Abstract Past studies highlight a narrowing gender gap and the existence of a shared etiology across substances of abuse; however, few have tested developmental models using longitudinal data. We ...present data on developmental trends of alcohol, tobacco, and marijuana use, abuse and dependence assessed during adolescence and young adulthood in a community-based Colorado twin sample of 1733 respondents through self-report questionnaires and structured psychiatric interviews. Additionally, we report on the rates of multiple substance use and disorders at each developmental stage, and the likelihood of a substance use disorder (SUD; i.e., abuse or dependence) diagnosis in young adulthood based on adolescent drug involvement. Most notably, we evaluate whether the pattern of multiple substance use and disorders and likelihood ratios across substances support a model of generalized risk. Lastly, we evaluate whether the ranked magnitudes of substance-specific risk match the addiction liability ranking. Substance use and SUDs are developmental phenomena, which increase from adolescence to young adulthood with few and inconsistent gender differences. Adolescents and young adults are not specialized users, but rather tend to use or abuse multiple substances increasingly with age. Risk analyses indicated that progression toward a SUD for any substance was increased with prior involvement with any of the three substances during adolescence. Despite the high prevalence of alcohol use, tobacco posed the greatest substance-specific risk for developing subsequent problems. Our data also confirm either a generalized risk or correlated risk factors for early onset substance use and subsequent development of SUDs.
Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions, principally in cells of myeloid lineage. Cell culture studies suggest that itaconate ...regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and
mice with
(
) and monitored disease progression.
, but not WT, mice succumbed rapidly to
, and mortality was associated with increased infection, inflammation, and pathology. Infection of
-Cre
,
-Cre
, and
-Cre
conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in
myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA sequencing analyses suggest that Irg1 and its production of itaconate temper
-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, an Irg1 regulatory axis modulates inflammation to curtail
-induced lung disease.
Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and ...relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
We present data on the lifetime prevalence of substance use, abuse and dependence in adolescents obtained through structured psychiatric interviews and self-report questionnaires. Most notably, we ...evaluate symptom profiles based on DSM-IV abuse and dependence criteria for tobacco, alcohol and marijuana, including a gender comparison. Participants are 3072 adolescents (12–18 years) drawn from three community-based family samples in Colorado. Age trends suggest that substance use is a developmental phenomenon, which increases almost linearly from early to late adolescence. Substance use
disorders are less common than experimentation in adolescence, but approximately 1 in 4 adolescents in the oldest cohorts meets criteria for abuse for at least one substance, and 1 in 5 meets criteria for substance dependence. By age 18 nearly 1 in 3 adolescents report daily smoking and 8.6% meet criteria for tobacco dependence. Although alcohol is the most commonly
abused substance (10%), a slightly larger proportion of adolescents meet criteria for
dependence on marijuana (4.3%) than alcohol (3.5%). Gender differences in prevalence of use more often show greater use in males than females. Males more frequently meet criteria for dependence on alcohol and marijuana in late adolescence, while females are more often nicotine dependent. A comparison of abuse and dependence symptom profiles shows some interesting variability across substances, and suggests that manifestations of a subset of symptoms are gender specific.
Nicotine binds to nicotinic acetylcholine receptors and studies in animal models have shown that α4β2 receptors mediate many behavioral effects of nicotine. Human genetics studies have provided ...support that variation in the gene that codes for the α4 subunit influences nicotine dependence (ND), but the evidence for the involvement of the β2 subunit gene is less convincing. In this study, we examined the genetic association between variation in the genes that code for the α4 (CHRNA4) and β2 (CHRNB2) subunits of the nicotinic acetylcholine receptor and a quantitative measure of lifetime DSM‐IV ND symptom counts. We performed this analysis in two longitudinal family‐based studies focused on adolescent antisocial drug abuse: the Center on Antisocial Drug Dependence (CADD, N = 313 families) and Genetics of Antisocial Drug Dependence (GADD, N = 111 families). Family‐based association tests were used to examine associations between 14 single nucleotide polymorphisms (SNPs) in CHRNA4 and CHRNB2 and ND symptoms. Symptom counts were corrected for age, sex and clinical status prior to the association analysis. Results, when the samples were combined, provided modest evidence that SNPs in CHRNA4 are associated with ND. The minor allele at both rs1044394 (A; Z = 1.988, P = 0.047, unadjusted P‐value) and rs1044396 (G; Z = 2.398, P = 0.017, unadjusted P‐value) was associated with increased risk of ND symptoms. These data provide suggestive evidence that variation in the α4 subunit of the nicotinic acetylcholine receptor may influence ND liability.
Genetic variation in the α4 subunit of the nicotinic acetylcholine receptor is nominally associated with nicotine dependence liability.
Comorbidity among childhood disruptive behavioral disorders is commonly reported in both epidemiologic and clinical studies. These problems are also associated with early substance use and other ...markers of behavioral disinhibition. Previous twin research has suggested that much of the covariation between antisocial behavior and alcohol dependence is due to common genetic influences. Similar results have been reported for conduct problems and hyperactivity. For the present study, an adolescent sample consisting of 172 MZ and 162 DZ twin pairs, recruited through the Colorado Twin Registry and the Colorado Longitudinal Twin Study were assessed using standardized psychiatric interviews and personality assessments. DSM-IV symptom counts for conduct disorder and attention deficit hyperactivity disorder, along with a measure of substance experimentation and novelty seeking, were used as indices of a latent behavioral disinhibition trait. A confirmatory factor model fit to individual-level data showed a strong common factor accounting for 16-42% of the observed variance in each measure. A common pathway model evaluating the genetic and environmental architecture of the latent phenotype suggested that behavioral disinhibition is highly heritable (a(2) = 0.84), and is not influenced significantly by shared environmental factors. A residual correlation between conduct disorder and substance experimentation was explained by shared environmental effects, and a residual correlation between attention deficit hyperactivity disorder and novelty seeking was accounted for by genetic dominance. These results suggest that a variety of adolescent problem behaviors may share a common underlying genetic risk.
Previous phenotypic factor analyses suggest that
C. R. Cloninger's Tridimensional Personality Questionnaire (TPQ; 1987c)
assesses 4 rather than 3 temperament dimensions. The purpose of this study was ...to determine whether Cloninger's revised 4-factor model showed incremental validity over his original model and to investigate the convergent and discriminant validity of Cloninger's dimensions in comparison to the personality dimensions proposed by
H. J. Eysenck (1981)
and
J. A. Gray (1970)
.
The sample included 2, 420 women and 870 men (aged 50-96) from a volunteer population-based sample of twins. Joint phenotypic factor analyses supported Cloninger's 4-dimensional temperament model. A 4-dimensional genetical factor structure was also confirmed in genetic analyses of the TPQ higher order dimensions in women. For men only 3 genetic factors were necessary to explain the genetic variance among the TPQ dimensions.
Abstract Objective To identify robust predictors of drug dependence. Methods This longitudinal study included 2361 male and female twins from an ongoing longitudinal study at the Center for ...Antisocial Drug Dependence (CADD) at the University of Colorado Boulder and Denver campuses. Twins were recruited for the CADD project while they were between the ages of 12 and 18. Participants in the current study were on average approximately 15 years of age during the first wave of assessment and approximately 20 years of age at the second wave of assessment. The average time between assessments was five years. A structured interview was administered at each assessment to determine patterns of substance use and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; Fourth Edition) attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and drug dependence symptoms. Cloninger's Tridimensional Personality Questionnaire was also used to assess novelty seeking tendencies (NS). At the second wave of assessment, DSM-IV dependence symptoms were reassessed using the same interview. Path analyses were used to examine direct and indirect mechanisms linking psychopathology and drug outcomes. Results Adolescent substance use, CD, and NS predicted young adult substance dependence, whereas the predictive effects of ADHD were few and inconsistent. Furthermore, CD and NS effects were partially mediated by adolescent substance use. Conclusions Adolescent conduct problems, novelty seeking, and drug use are important indices of future drug problems. The strongest predictor was novelty seeking.
This study investigated the stability of genetic and environmental effects on the common liability to alcohol, tobacco, and cannabis dependence across adolescence and young adulthood. DSM-IV symptom ...counts from 2,361 adolescents were obtained using a structured diagnostic interview. Several sex-limited longitudinal common pathway models were used to examine gender differences in the magnitude of additive genetic (A), shared environment, and non-shared environmental effects over time. Model fitting indicated limited gender differences. Among older adolescents (i.e., age >14), the heritability of the latent trait was estimated at 0.43 (0.05, 0.94) during the first wave and 0.63 (0.21, 0.83) during the second wave of assessment. A common genetic factor could account for genetic influences at both assessments, as well as the majority of the stability of SAV over time rA = 1.00 (0.55, 1.00). These results suggest that early genetic factors continue to play a key role at later developmental stages.
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