Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

Lifetime tobacco, alcohol and other substance use in adolescent Minnesota twins: univariate and multivariate behavioral genetic analyses.

AIMS: We sought to estimate the contribution of genetic and environmental factors to adolescent tobacco, alcohol and other substance use. DESIGN, SETTING AND PARTICIPANTS: The sample consisted of 327 monozygotic and 174 like-sex dizygotic twin pairs born in Minnesota and aged 17-18 years at time of assessment. Biometrical methods were used to estimate the contribution of additive genetic, shared and non-shared environmental factors to adolescent substance use. MEASUREMENTS: As part of a day-long psychological assessment, adolescent twins completed a computerized substance use interview to determine whether they had ever used tobacco, alcohol or other illicit drugs. FINDINGS: The heritability for the liabilities to tobacco, alcohol and other drug use was estimated to be 59%, 60% and 33% among males, and 11%, 10% and 11% among females. However, the gender difference was not statistically significant. Estimates of shared environmental effect were substantial and insignificantly higher among females (71%, 68% and 36%, respectively) than among males (18%, 23% and 23%, respectively). The covariation among the three substance use phenotypes could be accounted for by a common underlying substance use factor. Estimates of the contributions of genetic, shared environmental and non-shared environmental factors to variance in this factor were 23% 63% and 14%, respectively. CONCLUSIONS: These findings add to the growing behavioral genetic literature indicating that adolescent initiation of substance use, a powerful predictor of adult substance use diagnosis, is influenced primarily by environmental rather than genetic factors.

The psychological adjustment of United States adopted adolescents and their nonadopted siblings.

Using data from a national sample of 715 United States adoptive families, comparisons were made between adopted adolescents and birth adolescents (children born to the adoptive parents) on the Youth Self-Report (Achenbach), 8 psychological and behavioral adjustment factor scales from the Attitudes and Behaviors survey (Benson), and an identity scale (Search Institute). Multivariate, followed by univariate, analyses of variance showed significant differences between the 2 groups on the psychological factor scales of Licit Drug Use and School Adjustment. A subsample of nonclinically referred adopted adolescents were also compared to norms on the Youth Self-Report. Nonreferred adopted boys showed higher levels of adjustment than the norm group on Withdrawn behaviors. Nonreferred adopted girls showed better adjustment than the norm group on Social Problems and Withdrawn behaviors and poorer adjustment on Delinquent Behavior and Externalizing behavior. (Standardized effect sizes were in the small to moderate range.) These same patterns were evidenced when controlling for ethnicity. These data are examined within Brodzinsky's stress and coping model of adoptee adjustment and support a body of adoption research that finds a pattern of small but significant differences between adopted and nonadopted persons. The differences showing poorer adoptee adjustment in comparison to nonadoptees should not be overstated as is sometimes the case in the adoption clinical literature, and areas in which adoptees evidence higher levels of psychological functioning should be further researched.

Antisocial Personality Disorder and depression in relation to alcoholism: a community-based sample.

OBJECTIVE: Antisocial Personality Disorder (ASPD) and depression frequently co-occur with alcoholism. This study examined the relationship between the presence of ASPD or depression and the course and severity of alcoholism. METHOD: Alcoholic men (n = 207), recruited from a community-based sample, the Minnesota Twin-Family Study (MTFS), were categorized according to comorbid diagnoses into the following four groups: alcoholics with ASPD (n = 25), alcoholics with depression (n = 24), alcoholics with neither ASPD nor depression, but who were allowed to have additional psychopathology (n = 130) and alcoholics with no other psychiatric diagnoses (n = 28). The four diagnostic subgroups were compared on alcohol and drug use, alcohol-related problems and personality dimensions. RESULTS: ASPD was associated with an earlier age of first intoxication, a more chronic and severe course of alcoholism, more social consequences of drinking and higher levels of drug use. On the whole, depression was associated with a less severe course of alcoholism. Alcoholics with depression and alcoholics with ASPD had higher negative emotionality, and alcoholics with ASPD had lower constraint scores on the Multidimensional Personality Questionnaire. CONCLUSIONS: These findings, derived from a community-based sample, indicate the importance of assessing comorbidity among alcoholics and confirm the association of ASPD with a more severe and chronic course of alcoholism and with higher likelihood of drug abuse.

Attention-deficit hyperactivity disorder dimensions: a twin study of inattention and impulsivity-hyperactivity.

OBJECTIVE: This study used a model-fitting strategy to estimate genetic and environmental contributions to the core behavioral dimensions associated with attention-deficit hyperactivity disorder (ADHD) in 576 twin boys, aged 11 and 12 years. METHOD: Teacher ratings and maternal structured interview reports composed of behavioral items including DSM-III and DSM-III-R criteria for ADHD were obtained for 194 pairs of monozygotic and 94 pairs of dizygotic twins. Factor analysis of these measures yielded two ADHD-related dimensions, inattention and impulsivity-hyperactivity. Scales representing these dimensions were used in the genetic analyses. RESULTS: Univariate analyses supported a substantial contribution of genetic factors in the expression of inattention and impulsivity-hyperactivity and smaller contributions of shared and nonshared environmental factors. Results varied according to informant source, with mothers' reports suggestive of rater bias effects. Bivariate analyses indicated that the correlation between these two ADHD dimensions was also genetically mediated. CONCLUSIONS: Genetic factors are etiologically important in the expression of the separate dimensions of ADHD and in the covariation between them. However, it is important to obtain reports from more than one informant because rater bias effects may be operative, particularly in maternal reports.

Twin concordance for attention deficit hyperactivity disorder: a comparison of teachers' and mothers' reports.

OBJECTIVE: The present study examined probandwise concordance rates for attention deficit hyperactivity disorder (ADHD) in a community sample of 194 monozygotic and 94 dizygotic male twins, ages 11-12 years. METHOD: DSM-III and DSM-III-R diagnoses of ADHD were based on rating scale reports from the twins' teachers and structured interview reports obtained from their mothers. Model-fitting analyses were used to estimate genetic and environmental effects on ADHD. RESULTS: Concordance rates for ADHD were greater for monozygotic than dizygotic twins according to both mothers' and teachers' reports; this finding indicates the importance of genetic factors in the etiology of this syndrome. Fifteen percent of subjects received an ADHD diagnosis by teachers' ratings, compared with 6% by mothers' reports. Three percent of subjects met criteria for ADHD in both school and home settings. Teachers' ratings yielded moderate monozygotic and dizygotic concordance rates, in contrast to mothers' reports, which indicated a high monozygotic and a zero dizygotic concordance for ADHD. A model that included additive genetic and nonshared environmental factors provided the best fit to these ADHD data. CONCLUSIONS: ADHD, as defined by DSM criteria, appears to be a genetically influenced disorder whether diagnoses are based on teachers' or mothers' reports. However, the extent of this genetic influence seems to vary by informant source. These findings suggest that obtaining diagnostic data from either teachers' or mothers' reports alone may provide an incomplete characterization of ADHD.

P300 event-related potential heritability in monozygotic and dizygotic twins.

The present study examined the heritability of the P3 waveform and the N1, P2, and N2 components by assessing the visual event-related potential (ERP) of 30 monozygotic (MZ) and 34 dizygotic (DZ) twin pairs. Electroencephalogram activity was recorded from Pz, P3, and P4 scalp sites while individuals performed a reaction time task involving two conditions differing in difficulty. Genetic modeling indicated substantial genetic influence on P3 amplitude, P3 latency, and manual reaction time for the difficult condition. No significant heritability was found for the latency of P3 or manual reaction time for the easy condition, but P3 amplitude was heritable for this condition. The amplitude of the early components (N1, P2, and N2) was heritable, but no significant genetic influences were found for the latency of these components. Compared with the DZ twins, the greater similarity of the MZ pairs on the event-related potential measures was not due to their greater similarity in either head dimensions or mental ability, despite the facts that IQ scores were weakly correlated with P3 and N2 amplitude and that amplitude and latency were related to some measures of head size. These findings suggest that P3 amplitude and the amplitude of earlier ERP components are under partial genetic control, supporting the notion that these ERP components could perhaps be used to identify genetic risk for psychopathology.

The association between P300 and age from preadolescence to early adulthood.

The present study examined the latency and amplitude of P300 in a large sample of subjects between 11 and 21 years old. The P300 components of the visual event-related potential showed consistent and significant age-related changes. Peak amplitude was found to diminish with increasing age, whereas peak latency decreased. Our data indicate that a linear relationship best explains the association between age and P300 amplitude and latency. The changes in P300 amplitude and latency across the different ages are likely to reflect developmental changes in mental processing that are not due to a decrease in general cortical reactivity with increasing age or the result of subject noncompliance.

Simulation of stochastic micropopulation models--IV. SNAPPERS: model implementation for genetic traits.

The current paper concerning stochastic micropopulation simulations describes SNAPPERS, which serves as a framework for simulation models of the genetic transmission of disease. The versions described are implemented using the simulation shell, SUMMERS, which includes the generic commonalities of several micropopulation models. Population members in SNAPPERS move through states related to the individual's status relative to the genotype (phenotype). Features of the model include one or two major loci, polygenic and common familial contribution to the phenotype, assortative mating, and flexibility in defining gene action. The user can select from multiple ascertainment strategies for analysis of simulated families.

Properties of alternative estimators of familial correlations under variable sibship size.

Selected distributional properties of a variety of estimators of familial correlations (spouse, parent-child, and sibling) were investigated numerically, focusing particularly on sibling correlations under variable sibship size. Maximum likelihood estimators were evaluated for each of the three familial relationships. An additional parent-offspring estimator was studied using a parent-midoffspring estimate pooled over variable sibship size. For sibling intraclass correlations, three estimators based on analysis of variance and three pairwise estimators using different weighting functions for variable sibship sizes were investigated. Correlations were estimated from data simulated under eight sampling conditions (each replicated 1,000 times) using two sets of true parameter values, moderate and large sample sizes, and normal versus highly non-normal sample distributions of data. The estimators are nearly unbiased and efficient, but none of the sibling correlation estimators are normally distributed in small samples. Estimates from highly non-normal data are nearly unbiased but are less efficient than those from normal data.

Mixed-model segregation analysis of schizophrenia in the Lindelius Swedish pedigrees.

To test if familial transmission of schizophrenia is consistent with a model of monogenic inheritance with a multifactorial background, a mixed-model segregation analysis was applied to Swedish pedigrees consisting of 270 probands in 263 nuclear families. Results of the best-fitting mixed-model solutions are consistent with multifactorial transmission and no major gene. However, numerical instabilities prevented formal hypothesis testing, so an irrefutable genetic mechanism remains unidentified. Alternative research strategies that exploit recent advances in molecular genetics are discussed.

On the properties of maximum likelihood estimators of familial correlations under variable sibship size.

Selected distributional properties of the maximum likelihood estimator and its z-transformation of three familial correlations (parental, parent-offspring, filial) were investigated numerically for the case of nuclear families with variable sibship size. This investigation was based on six different sets of the three correlations, and four different sample sizes, defining 24 sampling conditions, which were replicated 1,000 times each. It was found that the distributional properties of the correlation estimator are affected by the magnitude of the correlations even in large samples although approximate normality is achieved locally. Fisher's z-transformation, here used only in its interclass form, achieves reduction of skewness, stabilization of variance, and approach to normality already in small samples, except for the filial correlation (where it may be deemed inappropriate) in smaller samples. For both the correlation estimator and its z-transformation, the (estimated) relative efficiency was shown to be high (better than 90% in most sampling conditions), suggesting that the estimated minimum variance bound is a satisfactory estimator of the sampling variance. It is concluded that the maximum likelihood estimation of familial correlations under variable sibship size is feasible and, when prudently applied, especially in the form of their z-transformations, provides an appropriate method in analyses of family studies.

Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit.

One hundred seventy-four patients (179 admissions) were prospectively evaluated for the subsequent occurrence of upper gastrointestinal ("stress") bleeding after admission to a medical/respiratory intensive care unit. Evidence for either overt or occult gastrointestinal bleeding developed in 25 (14 percent). The group of bleeders had a higher mortality (64 percent versus 9 percent), duration of intensive care unit stay (median 14.2 versus 4.2 days), number of patients requiring mechanical ventilatory support (84 percent versus 26 percent), and duration of such support for those who required it (median 9.5 versus 4.2 days) than the group who did not bleed. In three patients, death was related to bleeding. Upon patients' admission to the intensive care unit, diagnoses of an acute respiratory illness (but not specifically chronic obstructive pulmonary disease), a malignancy, or sepsis were more common among those who subsequently bled. Of factors tested, a coagulopathy and the need for mechanical ventilation were most strongly associated with the risk of bleeding. Other factors did not add to the risk once these two were taken into account. Among patients receiving mechanical ventilation, the risk of overt bleeding was particularly low for those who required such support for less than five days (only 3 percent). It is concluded that (1) significant upper gastrointestinal bleeding occurring after medical intensive care unit admission is an uncommon event, and (2) prolonged mechanical ventilation and/or the presence of a coagulopathy are the most potent risk factors. Medical patients with either of the latter conditions are most likely to benefit from prophylaxis regimens against "stress"-induced upper gastrointestinal bleeding.

Serum enzyme changes during marathon training.

Blood enzyme activities that might be suggestive of organ-specific damage were measured over a six-week period in two, male, long-distance runners training for a marathon. Striking changes were observed in the CK and LD isoenzymes. Runner B exhibited a flipped LD1/LD2 isoenzyme ratio that paralleled his persistent MB CK elevation. The hepatic enzyme ALT was transiently elevated in Runner A. These data suggest that increases of cardiac isoenzymes (MB CK and LD1) and the specific hepatic enzyme ALT could lead to an inappropriate laboratory diagnosis of a myocardial infarction or liver disease, respectively, in a healthy runner during intense training for a marathon.