Soo Hyun Rhee

Genetic and environmental influences on antisocial behavior: a meta-analysis of twin and adoption studies.

A meta-analysis of 51 twin and adoption studies was conducted to estimate the magnitude of genetic and environmental influences on antisocial behavior. The best fitting model included moderate proportions of variance due to additive genetic influences (.32), nonadditive genetic influences (.09), shared environmental influences (.16), and nonshared environmental influences (.43). The magnitude of familial influences (i.e., both genetic and shared environmental influences) was lower in parent-offspring adoption studies than in both twin studies and sibling adoption studies. Operationalization, assessment method, zygosity determination method, and age were significant moderators of the magnitude of genetic and environmental influences on antisocial behavior, but there were no significant differences in the magnitude of genetic and environmental influences for males and females.

Substance use, abuse and dependence in adolescence: prevalence, symptom profiles and correlates

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 3,072 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.

How localized are age-related effects on neuropsychological measures?

The primary goal of the current study was to examine the degree of independence of the age-related influences on measures sometimes postulated to be sensitive to functioning in different regions of the brain. It is often assumed that levels of performance on different cognitive measures and the age-related effects on those measures are determined by separate and distinct mechanisms. In the case of measures from neuropsychological tests, the discovery of selective impairments by individuals with damage in particular regions of the brain has led to the inference that various brain structures are specialized for different types of processing. When combined with results indicating age-related deficits on those measures, these findings have led to speculation that certain regions of the brain are more sensitive to age-related decline than others. For example, at different times it has been suggested that the

The CHRNA5/A3/B4 Gene Cluster Variability as an Important Determinant of Early Alcohol and Tobacco Initiation in Young Adults

BACKGROUND One potential site of convergence of the nicotine and alcohol actions is the family of the neuronal nicotinic acetylcholine receptors. Our study examines the genetic association between variations in the genomic region containing the CHRNA5, A3, and B4 gene cluster (A5A3B4) and several phenotypes of alcohol and tobacco use in an ethnically diverse young adult sample. Significant results were then replicated in a separate adult population-representative sample. METHODS In a selected sample, nine single nucleotide polymorphisms (SNPs) were tested for association with various nicotine and alcohol phenotypes, including age of initiation and measures of frequency, quantity, and subjective responses to the substances. Analysis was conducted with the statistical genetics program WHAP in the full sample (1075 subjects) including ethnicities as covariates and within each ethnic group sub-sample. Replication of the significant results in a separate population-based sample was carried out with the PBAT statistical genetics program. RESULTS Two linked SNPs (rs8023462 and rs1948) located in a conserved region of the A5A3B4 gene cluster significantly predicted early age of initiation for tobacco with a hazard ratio (HR) of 1.35 (95% confidence interval [CI]1.08-1.70) for the CC genotype of rs8023462 and a HR of 1.29 (95% CI 1.01-1.63) for the TT genotype of rs1948 [corrected]. These findings were then replicated in a separate population-representative sample, showing rs1948 and rs8023462 to be associated with age of initiation for both tobacco and alcohol use (p < .01 and p < .001). CONCLUSIONS Variations in A5A3B4 genes might influence behaviors that promote early age of experimentation with drugs.

The relation between sluggish cognitive tempo and DSM-IV ADHD

To test the relation between sluggish cognitive tempo (SCT) and DSM-IV ADHD symptoms, parent and teacher ratings of the 18 DSM-IV ADHD items and five potential SCT items were obtained in a community sample of 8–18 year-old twins that was overselected for ADHD and learning disabilities (n = 296). Confirmatory factor analyses revealed that a three-factor model provided the best fit to the data for both parent and teacher ratings. DSM-IV inattention and hyperactivity–impulsivity symptoms loaded on two factors consistent with the DSM-IV model, and five SCT symptoms loaded primarily on a third factor. The SCT and inattention factors were highly correlated, whereas SCT and hyperactivity–impulsivity were weakly related. Both raters indicated that children meeting symptom criteria for the combined and inattentive subtypes exhibited significantly more SCT symptoms than those meeting symptom criteria for hyperactive–impulsive type and the comparison group without ADHD. Children meeting symptom criteria for the inattentive type exhibited significantly more SCT symptoms than those meeting criteria for the combined type, based on teacher ratings. These results suggest that SCT is an internally consistent construct that is significantly associated with DSM-IV inattention.

Association of the neuronal nicotinic receptor β2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine

Nicotine addiction and alcohol dependence are highly comorbid disorders that are likely to share overlapping genetic components. We have examined two neuronal nicotinic receptor subunit genes (CHRNA4 and CHRNB2) for possible associations with nicotine and alcohol phenotypes, including measures of frequency of use and measures of initial subjective response in the period shortly after first using the drugs. The subjects were 1,068 ethnically diverse young adults participating in ongoing longitudinal studies of adolescent drug behaviors at the University of Colorado, representing both clinical and community samples. Analysis of six SNPs in the CHRNA4 gene provided modest support for an association with past 6 month use of alcohol in Caucasians (three SNPs with P < 0.08), but no evidence for an association with tobacco and CHRNA4 was detected. However, a SNP (rs2072658) located immediately upstream of CHRNB2 was associated with the initial subjective response to both alcohol and tobacco. This study provides the first evidence for association between the CHRNB2 gene and nicotine‐ and alcohol‐related phenotypes, and suggests that polymorphisms in CHRNB2 may be important in mediating early responses to nicotine and alcohol. J. Cell. Physiol.

Selective Interference With the Maintenance of Location Information in Working Memory

In 3 experiments, the nature of the events that interfere with spatial working memory was examined in order to clarify the roles of imagery, attention, and other processes in the short-term maintenance of location information. Looking and pointing at secondary task stimuli selectively interfered with memory for the locations of primary task stimuli. Secondary tasks that involved either mentally rotating primary task stimuli or making color or shape discriminations about primary or secondary task stimuli interfered with spatial working memory only if the required response was visually guided, but not if the response was verbal. Taken together, these findings support P.S. Goldman-Rakics (1987) hypothesis regarding multiple representational domains and are consistent with known properties and connections of neurons believed to subserve the perception and maintenance of spatial information. A working memory task may be defined as one that requires holding onto information for a short time while it or other information is processed. Baddeley has proposed that there is a working memory system, specialized for concurrent storage and manipulation of information that is engaged by such tasks (for a recent overview, see Baddeley & Hitch, 1994). On the basis of studies of both intact and brain-damaged subjects (for a review, see Gathercole, 1994), Baddeley and his colleagues have divided the working memory system into three components: a phonological store for verbal information, a visuospatial sketchpad for visuospatial information, and a central executive that directs activities involved in manipulating and maintaining information in the two specialized stores. Perhaps the most studied example is the role of covert articulatory rehearsal in refreshing information in the phonological store. Performing a secondary task that requires articulation of verbal material decreases verbal memory span, a finding consistent with the hypothesized role of subvocalization in maintaining verbal information (e.g., Baddeley, Lewis, & Vallar, 1984). Much of the supporting evidence for the visuospatial component of Baddeleys model also comes from studies that use dual task procedures. These studies were designed to determine whether visuospatial and verbal working memory involve separate resources, and they have demonstrated that secondary verbal tasks interfere with memory for verbal information to a much greater extent than they interfere

Structure and etiology of co-occurring internalizing and externalizing disorders in adolescents.

Several studies suggest that a two-factor model positing internalizing and externalizing factors explains the interrelationships among psychiatric disorders. However, it is unclear whether the covariation between internalizing and externalizing disorders is due to common genetic or environmental influences. We examined whether a model positing two latent factors, internalizing and externalizing, explained the interrelationships among six psychiatric disorders (major depressive disorder, generalized anxiety disorder, separation anxiety disorder, attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder) in adolescents, and whether there are common genetic and environmental influences on internalizing and externalizing latent factors. Multivariate behavior genetic analyses of data from 1162 twin pairs and 426 siblings ascertained from the general population via the Colorado Center for Antisocial Drug Dependence (CADD) were conducted. We found support for a model positing two latent factors (internalizing and externalizing). These factors were moderately heritable and influenced by significant common genetic and nonshared environmental influences. These findings suggest that co-occurrence of internalizing and externalizing psychopathology in adolescents results from both genetic and environmental influences.

A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence

This study describes results from a genome-wide search for quantitative trait loci (QTL) influencing substance dependence vulnerability in adolescence. We utilized regression-based multipoint (and single-point) QTL mapping procedures designed for selected sibpair samples. Selected sibling pairs included 250 proband-sibling pairs from 192 families. Clinical probands (13-19 years of age) were drawn from consecutive admissions to substance abuse treatment facilities in the Denver metropolitan area; siblings of probands ranged in age from 12 to 25 years. In addition to the selected sample, a community-based sample of 3676 adolescents and young adults were utilized to define a clinically-significant, heritable, age- and sex-normed index of substance dependence vulnerability-a priori and independent of our linkage results. Siblings and their parents were genotyped for 374 STR micro-satellite markers distributed across the 22 autosomes (average inter-marker distance=9.2 cM). Non-parametric single-point linkage results indicated 17 markers on 11 chromosomes with nominally significant tests of linkage; six markers with LOD scores greater than 1.0 and one marker (D3S1614) with a LOD score of 2.2. Multipoint mapping corroborated two locations and provided preliminary evidence for linkage to regions on chromosome 3q24-25 (near markers D3S1279 and D3S1614) and chromosome 9q34 (near markers D9S1826 and D9S1838).

Cannabis Receptor Haplotype Associated With Fewer Cannabis Dependence Symptoms In Adolescents

Cannabis is a major substance of abuse, and the gene encoding for the central cannabinoid receptor (CNR1) is a logical candidate gene for vulnerability toward developing symptoms of cannabis dependence. We studied four single‐nucleotide polymorphisms (SNPs) in the CNR1 gene for association with having one or more symptoms of cannabis dependence in 541 adolescent subjects who had all tried cannabis five or more times. Cases (327) were defined as those who had tried marijuana and developed one or more symptoms, and controls (214) as those who had tried marijuana but developed no dependence symptoms. Cannabis dependence symptoms were assessed in these youth when they were 17 or older with the Composite International Diagnostic Interview—Substance Abuse Module. Univariate (single‐marker) association tests demonstrated that SNP rs806380, located in intron 2 of the CNR1 gene, was significantly associated with developing one or more cannabis dependence symptoms, with the G allele having a protective effect (P < 0.02). This was consistent with the results of the global haplotype test (P < 0.01). One of the common haplotypes examined (present in 21% of the subjects) was significantly associated with a lower rate of having one or more cannabis dependence symptoms. Our findings provide evidence suggesting that a common CNR1 haplotype is associated with developing fewer cannabis dependence symptoms among adolescents who have experimented with cannabis.