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1.  DSM-5 Cannabis Use Disorder: A Phenotypic and Genomic Perspective* 
Drug and alcohol dependence  2013;134:362-369.
Background
We explore the factor structure of DSM-5 cannabis use disorders, examine its prevalence across European- and African-American respondents as well as its genetic underpinnings, utilizing data from a genome-wide study of single nucleotide polymorphisms (SNPs). We also estimate the heritability of DSM-5 cannabis use disorders explained by these common SNPs.
Methods
Data on 3053 subjects reporting a lifetime history of cannabis use were utilized. Exploratory and confirmatory factor analyses were conducted to create a factor score, which was used in a genomewide association analysis. P-values from the single SNP analysis were examined for evidence of gene-based association. The aggregate effect of all SNPs was also estimated using Genome-Wide Complex Traits Analysis.
Results
The unidimensionality of DSM-5 cannabis use disorder criteria was demonstrated. Comparing DSM-IV to DSM-5, a decrease in prevalence of cannabis use disorders was only noted in European-American respondents and was exceedingly modest. For the DSM-5 cannabis use disorders factor score, no SNP surpassed the genome-wide significance testing threshold. However, in the European-American subsample, gene-based association testing resulted in significant associations in 3 genes (C17orf58, BPTF and PPM1D) on chromosome 17q24. In aggregate, 21% of the variance in DSM-5 cannabis use disorders was explained by the genomewide SNPs; however, this estimate was not statistically significant.
Conclusions
DSM-5 cannabis use disorder represents a unidimensional construct, the prevalence of which is only modestly elevated above the DSM-IV version. Considerably larger sample sizes will be required to identify individual SNPs associated with cannabis use disorders and unequivocally establish its polygenic underpinnings.
doi:10.1016/j.drugalcdep.2013.11.008
PMCID: PMC3943464  PMID: 24315570
Cannabis; DSM-5; GWAS; association; genetics; heritability
2.  A genome wide association study of alcohol dependence symptom counts in extended pedigrees identifies C15orf53 
Molecular psychiatry  2012;18(11):10.1038/mp.2012.143.
Several studies have identified genes associated with alcohol use disorders, but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism (COGA) to identify novel genes affecting risk for alcohol dependence. To maximize the power of the extended family design we used a quantitative endophenotype, measured in all individuals: number of alcohol dependence symptoms endorsed (symptom count). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with symptom count were also associated with the dichotomous phenotype, DSM-IV alcohol dependence. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol (p=4.5×10−8, inflation corrected p=9.4×10−7). Results with DSM-IV alcohol dependence in the regions of interest support our findings with symptom count, though the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: non-overlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian twin-family study of alcohol use disorders (OZALC). Nominal association of C15orf53 with symptom count was observed in SAGE. The variant that showed strongest association with symptom count, rs12912251 and its highly correlated variants (D′=1, r2≥ 0.95), has previously been associated with risk for bipolar disorder.
doi:10.1038/mp.2012.143
PMCID: PMC3752321  PMID: 23089632
DSM-IV alcohol dependence symptoms; Family-based GWAS; C15orf53; Quantitative traits
3.  Genetic influences on craving for alcohol 
Addictive behaviors  2012;38(2):1501-1508.
Introduction
Craving is being considered for inclusion in the Diagnostic and Statistical Manual (DSM) DSM-5. However, little is known of its genetic underpinnings – specifically, whether genetic influences on craving are distinct from those influencing DSM-IV alcohol dependence.
Method
Analyses were conducted in a sample of unrelated adults ascertained for alcohol dependence (N=3976). Factor analysis was performed to examine how alcohol craving loaded with the existing DSM-IV alcohol dependence criteria. For genetic analyses, we first examined whether genes in the dopamine pathway, including dopamine receptor genes (DRD1, DRD2, DRD3, DRD4) and the dopamine transporter gene (SLC6A3), which have been implicated in neurobiological studies of craving, as well as alpha-synuclein (SNCA), which has been previously found to be associated with craving, were associated with alcohol craving in this sample. Second, in an effort to identify novel genetic variants associated with craving, we conducted a genomewide association study (GWAS). For variants that were implicated in the primary analysis of craving, we conducted additional comparisons - to determine if these variants were uniquely associated with alcohol craving as compared with alcohol dependence. We contrasted our results to those obtained for DSM-IV alcohol dependence, and also compared alcohol dependent individuals without craving to non-dependent individuals who also did not crave alcohol.
Results
Twenty-one percent of the full sample reported craving alcohol. Of those reporting craving, 97.3% met criteria for DSM-IV alcohol dependence with 48% endorsing all 7 dependence criteria. Factor analysis found a high factor loading (0.89) for alcohol craving. When examining genes in the dopamine pathway, single nucleotide polymorphisms (SNPs) in DRD3 and SNCA were associated with craving (p<0.05). There was evidence for association of these SNPs with DSM-IV alcohol dependence (p<0.05) but less evidence for dependence without craving (p>0.05), suggesting that the association was due in part to craving. In the GWAS, the greatest evidence of association with craving was for a SNP in the integrin alpha D (ITGAD) gene on chromosome 7 (rs2454908; p=1.8×10−6). The corresponding p-value for this SNP with DSM-IV alcohol dependence was similar (p=4.0×10−5) but was far less with dependence without craving (p=0.02), again suggesting the association was due to alcohol craving. Adjusting for dependence severity (number of endorsed criteria) attenuated p-values but did not eliminate association.
Conclusions
Craving is frequently reported by those who report multiple other alcohol dependence symptoms. We found that genes providing evidence of association with craving were also associated with alcohol dependence; however, these same SNPs were not associated with alcohol dependence in the absence of alcohol craving. These results suggest that there may be unique genetic factors affecting craving among those with alcohol dependence.
doi:10.1016/j.addbeh.2012.03.021
PMCID: PMC3394913  PMID: 22481050
4.  A Model to Determine the Likely Age of an Adolescent’s First Drink of Alcohol 
Pediatrics  2013;131(2):242-248.
OBJECTIVE:
With the use of a new cohort of adolescent subjects, predictors from the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) interview and the Achenbach Youth Self Report (YSR) were combined to model age of first drink (AFD).
METHODS:
Subjects consisted of 820 adolescents (ages 14–17) drawn from the current phase of the Collaborative Study on the Genetics of Alcoholism. Three Cox proportional hazards models were considered. Model 1 contained SSAGA variables equivalent to AFD predictors from our previous study: interview age, family history of alcohol dependence, and number of conduct disorder symptoms. Model 2 incorporated 2 additional SSAGA questions (best friends drink and smoked a cigarette before a reported AFD) plus 8 YSR-derived scale scores. Model 3 was a reduced version of model 2, retaining only significant predictors.
RESULTS:
Model 2 was a significant improvement over model 1. Model 3 was the best and the most parsimonious of the 3 with respect to likelihood ratio and Wald χ2 tests and retained only 5 variables from model 2. Included variables were the following: (1) best friends drink, (2) membership in a high-risk alcohol dependence family, (3) number of conduct disorder symptoms, (4) YSR externalizing score, and (5) YSR social problems score.
CONCLUSIONS:
Adding variables to those from our original study improved our ability to model the likely age of alcohol initiation. In addition to the SSAGA, the YSR appears to have utility as a research tool to predict the age of alcohol initiation.
doi:10.1542/peds.2012-0880
PMCID: PMC3557403  PMID: 23296431
alcohol/drug use; age of first use; predictor variables; modeling age of first use
5.  How Phenotype and Developmental Stage Affect the Genes We Find: GABRA2 and Impulsivity 
Context
The detection and replication of genes involved in psychiatric outcome has been notoriously difficult. Phenotypic measurement has been offered as one explanation, although most of this discussion has focused on problems with binary diagnoses.
Objective
This article focuses on two additional components of phenotypic measurement that deserve further consideration in evaluating genetic associations: (1) the measure used to reflect the outcome of interest, and (2) the developmental stage of the study population. We focus our discussion of these issues around the construct of impulsivity and externalizing disorders, and the association of these measures with a specific gene, GABRA2.
Design, Setting, and Participants
Data were analyzed from the Collaborative Study on the Genetics of Alcoholism Phase IV assessment of adolescents and young adults (ages 12–26; N = 2,128).
Main Outcome Measures
Alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder symptoms were measured by psychiatric interview; Achenbach youth/adult self-report externalizing scale; Zuckerman Sensation-Seeking scale; Barratt Impulsivity scale; NEO extraversion and consciousness.
Results
GABRA2 was associated with subclinical levels of externalizing behavior as measured by the Achenbach in both the adolescent and young adult samples. Contrary to previous associations in adult samples, it was not associated with clinical-level DSM symptom counts of any externalizing disorders in these younger samples. There was also association with sensation-seeking and extraversion, but only in the adolescent sample. There was no association with the Barratt impulsivity scale or conscientiousness.
Conclusions
Our results suggest that the pathway by which GABRA2 initially confers risk for eventual alcohol problems begins with a predisposition to sensation-seeking early in adolescence. The findings support the heterogeneous nature of impulsivity and demonstrate that both the measure used to assess a construct of interest and the age of the participants can have profound implications for the detection of genetic associations.
doi:10.1017/thg.2013.20
PMCID: PMC3663593  PMID: 23561058
GABRA2; association; impulsivity; sensation-seeking; externalizing; adolescence
6.  A Systematic SNP Screen to Fine-Map Alcohol Dependence Genes on Chromosome 7 Identifies Association with a Novel Susceptibility Gene ACN9 
Biological psychiatry  2007;63(11):10.1016/j.biopsych.2007.11.005.
Background
Chromosome 7 has shown consistent evidence of linkage with a variety of phenotypes related to alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) project. Using a sample of 262 densely affected families, a peak lod score for alcohol dependence of 2.9 was observed at D7S1799 (Wang et al., 2004, Hum Mol Genet). The lod score in the region increased to 4.1 when a subset of the sample was genotyped with the Illumina Linkage III panel for the Genetic Analysis Workshop 14 (GAW14; Dunn et al., 2005, BMC Genetics). To follow-up on this linkage region, we systematically screened SNPs across a 2 LOD support interval surrounding the alcohol dependence peak.
Methods
SNPs were selected from the HapMap Phase I CEPH data to tag linkage disequilibrium bins across the region. 1340 across the 18Mb region, genotyped by the Center for Inherited Disease Research (CIDR), were analyzed. Family-based association analyses were performed on a sample of 1172 individuals from 217 Caucasian families. Results: Eight SNPs showed association with alcohol dependence at p<0.01. Four of the eight most significant SNPs were located in or very near the ACN9 gene. We conducted additional genotyping across ACN9 and identified multiple variants with significant evidence of association with alcohol dependence.
Conclusions
These analyses suggest that ACN9 is involved in the predisposition to alcohol dependence. Data from yeast suggest that ACN9 is involved in gluconeogenesis and the assimilation of ethanol or acetate into carbohydrate.
doi:10.1016/j.biopsych.2007.11.005
PMCID: PMC3823371  PMID: 18163977
genetics; association; linkage disequilibrium; alcohol dependence; ACN9
7.  CHRNB3 is more strongly associated with FTCD-based nicotine dependence than cigarettes per day: phenotype definition changes GWAS results 
Addiction (Abingdon, England)  2012;107(11):2019-2028.
Aims
Nicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta-analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.e. CPD versus Fagerström Test for Cigarette Dependence (FTCD) score as a measure of nicotine dependence) on genome-wide association studies of nicotine dependence.
Design
Genome-wide association study
Setting
Community sample
Participants
A total of 3,365 subjects who had smoked at least one cigarette were selected from the Study of Addiction: Genetics and Environment (SAGE). Of the participants, 2,267 were European Americans,999 were African Americans.
Measurements
Nicotine dependence defined by FTCD score ≥4, CPD
Findings
The genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 (OR=0.65, p=2.4×10−8). This association was further strengthened in a meta-analysis with a previously published dataset (combined p=6.7 ×10−16, total n=4,200).When CPD was used as an alternate phenotype, the association no longer reached genome-wide significance (β=−0.08, p=0.0007).
Conclusions
Daily cigarette consumption and the Fagerstrom Test for Cigarette Dependence (FTCD) show different associations with polymorphisms in genetic loci.
doi:10.1111/j.1360-0443.2012.03922.x
PMCID: PMC3427406  PMID: 22524403
8.  Sex differences in how a low sensitivity to alcohol relates to later heavy drinking 
Drug and alcohol review  2012;31(7):871-880.
Introduction and Aims
A low level of response (LR), or low sensitivity, to alcohol is a genetically-influenced characteristic that predicts future heavy drinking and alcohol problems. While previous analyses of how LR relates to heavier drinking reported the process is similar in males and females, some potential sex differences have been identified. This difference is further explored in these analyses.
Design and Methods
Prospective structural equation models (SEMs) were evaluated for 183 young adult females and 162 males, none of Asian background, from the Collaborative Study on the Genetics of Alcoholism (COGA). Invariance analyses and SEM evaluations by sex were used to compare across females and males for these primarily Caucasian (75%), non-Asian young (mean age 19) subjects.
Results
The prospective SEM for the full set of 345 subjects had good fit characteristics and explained 37% of the variance. While the initial invariance analyses identified few sex differences, comparisons of correlations and direct evaluations of path coefficients across males and females indicated that only females showed a link between a low LR and future alcohol problems that was partially mediated by more positive alcohol expectancies and drinking to cope. These sex differences were reflected in the different structures of the SEM results for female vs. male subjects.
Discussion and Conclusions
These prospective results indicate that there might be some important sex differences regarding how a lower LR relates to alcohol outcomes that should be considered in protocols focusing on preventing the impact of LR on future drinking problems.
doi:10.1111/j.1465-3362.2012.00469.x
PMCID: PMC3459074  PMID: 22708705
drinking; alcoholism; sex; genetics; structural equation models
9.  Copy number variations in 6q14.1 and 5q13.2 are associated with alcohol dependence 
Background
Excessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between DSM-IV alcohol dependence and all common copy number variations (CNV) with good reliability in the Study of Addiction: Genetics and Environment (SAGE).
Methods
All participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), as a part of three contributing studies. 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVpartition, PennCNV and QuantiSNP and only CNVs identified by all three software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory.
Results
CNVs in 6q14.1 (P= 1.04 × 10−6) and 5q13.2 (P= 3.37 × 10−4) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2 there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation, and language delay. The CNV in 5q13.2 was validated whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution.
Conclusion
This is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence.
doi:10.1111/j.1530-0277.2012.01758.x
PMCID: PMC3436997  PMID: 22702843
Copy Number Variations; Alcohol dependence; CNV Accuracy
10.  Priming deficiency in male subjects at risk for alcoholism: the N4 during a lexical decision task 
Background
While there is extensive literature on the relationship between the P3 component of event-related potentials (ERPs) and risk for alcoholism, there are few published studies regarding other potentially important ERP components. One important candidate is the N4(00) component in the context of semantic processing, as abnormalities in this component have been reported for adult alcoholics.
Method
A semantic priming task was administered to non-alcohol dependent male offspring (18 to 25 years) of alcoholic fathers [high risk (HR) n=23] and non-alcoholic fathers [low risk (LR) n=28], to study whether the two groups differ in terms of the N4 component. Subjects were presented with 150 words and 150 non-words. Among the words, 50 words (primed) were preceded by their antonyms (prime, n=50), whereas the remaining 50 words were unprimed. For the analysis, N4 amplitude and latency, as well as behavioral measures for the primed and unprimed words were considered.
Results
A significant interaction effect was observed between semantic condition and group, where HR subjects did not show N4 attenuation for primed stimuli.
Conclusion
The lack of N4 attenuation to primed stimuli and/or inability to differentiate between primed and unprimed stimuli, without latency and reaction time being affected, suggest deficits in semantic priming, especially in semantic expectancy and/or post-lexical semantic processing in HR male offspring. Further, it indicates that it might be an electrophysiological endophenotype that reflects genetic vulnerability to develop alcoholism.
doi:10.1111/j.1530-0277.2009.01042.x
PMCID: PMC3601897  PMID: 19764939
Semantic priming; N4; alcoholism; high risk; endophenotype
11.  Genome-wide association study of comorbid depressive syndrome and alcohol dependence 
Psychiatric genetics  2012;22(1):31-41.
Objective
Depression and alcohol dependence are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35–60%. In addition, evidence from twin studies suggests that alcohol dependence and depression are genetically correlated. Here we report results from a genome-wide association study (GWAS) of a comorbid phenotype in which cases meet the DSM-IV symptom threshold for major depressive symptomatology and DSM-IV criteria for alcohol dependence.
Methods
Samples (N=467 cases and N=407 controls) were of European-American descent, and were genotyped using the Illumina Human 1M BeadChip array.
Results
Although no SNP meets genome-wide significance criteria, we identify ten markers with p-values < 1 × 10−5, seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding p<1 × 10−3 are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, alcohol dependence, or other addiction-related phenotypes – such as CDH13, CSMD2, GRID1, and HTR1B – were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an alcohol dependence-only phenotype is modest.
Conclusions
These results underscore the complex genomic influences on psychiatric phenotypes, and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect alcohol dependence alone.
doi:10.1097/YPG.0b013e32834acd07
PMCID: PMC3241912  PMID: 22064162
genetics of alcoholism; comorbidity; genetic risk; depressive syndrome
12.  ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry 
Molecular Psychiatry  2011;17(4):445-450.
A coding variant in ADH1B (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by DSM-IV criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio of 0.34, 95% confidence interval 0.24, 0.48) for alcohol dependence, with genome-wide significance (6.6 × 10−10). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24 hour period (lifetime), with p = 3×10−13. We also tested the effects of this allele on the development of alcoholism in adolescents and young adults and demonstrated a significant protective effect. This variant has the strongest effect on risk for alcohol dependence of any tested in European populations.
doi:10.1038/mp.2011.124
PMCID: PMC3252425  PMID: 21968928
alcohol dependence; ADH1B; alcohol dehydrogenase; protective allele; genetics; association study
13.  A Genomewide Association Study of DSM-IV Cannabis Dependence 
Addiction biology  2010;16(3):514-518.
Despite twin studies showing that 50–70% of variation in DSM-IV cannabis dependence is attributable to heritable influences, little is known of specific genotypes that influence vulnerability to cannabis dependence. We conducted a genomewide association study of DSM-IV cannabis dependence. Association analyses of 708 DSM-IV cannabis dependent cases with 2,346 cannabis exposed nondependent controls was conducted using logistic regression in PLINK. None of the 948,142 SNPs met genomewide significance (p < E−8). The lowest p-values were obtained for polymorphisms on chromosome 17 (rs1019238 and rs1431318, p-values at E−7) in the ANKFN1 gene. While replication is required, this study represents an important first step towards clarifying the biological underpinnings of cannabis dependence.
doi:10.1111/j.1369-1600.2010.00255.x
PMCID: PMC3117436  PMID: 21668797
14.  Genome-Wide Association Study of Theta Band Event-Related Oscillations Identifies Serotonin Receptor Gene HTR7 Influencing Risk of Alcohol Dependence 
Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome-wide association study (GWAS) of an ERO endophenotype – frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty-two SNPs of the Illumina HumanHap 1M microarray were selected from the theta ERO GWAS for replication in family-based samples (N = 1,095), with four markers revealing nominally significant association. The most significant marker from the two-stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher’s combined P = 3.68 × 10−6). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P = 1.53 × 10−4), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM-IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case-controls (P = 0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case-control and family-based samples (P = 0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders.
doi:10.1002/ajmg.b.31136
PMCID: PMC3139811  PMID: 21184583
serotonin receptor gene (HTR7); serotonin receptor (5-HT7); event-related oscillation (ERO); alcohol dependence; genome-wide association study (GWAS)
15.  Variants Located Upstream of CHRNB4 on Chromosome 15q25.1 Are Associated with Age at Onset of Daily Smoking and Habitual Smoking 
PLoS ONE  2012;7(3):e33513.
Several genome-wide association and candidate gene studies have linked chromosome 15q24–q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking the CHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were recruited from families affected with alcoholism (either as a first or second degree relative) and the comparison families. Participants completed the SSAGA interview, a comprehensive assessment of alcohol and other substance use and related behaviors. Using the Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. Multivariate analysis using a Cox proportional hazards model further revealed that these variants significantly predict the age at onset of habitual smoking among daily smokers. These variants were not in high linkage disequilibrium (0.28
doi:10.1371/journal.pone.0033513
PMCID: PMC3306405  PMID: 22438940
Background
Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders. There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders. Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 (CRHR1) in the environmental stress response and ethanol self-administration in animal models. The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis.
Methods
We analyzed a sample from the Collaborative Study on the Genetics of Alcoholism (COGA) comprising 1049 Caucasian subjects from 209 families (including 472 alcohol-dependent individuals). Quantitative transmission disequilibrium test (QTDT) and family-based association test (FBAT) were used to test the association, and false discovery rate (FDR) was applied to correct for multiple comparisons.
Results
Significant associations (p < 0.05) were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene.
Conclusions
Our results suggest that CRHR1 may be involved in modulating the P3 component of the ERP during information processing and in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders.
doi:10.1111/j.1530-0277.2010.01173.x
PMCID: PMC3248053  PMID: 20374216
P3; Disinhibition; Endophenotype; Stress; Corticotropin Releasing Factor (CRF)
Psychological science  2010;21(9):1282-1290.
Sensation seeking is a heritable personality trait that has been reliably linked to behavior disorders. The dopamine system has been hypothesized to contribute to individual differences in sensation seeking, and both experimental and observational studies in humans and non-human animals provide evidence for this relationship. We present here a candidate-system approach to genetic association analysis of sensation seeking, in which single nucleotide polymorphisms (SNPs) from a number of dopaminergic genes were analyzed. Using 273 SNPs from eight dopamine genes in a sample of 635 unrelated individuals, we examined the aggregate effects of those SNPs significantly associated with sensation seeking. Multiple SNPs in four dopamine genes accounted for significant variance in sensation seeking. These results suggest that aggregation of multiple SNPs within genes relevant to a specific neurobiological system into a “genetic risk score” may explain a nontrivial proportion of variance in human traits.
doi:10.1177/0956797610380699
PMCID: PMC3031097  PMID: 20732903
sensation seeking; dopamine; candidate gene; association study
Objective
The aim of the present study was to investigate the effect of risperidone-induced hyperprolactinemia on trabecular bone mineral density (BMD) in children and adolescents.
Methods
Medically healthy 7–17yo males chronically treated, in a naturalistic setting, with risperidone were recruited through child psychiatry outpatient clinics between November 2005 and June 2007. Anthropometric measurements and laboratory testing were conducted. Developmental and treatment history was obtained from the medical record. Volumetric BMD of the ultra-distal radius was measured using peripheral quantitative computerized tomography and areal BMD of the lumbar spine was estimated using dual energy X-ray absorptiometry.
Results
Hyperprolactinemia was present in 49% of 83 boys (n=41) treated with risperidone for an average of 2.9 years. Serum testosterone concentration increased with pubertal status but was not affected by hyperprolactinemia. As expected, bone mineral content and BMD increased with sexual maturity. After adjusting for the stage of sexual development, height and BMI Z-scores, serum prolactin was negatively associated with trabecular volumetric BMD at the ultra-distal radius (p<0.03). Controlling for relevant covariates, we also found treatment with selective serotonin reuptake inhibitors (SSRIs) to be associated with lower trabecular BMD at the radius (p=0.03) and BMD Z-score at the lumbar spine (p<0.05). These findings became more marked when the analysis was restricted to non-Hispanic Caucasians. Of 13 documented fractures, only two occurred after risperidone and SSRIs were started and none in patients with hyperprolactinemia.
Conclusions
This is the first study to link risperidone-induced hyperprolactinemia and SSRI treatment to lower BMD in children and adolescents. Future research should evaluate the longitudinal course of this adverse event to determine its temporal stability and whether a higher fracture rate ensues.
doi:10.4088/JCP.08m04595gre
PMCID: PMC2845988  PMID: 20331935
Obesity, smoking, and conduct problems have all been associated with decrements in brain function. However, their additive and interactive effects have rarely been examined. To address the deficiency, we studied P300a and P300b electroencephalographic potentials in 218 women grouped by the presence versus absence of: (1) a BMI ≥30 kg/m2; (2) recent smoking; and (3) ≥2 childhood conduct problems. Analyses revealed smaller P300a and P300b amplitudes over the posterior scalp among recent smokers versus nonsmokers. No corresponding group differences were found in P300 latencies or frontal scalp amplitudes. The most interesting analysis result was an interaction between conduct problems and obesity limited to the frontally-generated P300a component: its latency was significantly greater in women with both attributes than in those with either or neither attribute. An exploratory ANOVA, substituting the genotype of a GABRA2 SNP for conduct problems, also demonstrated the interaction. It is hypothesized that conduct problems, and a conduct-problem-associated GABRA2 genotype, decrease the age-of-onset and/or increase the lifetime duration of obesity. As a result, they may potentiate the adverse effects of obesity on frontal white matter and thereby increase P300a latency. Smoking may affect brain function by a different mechanism to reduce posterior scalp P300a and P300b amplitudes while preserving frontal scalp P300a latency and amplitude.
doi:10.1111/j.1521-0391.2010.00069.x
PMCID: PMC2924769  PMID: 20716301
GABRA2; gene; smoking; obesity; Conduct Disorder
Archives of sexual behavior  2008;39(3):664-673.
The present study examined the extent to which variables within the self system (i.e., symptoms of alcohol dependence and conduct disorder, gender, race, and metropolitan status) and the familial system (i.e., having an alcohol dependent biological parent or second-degree relative, religious background, educational background of parents, and being born to a teenage mother) were associated with sexual debut at 16 years old or earlier. Participants were 1,054 biological relatives, aged 18–25 years, of alcohol dependent probands who participated in the Collaborative Study on the Genetics of Alcoholism project. Comparison participants (N = 234) without alcohol dependent biological parents were also evaluated. Clinical and sociodemographic variables were assessed by structured, personal interviews. Parental history of alcohol dependence was evaluated by direct interview of parents in most cases and family history in uninterviewed parents. In a multivariate survival analysis, increased risk of becoming sexually active at 16 years of age or earlier was significantly associated with 6 of the 10 predictor variables, including race, one or more alcohol dependence symptoms, and/or one or more conduct disorder symptoms. Having an alcohol dependent biological parent or second-degree relative (e.g., aunt, uncle, or grandparent), educational background of mother, and being born to a teenage mother were also significantly associated with increased risk. These results provide evidence that specific variables in the self and familial systems of influence are important in predicting sexual debut at 16 years old or earlier.
doi:10.1007/s10508-008-9397-y
PMCID: PMC2855761  PMID: 18846417
High risk behaviors; Familial alcoholism; Sexual debut; Conduct disorder
Evidence suggests the P3 amplitude of the event-related potential and its underlying superimposed event-related oscillations (EROs), primarily in the theta (4–5 Hz) and delta (1–3 Hz) frequencies, as endophenotypes for the risk of alcoholism and other disinhibitory disorders. Major neurochemical substrates contributing to theta and delta rhythms and P3 involve strong GABAergic, cholinergic and glutamatergic system interactions. The aim of this study was to test the potential associations between single nucleotide polymorphisms (SNPs) in glutamate receptor genes and ERO quantitative traits. GRM8 was selected because it maps at chromosome 7q31.3–q32.1 under the peak region where we previously identified significant linkage (peak LOD=3.5) using a genome-wide linkage scan of the same phenotype (event-related theta band for the target visual stimuli). Neural activities recorded from scalp electrodes during a visual oddball task in which rare target elicited P3s were analyzed in a subset of the Collaborative Study on the Genetics of Alcoholism (COGA) sample comprising 1,049 Caucasian subjects from 209 families (with 472 DSM-IV alcohol dependent individuals). The family based association test (FBAT) detected significant association (p<0.05) with multiple SNPs in the GRM8 gene and event-related theta power to target visual stimuli, and also with alcohol dependence, even after correction for multiple comparisons by false discovery rate (FDR). Our results suggest that variation in GRM8 may be involved in modulating event-related theta oscillations during information processing and also in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders.
doi:10.1002/ajmg.b.30818
PMCID: PMC2660384  PMID: 18618593
P3; Alcohol dependence; Disinhibition; Endophenotype; mGluR8
Objective
The aim of this study was to investigate the prevalence of clinical and laboratory metabolic abnormalities during long-term risperidone treatment in children and adolescents.
Methods
Medically healthy 7- to 17-year-old children chronically treated, in a naturalistic setting, with risperidone were recruited through child psychiatry clinics. Anthropometric measurements and laboratory testing were conducted. Developmental and medication histories were obtained from medical records.
Results
In 99 patients treated with risperidone for an average of 2.9 years, a significant increase in age- and gender-adjusted weight and body mass index (BMI) (i.e., z-scores) was observed. Concomitant treatment with psychostimulants did not attenuate this weight gain. Risperidone-associated weight gain was negatively correlated with the BMI z-score obtained at the onset of risperidone treatment. Compared to lean children, overweight and obese children had higher odds of metabolic abnormalities, including increased waist circumference, hypertriglyceridemia, and low high-density lipoprotein cholesterol (HDL-C). They also tended to have a higher insulin level and homeostasis model assessment insulin resistance (HOMA-IR) index. As a result, upon recruitment in the study, children with excessive weight were 12 times more likely to have at least one laboratory metabolic abnormality and seven times more likely to have at least one criterion of the metabolic syndrome compared to lean subjects. In contrast to excessive weight status, gaining ≥0.5 BMI z-score point during risperidone treatment was not associated with a significantly higher occurrence of metabolic disturbances.
Conclusions
The long-term use of risperidone, especially when weight is above normal, is associated with a number of metabolic abnormalities but a low prevalence of the metabolic syndrome phenotype. Future studies should evaluate the stability of these abnormalities over time.
doi:10.1089/cap.2008.007
PMCID: PMC2715008  PMID: 19364288
Abstract
Objective
The aim of this study was to investigate the prevalence of clinical and laboratory metabolic abnormalities during long-term risperidone treatment in children and adolescents.
Methods
Medically healthy 7- to 17-year-old children chronically treated, in a naturalistic setting, with risperidone were recruited through child psychiatry clinics. Anthropometric measurements and laboratory testing were conducted. Developmental and medication histories were obtained from medical records.
Results
In 99 patients treated with risperidone for an average of 2.9 years, a significant increase in age- and gender-adjusted weight and body mass index (BMI) (i.e., z-scores) was observed. Concomitant treatment with psychostimulants did not attenuate this weight gain. Risperidone-associated weight gain was negatively correlated with the BMI z-score obtained at the onset of risperidone treatment. Compared to lean children, overweight and obese children had higher odds of metabolic abnormalities, including increased waist circumference, hypertriglyceridemia, and low high-density lipoprotein cholesterol (HDL-C). They also tended to have a higher insulin level and homeostasis model assessment insulin resistance (HOMA-IR) index. As a result, upon recruitment in the study, children with excessive weight were 12 times more likely to have at least one laboratory metabolic abnormality and seven times more likely to have at least one criterion of the metabolic syndrome compared to lean subjects. In contrast to excessive weight status, gaining ≥0.5 BMI z-score point during risperidone treatment was not associated with a significantly higher occurrence of metabolic disturbances.
Conclusions
The long-term use of risperidone, especially when weight is above normal, is associated with a number of metabolic abnormalities but a low prevalence of the metabolic syndrome phenotype. Future studies should evaluate the stability of these abnormalities over time.
doi:10.1089/cap.2008.007
PMCID: PMC2715008  PMID: 19364288
Drug and alcohol dependence  2007;93(1-2):12-20.
Dependence on alcohol and illicit drugs frequently co-occur. Results from a number of twin studies suggest that heritable influences on alcohol dependence and drug dependence may substantially overlap. Using large, genetically informative pedigrees from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed quantitative linkage analyses using a panel of 1717 SNPs. Genome-wide linkage analyses were conducted for quantitative measures of DSM-IV alcohol dependence criteria, cannabis dependence criteria and dependence criteria across any illicit drug (including cannabis) individually and in combination as an average score across alcohol and illicit drug dependence criteria. For alcohol dependence, LOD scores exceeding 2.0 were noted on chromosome 1 (2.0 at 213 cM), 2 (3.4 at 234 cM) and 10 (3.7 at 60 cM). For cannabis dependence, a maximum LOD of 1.9 was noted at 95 cM on chromosome 14. For any illicit drug dependence, LODs of 2.0 and 2.4 were observed on chromosome 10 (116 cM) and 13 (64 cM) respectively. Finally, the combined alcohol and/or drug dependence symptoms yielded LODs > 2.0 on chromosome 2 (3.2, 234 cM), 10 (2.4 and 2.6 at 60 cM and 116 cM) and 13 (2.1 at 64 cM). These regions may harbor genes that contribute to the biological basis of alcohol and drug dependence.
doi:10.1016/j.drugalcdep.2007.08.015
PMCID: PMC2266629  PMID: 17942244
Linkage; alcohol; cannabis; illicit drugs; dependence; COGA
Biological psychiatry  2008;64(11):922-929.
Background
A non-synonymous coding polymorphism, rs16969968, of the CHRNA5 gene which encodes the alpha-5 subunit of the nicotinic acetylcholine receptor (nAChR) has been found to be associated with nicotine dependence (20). The goal of the present study is to examine the association of this variant with cocaine dependence.
Methods
Genetic association analysis in two, independent samples of unrelated cases and controls; 1.) 504 European-American participating in the Family Study on Cocaine Dependence (FSCD); 2.) 814 European Americans participating in the Collaborative Study on the Genetics of Alcoholsim (COGA).
Results
In the FSCD, there was a significant association between the CHRNA5 variant and cocaine dependence (OR = 0.67 per allele, p = 0.0045, assuming an additive genetic model), but in the reverse direction compared to that previously observed for nicotine dependence. In multivariate analyses that controlled for the effects of nicotine dependence, both the protective effect for cocaine dependence and the previously documented risk effect for nicotine dependence were statistically significant. The protective effect for cocaine dependence was replicated in the COGA sample. In COGA, effect sizes for habitual smoking, a proxy phenotype for nicotine dependence, were consistent with those observed in FSCD.
Conclusion
The minor (A) allele of rs16969968, relative to the major G allele, appears to be both a risk factor for nicotine dependence and a protective factor for cocaine dependence. The biological plausibility of such a bidirectional association stems from the involvement of nAChRs with both excitatory and inhibitory modulation of dopamine-mediated reward pathways.
doi:10.1016/j.biopsych.2008.04.018
PMCID: PMC2582594  PMID: 18519132
Smoking; Nicotine dependence; Addiction; Substance-use disorders; Genetics; Receptors; nicotinic; Cocaine

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