality traits at ages 11, 14, and 17 years-old in the Minnesota Twin Family Study (N = 3225). ResultsThe smoking PRS had strong associations with the random intercept factors for all the externalizing measures (mean standardized {beta} = .27), agreeableness ({beta}=-.22, 95% CI: -.28, -.16), and conscientiousness ({beta}=-.19, 95% CI: -.24, -.13), but was not significantly associated with the internalizing measures (mean {beta} = .06) or extraversion ({beta}=.01, 95% CI: -.05, .07). After controlling for smoking at age 17, the associations with the externalizing measures (mean {beta} = .13) and personality traits related to Behavioral control (mean {beta} = -.10) remained statistically significant. Conclusions and RelevanceThe smoking PRS measures genetic influences that contribute to a spectrum of phenotypes related to Behavioral Disinhibition including externalizing psychopathology and normal-range personality traits related to Behavioral control, but not internalizing psychopathology. Continuing to identify the correlates and delineate the mechanisms of the genetic influences associated with Disinhibition could have substantial impact in mitigating a variety of public health problems (e.g., mental health, academic achievement, criminality). Key PointsO_ST_ABSQuestionC_ST_ABSDoes a polygenic risk scores (PRS) for smoking measure genetic risk for Behavioral Disinhibition in general? FindingsThe smoking PRS was associated with externalizing psychopathology and personality traits related to Behavioral control, but not internalizing psychopathology and extraversion during adolescence, even after controlling for smoking status. MeaningThe smoking PRS measures genetic influences on Behavioral Disinhibition in general which is associated with a variety of important outcomes including mental health, academic success, and criminality.

  • Genome-Wide Association Study of Behavioral Disinhibition in a Selected Adolescent Sample
    Behavior Genetics, 2015
    Co-Authors: Jaime Derringer, Brett C Haberstick, William G Iacono, Matt Mcgue, Susan E Young, Robin P Corley, Brittany A. Demmitt, Daniel P. Howrigan, Robert M. Kirkpatrick, Matthew C. Keller
    Abstract:

    Behavioral Disinhibition (BD) is a quantitative measure designed to capture the heritable variation encompassing risky and impulsive behaviors. As a result, BD represents an ideal target for discovering genetic loci that predispose individuals to a wide range of antisocial behaviors and substance misuse that together represent a large cost to society as a whole. Published genome-wide association studies (GWAS) have examined specific phenotypes that fall under the umbrella of BD (e.g. alcohol dependence, conduct disorder); however no GWAS has specifically examined the overall BD construct. We conducted a GWAS of BD using a sample of 1,901 adolescents over-selected for characteristics that define high BD, such as substance and antisocial behavior problems, finding no individual locus that surpassed genome-wide significance. Although no single SNP was significantly associated with BD, restricted maximum likelihood analysis estimated that 49.3 % of the variance in BD within the Caucasian sub-sample was accounted for by the genotyped SNPs ( p  = 0.06). Gene-based tests identified seven genes associated with BD ( p  ≤ 2.0 × 10^−6). Although the current study was unable to identify specific SNPs or pathways with replicable effects on BD, the substantial sample variance that could be explained by all genotyped SNPs suggests that larger studies could successfully identify common variants associated with BD.

  • rare nonsynonymous exonic variants in addiction and Behavioral Disinhibition
    Biological Psychiatry, 2014
    Co-Authors: Scott I. Vrieze, Brian M Hicks, William G Iacono, Michael B Miller, Shuang Feng, Nathan Pankratz, Goncalo R Abecasis, Matt Mcgue
    Abstract:

    Background Substance use is heritable, but few common genetic variants have been associated with these behaviors. Rare nonsynonymous exonic variants can now be efficiently genotyped, allowing exome-wide association tests. We identified and tested 111,592 nonsynonymous exonic variants for association with Behavioral Disinhibition and the use/misuse of nicotine, alcohol, and illicit drugs. Methods Comprehensive genotyping of exonic variation combined with single-variant and gene-based tests of association was conducted in 7181 individuals; 172 candidate addiction genes were evaluated in greater detail. We also evaluated the aggregate effects of nonsynonymous variants on these phenotypes using Genome-wide Complex Trait Analysis. Results No variant or gene was significantly associated with any phenotype. No association was found for any of the 172 candidate genes, even at reduced significance thresholds. All nonsynonymous variants jointly accounted for 35% of the heritability in illicit drug use and, when combined with common variants from a genome-wide array, accounted for 84% of the heritability. Conclusions Rare nonsynonymous variants may be important in etiology of illicit drug use, but detection of individual variants will require very large samples.

  • a genome wide association study of Behavioral Disinhibition
    Behavior Genetics, 2013
    Co-Authors: Saonli Basu, Brian M Hicks, William S Oetting, Scott I. Vrieze, Steve Malone, Matt Mcgue, Yiwei Zhang, Michael B Miller, William G Iacono
    Abstract:

    We report results from a genome wide association study (GWAS) of five quantitative indicators of Behavioral Disinhibition: nicotine, alcohol consumption, alcohol dependence, illicit drugs, and non-substance related Behavioral Disinhibition. The sample, consisting of 7,188 Caucasian individuals clustered in 2,300 nuclear families, was genotyped on over 520,000 SNP markers from Illumina’s Human 660W-Quad Array. Analysis of individual SNP associations revealed only one marker-component phenotype association, between rs1868152 and illicit drugs, with a p value below the standard genome-wide threshold of 5 × 10−8. Because we had analyzed five separate phenotypes, we do not consider this single association to be significant. However, we report 13 SNPs that were associated at p < 10−5 for one phenotype and p < 10−3 for at least two other phenotypes, which are potential candidates for future investigations of variants associated with general Behavioral Disinhibition. Biometric analysis of the twin and family data yielded estimates of additive heritability for the component phenotypes ranging from 49 to 70 %, GCTA estimates of heritability for the same phenotypes ranged from 8 to 37 %. Consequently, even though the common variants genotyped on the GWAS array appear in aggregate to account for a sizable proportion of heritable effects in multiple indicators of Behavioral Disinhibition, our data suggest that most of the additive heritability remains “missing”.

  • three mutually informative ways to understand the genetic relationships among Behavioral Disinhibition alcohol use drug use nicotine use dependence and their co occurrence twin biometry gcta and genome wide scoring
    Behavior Genetics, 2013
    Co-Authors: Scott I. Vrieze, Brian M Hicks, Matt Mcgue, Michael B Miller, William G Iacono
    Abstract:

    Behavioral Disinhibition is a trait hypothesized to represent a general vulnerability to the development of substance use disorders. We used a large community-representative sample (N = 7,188) to investigate the genetic and environmental relationships among measures of Behavioral Disinhibition, Nicotine Use/Dependence, Alcohol Consumption, Alcohol Dependence, and Drug Use. First, using a subsample of twins (N = 2,877), we used standard twin models to estimate the additive genetic, shared environmental, and non-shared environmental contributions to these five traits. Heritabilities ranged from .42 to .58 and shared environmental effects ranged from .12 to .24. Phenotypic correlations among the five traits were largely attributable to shared genetic effects. Second, we used Genome-wide Complex Trait Analysis (GCTA) to estimate as a random effect the aggregate genetic effect attributable to 515,384 common SNPs. The aggregated SNPs explained 10–30 % of the variance in the traits. Third, a genome-wide scoring approach summed the actual SNPs, creating a SNP-based genetic risk score for each individual. After tenfold internal cross-validation, the SNP sumscore correlated with the traits at .03 to .07 (p < .05), indicating small but detectable effects. SNP sumscores generated on one trait correlated at approximately the same magnitude with other traits, indicating detectable pleiotropic effects among these traits. Behavioral Disinhibition thus shares genetic etiology with measures of substance use, and this relationship is detectable at the level of measured genomic variation.

William G Iacono - One of the best experts on this subject based on the ideXlab platform.

  • polygenic risk score for smoking is associated with externalizing psychopathology and disinhibited personality traits but not internalizing psychopathology in adolescence
    bioRxiv, 2020
    Co-Authors: Brian M Hicks, William G Iacono, Matt Mcgue, Emily C Durbin, Angus D Clark, Joseph D Deak, Mengzhen Liu, Jonathan D Schaefer, Sylia Wilson, Scott I. Vrieze
    Abstract:

    ImportanceLarge consortia of genome wide association studies have yielded more accurate polygenic risk scores (PRS) that aggregate the small effects of many genetic variants to characterize the genetic architecture of disorders and provide a personalized measure of genetic risk. ObjectiveWe examined whether a PRS for smoking measured genetic risk for general Behavioral Disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits. We examined these associations at multiple time points in adolescence using more refined phenotypes defined by stable characteristics across time and at young ages, which reduced potential confounds associated with cumulative exposure to substances and reverse causality. MethodsRandom intercept panel models were fit to symptoms of conduct disorder, oppositional defiant disorder, major depressive disorder (MDD), and teacher ratings of externalizing and internalizing problems and personality traits at ages 11, 14, and 17 years-old in the Minnesota Twin Family Study (N = 3225). ResultsThe smoking PRS had strong associations with the random intercept factors for all the externalizing measures (mean standardized {beta} = .27), agreeableness ({beta}=-.22, 95% CI: -.28, -.16), and conscientiousness ({beta}=-.19, 95% CI: -.24, -.13), but was not significantly associated with the internalizing measures (mean {beta} = .06) or extraversion ({beta}=.01, 95% CI: -.05, .07). After controlling for smoking at age 17, the associations with the externalizing measures (mean {beta} = .13) and personality traits related to Behavioral control (mean {beta} = -.10) remained statistically significant. Conclusions and RelevanceThe smoking PRS measures genetic influences that contribute to a spectrum of phenotypes related to Behavioral Disinhibition including externalizing psychopathology and normal-range personality traits related to Behavioral control, but not internalizing psychopathology. Continuing to identify the correlates and delineate the mechanisms of the genetic influences associated with Disinhibition could have substantial impact in mitigating a variety of public health problems (e.g., mental health, academic achievement, criminality). Key PointsO_ST_ABSQuestionC_ST_ABSDoes a polygenic risk scores (PRS) for smoking measure genetic risk for Behavioral Disinhibition in general? FindingsThe smoking PRS was associated with externalizing psychopathology and personality traits related to Behavioral control, but not internalizing psychopathology and extraversion during adolescence, even after controlling for smoking status. MeaningThe smoking PRS measures genetic influences on Behavioral Disinhibition in general which is associated with a variety of important outcomes including mental health, academic success, and criminality.

  • Genome-Wide Association Study of Behavioral Disinhibition in a Selected Adolescent Sample
    Behavior Genetics, 2015
    Co-Authors: Jaime Derringer, Brett C Haberstick, William G Iacono, Matt Mcgue, Susan E Young, Robin P Corley, Brittany A. Demmitt, Daniel P. Howrigan, Robert M. Kirkpatrick, Matthew C. Keller
    Abstract:

    Behavioral Disinhibition (BD) is a quantitative measure designed to capture the heritable variation encompassing risky and impulsive behaviors. As a result, BD represents an ideal target for discovering genetic loci that predispose individuals to a wide range of antisocial behaviors and substance misuse that together represent a large cost to society as a whole. Published genome-wide association studies (GWAS) have examined specific phenotypes that fall under the umbrella of BD (e.g. alcohol dependence, conduct disorder); however no GWAS has specifically examined the overall BD construct. We conducted a GWAS of BD using a sample of 1,901 adolescents over-selected for characteristics that define high BD, such as substance and antisocial behavior problems, finding no individual locus that surpassed genome-wide significance. Although no single SNP was significantly associated with BD, restricted maximum likelihood analysis estimated that 49.3 % of the variance in BD within the Caucasian sub-sample was accounted for by the genotyped SNPs ( p  = 0.06). Gene-based tests identified seven genes associated with BD ( p  ≤ 2.0 × 10^−6). Although the current study was unable to identify specific SNPs or pathways with replicable effects on BD, the substantial sample variance that could be explained by all genotyped SNPs suggests that larger studies could successfully identify common variants associated with BD.

  • rare nonsynonymous exonic variants in addiction and Behavioral Disinhibition
    Biological Psychiatry, 2014
    Co-Authors: Scott I. Vrieze, Brian M Hicks, William G Iacono, Michael B Miller, Shuang Feng, Nathan Pankratz, Goncalo R Abecasis, Matt Mcgue
    Abstract:

    Background Substance use is heritable, but few common genetic variants have been associated with these behaviors. Rare nonsynonymous exonic variants can now be efficiently genotyped, allowing exome-wide association tests. We identified and tested 111,592 nonsynonymous exonic variants for association with Behavioral Disinhibition and the use/misuse of nicotine, alcohol, and illicit drugs. Methods Comprehensive genotyping of exonic variation combined with single-variant and gene-based tests of association was conducted in 7181 individuals; 172 candidate addiction genes were evaluated in greater detail. We also evaluated the aggregate effects of nonsynonymous variants on these phenotypes using Genome-wide Complex Trait Analysis. Results No variant or gene was significantly associated with any phenotype. No association was found for any of the 172 candidate genes, even at reduced significance thresholds. All nonsynonymous variants jointly accounted for 35% of the heritability in illicit drug use and, when combined with common variants from a genome-wide array, accounted for 84% of the heritability. Conclusions Rare nonsynonymous variants may be important in etiology of illicit drug use, but detection of individual variants will require very large samples.

  • a genome wide association study of Behavioral Disinhibition
    Behavior Genetics, 2013
    Co-Authors: Saonli Basu, Brian M Hicks, William S Oetting, Scott I. Vrieze, Steve Malone, Matt Mcgue, Yiwei Zhang, Michael B Miller, William G Iacono
    Abstract:

    We report results from a genome wide association study (GWAS) of five quantitative indicators of Behavioral Disinhibition: nicotine, alcohol consumption, alcohol dependence, illicit drugs, and non-substance related Behavioral Disinhibition. The sample, consisting of 7,188 Caucasian individuals clustered in 2,300 nuclear families, was genotyped on over 520,000 SNP markers from Illumina’s Human 660W-Quad Array. Analysis of individual SNP associations revealed only one marker-component phenotype association, between rs1868152 and illicit drugs, with a p value below the standard genome-wide threshold of 5 × 10−8. Because we had analyzed five separate phenotypes, we do not consider this single association to be significant. However, we report 13 SNPs that were associated at p < 10−5 for one phenotype and p < 10−3 for at least two other phenotypes, which are potential candidates for future investigations of variants associated with general Behavioral Disinhibition. Biometric analysis of the twin and family data yielded estimates of additive heritability for the component phenotypes ranging from 49 to 70 %, GCTA estimates of heritability for the same phenotypes ranged from 8 to 37 %. Consequently, even though the common variants genotyped on the GWAS array appear in aggregate to account for a sizable proportion of heritable effects in multiple indicators of Behavioral Disinhibition, our data suggest that most of the additive heritability remains “missing”.

  • three mutually informative ways to understand the genetic relationships among Behavioral Disinhibition alcohol use drug use nicotine use dependence and their co occurrence twin biometry gcta and genome wide scoring
    Behavior Genetics, 2013
    Co-Authors: Scott I. Vrieze, Brian M Hicks, Matt Mcgue, Michael B Miller, William G Iacono
    Abstract:

    Behavioral Disinhibition is a trait hypothesized to represent a general vulnerability to the development of substance use disorders. We used a large community-representative sample (N = 7,188) to investigate the genetic and environmental relationships among measures of Behavioral Disinhibition, Nicotine Use/Dependence, Alcohol Consumption, Alcohol Dependence, and Drug Use. First, using a subsample of twins (N = 2,877), we used standard twin models to estimate the additive genetic, shared environmental, and non-shared environmental contributions to these five traits. Heritabilities ranged from .42 to .58 and shared environmental effects ranged from .12 to .24. Phenotypic correlations among the five traits were largely attributable to shared genetic effects. Second, we used Genome-wide Complex Trait Analysis (GCTA) to estimate as a random effect the aggregate genetic effect attributable to 515,384 common SNPs. The aggregated SNPs explained 10–30 % of the variance in the traits. Third, a genome-wide scoring approach summed the actual SNPs, creating a SNP-based genetic risk score for each individual. After tenfold internal cross-validation, the SNP sumscore correlated with the traits at .03 to .07 (p < .05), indicating small but detectable effects. SNP sumscores generated on one trait correlated at approximately the same magnitude with other traits, indicating detectable pleiotropic effects among these traits. Behavioral Disinhibition thus shares genetic etiology with measures of substance use, and this relationship is detectable at the level of measured genomic variation.

Rick Kosterman - One of the best experts on this subject based on the ideXlab platform.

  • time varying effects of family smoking and family management on adolescent daily smoking the moderating roles of Behavioral Disinhibition and anxiety
    Drug and Alcohol Dependence, 2019
    Co-Authors: Christine M Steeger, Marina Epstein, Allison N Kristmanvalente, Jennifer A Bailey, Karl G Hill, Rick Kosterman
    Abstract:

    Abstract Background Family smoking environment and family management are associated with risk of teen smoking behaviors. However, less is known about whether these associations increase or decrease in strength across adolescence, and whether there are person-environment interactions. The current study examined 1) the age-varying main effects of family smoking and family management on adolescent daily smoking from ages 12–18 and tested 2) whether Behavioral Disinhibition and anxiety moderated these relationships. Methods Data were drawn from the Seattle Social Development Project (SSDP; N = 808), a longitudinal study examining prosocial and antisocial behavior. Analyses used time-varying effect modeling (TVEM), which tested the stability of the relationship between family smoking and family management and youth daily smoking across adolescence. Results Greater family smoking increased the likelihood of adolescent daily smoking, whereas greater family management reduced the likelihood of daily smoking. Significant interactions between family management and youth Behavioral Disinhibition and anxiety during early and mid-adolescence indicated that family management was more protective for adolescents with low (compared to high) Behavioral Disinhibition and anxiety. The effect of family smoking was not moderated by Behavioral Disinhibition or anxiety. Conclusions Family smoking and family management are key risk and protective factors that may be targeted for adolescent smoking prevention. Our interaction results for individual differences in Behavioral Disinhibition and anxiety suggest that certain types of youth may respond differently to family management practices. Findings also show periods during adolescence where family-centered preventive interventions could be optimally timed to prevent or reduce persistent adolescent smoking.

  • time varying effects of family smoking and family management on adolescent daily smoking the moderating roles of Behavioral Disinhibition and anxiety
    Drug and Alcohol Dependence, 2019
    Co-Authors: Christine M Steeger, Marina Epstein, Allison N Kristmanvalente, Jennifer A Bailey, Karl G Hill, Rick Kosterman
    Abstract:

    Abstract Background Family smoking environment and family management are associated with risk of teen smoking behaviors. However, less is known about whether these associations increase or decrease in strength across adolescence, and whether there are person-environment interactions. The current study examined 1) the age-varying main effects of family smoking and family management on adolescent daily smoking from ages 12–18 and tested 2) whether Behavioral Disinhibition and anxiety moderated these relationships. Methods Data were drawn from the Seattle Social Development Project (SSDP; N = 808), a longitudinal study examining prosocial and antisocial behavior. Analyses used time-varying effect modeling (TVEM), which tested the stability of the relationship between family smoking and family management and youth daily smoking across adolescence. Results Greater family smoking increased the likelihood of adolescent daily smoking, whereas greater family management reduced the likelihood of daily smoking. Significant interactions between family management and youth Behavioral Disinhibition and anxiety during early and mid-adolescence indicated that family management was more protective for adolescents with low (compared to high) Behavioral Disinhibition and anxiety. The effect of family smoking was not moderated by Behavioral Disinhibition or anxiety. Conclusions Family smoking and family management are key risk and protective factors that may be targeted for adolescent smoking prevention. Our interaction results for individual differences in Behavioral Disinhibition and anxiety suggest that certain types of youth may respond differently to family management practices. Findings also show periods during adolescence where family-centered preventive interventions could be optimally timed to prevent or reduce persistent adolescent smoking.

Christine M Steeger - One of the best experts on this subject based on the ideXlab platform.

  • time varying effects of family smoking and family management on adolescent daily smoking the moderating roles of Behavioral Disinhibition and anxiety
    Drug and Alcohol Dependence, 2019
    Co-Authors: Christine M Steeger, Marina Epstein, Allison N Kristmanvalente, Jennifer A Bailey, Karl G Hill, Rick Kosterman
    Abstract:

    Abstract Background Family smoking environment and family management are associated with risk of teen smoking behaviors. However, less is known about whether these associations increase or decrease in strength across adolescence, and whether there are person-environment interactions. The current study examined 1) the age-varying main effects of family smoking and family management on adolescent daily smoking from ages 12–18 and tested 2) whether Behavioral Disinhibition and anxiety moderated these relationships. Methods Data were drawn from the Seattle Social Development Project (SSDP; N = 808), a longitudinal study examining prosocial and antisocial behavior. Analyses used time-varying effect modeling (TVEM), which tested the stability of the relationship between family smoking and family management and youth daily smoking across adolescence. Results Greater family smoking increased the likelihood of adolescent daily smoking, whereas greater family management reduced the likelihood of daily smoking. Significant interactions between family management and youth Behavioral Disinhibition and anxiety during early and mid-adolescence indicated that family management was more protective for adolescents with low (compared to high) Behavioral Disinhibition and anxiety. The effect of family smoking was not moderated by Behavioral Disinhibition or anxiety. Conclusions Family smoking and family management are key risk and protective factors that may be targeted for adolescent smoking prevention. Our interaction results for individual differences in Behavioral Disinhibition and anxiety suggest that certain types of youth may respond differently to family management practices. Findings also show periods during adolescence where family-centered preventive interventions could be optimally timed to prevent or reduce persistent adolescent smoking.

  • time varying effects of family smoking and family management on adolescent daily smoking the moderating roles of Behavioral Disinhibition and anxiety
    Drug and Alcohol Dependence, 2019
    Co-Authors: Christine M Steeger, Marina Epstein, Allison N Kristmanvalente, Jennifer A Bailey, Karl G Hill, Rick Kosterman
    Abstract:

    Abstract Background Family smoking environment and family management are associated with risk of teen smoking behaviors. However, less is known about whether these associations increase or decrease in strength across adolescence, and whether there are person-environment interactions. The current study examined 1) the age-varying main effects of family smoking and family management on adolescent daily smoking from ages 12–18 and tested 2) whether Behavioral Disinhibition and anxiety moderated these relationships. Methods Data were drawn from the Seattle Social Development Project (SSDP; N = 808), a longitudinal study examining prosocial and antisocial behavior. Analyses used time-varying effect modeling (TVEM), which tested the stability of the relationship between family smoking and family management and youth daily smoking across adolescence. Results Greater family smoking increased the likelihood of adolescent daily smoking, whereas greater family management reduced the likelihood of daily smoking. Significant interactions between family management and youth Behavioral Disinhibition and anxiety during early and mid-adolescence indicated that family management was more protective for adolescents with low (compared to high) Behavioral Disinhibition and anxiety. The effect of family smoking was not moderated by Behavioral Disinhibition or anxiety. Conclusions Family smoking and family management are key risk and protective factors that may be targeted for adolescent smoking prevention. Our interaction results for individual differences in Behavioral Disinhibition and anxiety suggest that certain types of youth may respond differently to family management practices. Findings also show periods during adolescence where family-centered preventive interventions could be optimally timed to prevent or reduce persistent adolescent smoking.

Brian M Hicks - One of the best experts on this subject based on the ideXlab platform.

  • polygenic risk score for smoking is associated with externalizing psychopathology and disinhibited personality traits but not internalizing psychopathology in adolescence
    bioRxiv, 2020
    Co-Authors: Brian M Hicks, William G Iacono, Matt Mcgue, Emily C Durbin, Angus D Clark, Joseph D Deak, Mengzhen Liu, Jonathan D Schaefer, Sylia Wilson, Scott I. Vrieze
    Abstract:

    ImportanceLarge consortia of genome wide association studies have yielded more accurate polygenic risk scores (PRS) that aggregate the small effects of many genetic variants to characterize the genetic architecture of disorders and provide a personalized measure of genetic risk. ObjectiveWe examined whether a PRS for smoking measured genetic risk for general Behavioral Disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits. We examined these associations at multiple time points in adolescence using more refined phenotypes defined by stable characteristics across time and at young ages, which reduced potential confounds associated with cumulative exposure to substances and reverse causality. MethodsRandom intercept panel models were fit to symptoms of conduct disorder, oppositional defiant disorder, major depressive disorder (MDD), and teacher ratings of externalizing and internalizing problems and personality traits at ages 11, 14, and 17 years-old in the Minnesota Twin Family Study (N = 3225). ResultsThe smoking PRS had strong associations with the random intercept factors for all the externalizing measures (mean standardized {beta} = .27), agreeableness ({beta}=-.22, 95% CI: -.28, -.16), and conscientiousness ({beta}=-.19, 95% CI: -.24, -.13), but was not significantly associated with the internalizing measures (mean {beta} = .06) or extraversion ({beta}=.01, 95% CI: -.05, .07). After controlling for smoking at age 17, the associations with the externalizing measures (mean {beta} = .13) and personality traits related to Behavioral control (mean {beta} = -.10) remained statistically significant. Conclusions and RelevanceThe smoking PRS measures genetic influences that contribute to a spectrum of phenotypes related to Behavioral Disinhibition including externalizing psychopathology and normal-range personality traits related to Behavioral control, but not internalizing psychopathology. Continuing to identify the correlates and delineate the mechanisms of the genetic influences associated with Disinhibition could have substantial impact in mitigating a variety of public health problems (e.g., mental health, academic achievement, criminality). Key PointsO_ST_ABSQuestionC_ST_ABSDoes a polygenic risk scores (PRS) for smoking measure genetic risk for Behavioral Disinhibition in general? FindingsThe smoking PRS was associated with externalizing psychopathology and personality traits related to Behavioral control, but not internalizing psychopathology and extraversion during adolescence, even after controlling for smoking status. MeaningThe smoking PRS measures genetic influences on Behavioral Disinhibition in general which is associated with a variety of important outcomes including mental health, academic success, and criminality.

  • rare nonsynonymous exonic variants in addiction and Behavioral Disinhibition
    Biological Psychiatry, 2014
    Co-Authors: Scott I. Vrieze, Brian M Hicks, William G Iacono, Michael B Miller, Shuang Feng, Nathan Pankratz, Goncalo R Abecasis, Matt Mcgue
    Abstract:

    Background Substance use is heritable, but few common genetic variants have been associated with these behaviors. Rare nonsynonymous exonic variants can now be efficiently genotyped, allowing exome-wide association tests. We identified and tested 111,592 nonsynonymous exonic variants for association with Behavioral Disinhibition and the use/misuse of nicotine, alcohol, and illicit drugs. Methods Comprehensive genotyping of exonic variation combined with single-variant and gene-based tests of association was conducted in 7181 individuals; 172 candidate addiction genes were evaluated in greater detail. We also evaluated the aggregate effects of nonsynonymous variants on these phenotypes using Genome-wide Complex Trait Analysis. Results No variant or gene was significantly associated with any phenotype. No association was found for any of the 172 candidate genes, even at reduced significance thresholds. All nonsynonymous variants jointly accounted for 35% of the heritability in illicit drug use and, when combined with common variants from a genome-wide array, accounted for 84% of the heritability. Conclusions Rare nonsynonymous variants may be important in etiology of illicit drug use, but detection of individual variants will require very large samples.

  • a genome wide association study of Behavioral Disinhibition
    Behavior Genetics, 2013
    Co-Authors: Saonli Basu, Brian M Hicks, William S Oetting, Scott I. Vrieze, Steve Malone, Matt Mcgue, Yiwei Zhang, Michael B Miller, William G Iacono
    Abstract:

    We report results from a genome wide association study (GWAS) of five quantitative indicators of Behavioral Disinhibition: nicotine, alcohol consumption, alcohol dependence, illicit drugs, and non-substance related Behavioral Disinhibition. The sample, consisting of 7,188 Caucasian individuals clustered in 2,300 nuclear families, was genotyped on over 520,000 SNP markers from Illumina’s Human 660W-Quad Array. Analysis of individual SNP associations revealed only one marker-component phenotype association, between rs1868152 and illicit drugs, with a p value below the standard genome-wide threshold of 5 × 10−8. Because we had analyzed five separate phenotypes, we do not consider this single association to be significant. However, we report 13 SNPs that were associated at p < 10−5 for one phenotype and p < 10−3 for at least two other phenotypes, which are potential candidates for future investigations of variants associated with general Behavioral Disinhibition. Biometric analysis of the twin and family data yielded estimates of additive heritability for the component phenotypes ranging from 49 to 70 %, GCTA estimates of heritability for the same phenotypes ranged from 8 to 37 %. Consequently, even though the common variants genotyped on the GWAS array appear in aggregate to account for a sizable proportion of heritable effects in multiple indicators of Behavioral Disinhibition, our data suggest that most of the additive heritability remains “missing”.

  • three mutually informative ways to understand the genetic relationships among Behavioral Disinhibition alcohol use drug use nicotine use dependence and their co occurrence twin biometry gcta and genome wide scoring
    Behavior Genetics, 2013
    Co-Authors: Scott I. Vrieze, Brian M Hicks, Matt Mcgue, Michael B Miller, William G Iacono
    Abstract:

    Behavioral Disinhibition is a trait hypothesized to represent a general vulnerability to the development of substance use disorders. We used a large community-representative sample (N = 7,188) to investigate the genetic and environmental relationships among measures of Behavioral Disinhibition, Nicotine Use/Dependence, Alcohol Consumption, Alcohol Dependence, and Drug Use. First, using a subsample of twins (N = 2,877), we used standard twin models to estimate the additive genetic, shared environmental, and non-shared environmental contributions to these five traits. Heritabilities ranged from .42 to .58 and shared environmental effects ranged from .12 to .24. Phenotypic correlations among the five traits were largely attributable to shared genetic effects. Second, we used Genome-wide Complex Trait Analysis (GCTA) to estimate as a random effect the aggregate genetic effect attributable to 515,384 common SNPs. The aggregated SNPs explained 10–30 % of the variance in the traits. Third, a genome-wide scoring approach summed the actual SNPs, creating a SNP-based genetic risk score for each individual. After tenfold internal cross-validation, the SNP sumscore correlated with the traits at .03 to .07 (p < .05), indicating small but detectable effects. SNP sumscores generated on one trait correlated at approximately the same magnitude with other traits, indicating detectable pleiotropic effects among these traits. Behavioral Disinhibition thus shares genetic etiology with measures of substance use, and this relationship is detectable at the level of measured genomic variation.

  • relationship between personality change and the onset and course of alcohol dependence in young adulthood
    Addiction, 2012
    Co-Authors: Brian M Hicks, William G Iacono, Emily C Durbin, Daniel M Blonigen, Matt Mcgue
    Abstract:

    Aims To examine the reciprocal effects between the onset and course of alcohol use disorder (AUD) and normative changes in personality traits of Behavioral Disinhibition and negative emotionality during the transition between adolescence and young adulthood. Design Longitudinal–epidemiological study assessing AUD and personality at ages 17 and 24 years.Setting Participants were recruited from the community and took part in a day-long, in-person assessment. Participants Male (n = 1161) and female (n = 1022) twins participating in the Minnesota Twin Family Study. Measurements The effects of onset (adolescent versus young adult) and course (persistent versus desistent) of AUD on change in personality traits of Behavioral Disinhibition and negative emotionality from ages 17 to 24 years. Findings Onset and course of AUD moderated personality change from ages 17 to 24 years. Adolescent onset AUD was associated with greater decreases in Behavioral Disinhibition. Those with an adolescent onset and persistent course failed to exhibit normative declines in negative emotionality. Desistence was associated with a ‘recovery’ towards psychological maturity in young adulthood, while persistence was associated with continued personality dysfunction. Personality traits at age 11 predicted onset and course of AUD, indicating personality differences were not due to active substance abuse.Conclusions Personality differences present prior to initiation of alcohol use increase risk for alcohol use disorder, but the course of alcohol use disorder affects the rate of personality change during emerging adulthood. Examining the reciprocal effects of personality and alcohol use disorder within a developmental context is necessary to improve understanding for theory and intervention.