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1. Priming deficiency in male subjects at risk for alcoholism: the N4 during a lexical decision task

Alcoholism, clinical and experimental research 2009;33(12):2027-2036.

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

2. 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

3. 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

4. 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

5. Genome-Wide Association Study of Theta Band Event-Related Oscillations Identifies Serotonin Receptor Gene HTR7 Influencing Risk of Alcohol Dependence

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2010;null.

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)

6. 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

7. Single-Nucleotide Polymorphisms in Corticotropin Releasing Hormone Receptor 1 Gene (CRHR1) Are Associated With Quantitative Trait of Event-Related Potential and Alcohol Dependence

Alcoholism, clinical and experimental research 2010;34(6):988-996.

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)

8. Predicting sensation seeking from dopamine genes: A candidate system approach

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

9. A Cross-sectional Evaluation of the Effect of Risperidone and Selective Serotonin Reuptake Inhibitors on Bone Mineral Density in Boys

Calarge, Chadi Albert | Zimmerman, Bridget | Xie, Diqiong | Kuperman, Samuel | Schlechte, Janet A.

The Journal of clinical psychiatry 2010;71(3):338-347.

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

10. Obesity, Smoking, and Frontal Brain Dysfunction

The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addictions 2010;19(5):391-400.

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

11. Predictors of Sexual Debut at Age 16 or Younger

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

12. Association of Single Nucleotide Polymorphisms in a Glutamate Receptor Gene (GRM8) with Theta Power of Event-Related Oscillations and Alcohol Dependence

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2009;150B(3):359-368.

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

13. Weight Gain and Metabolic Abnormalities During Extended Risperidone Treatment in Children and Adolescents

Calarge, Chadi A. | Acion, Laura | Kuperman, Samuel | Tansey, Michael | Schlechte, Janet A.

Journal of child and adolescent psychopharmacology 2009;19(2):101-109.

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

14. Weight Gain and Metabolic Abnormalities During Extended Risperidone Treatment in Children and Adolescents

Calarge, Chadi A. | Acion, Laura | Kuperman, Samuel | Tansey, Michael | Schlechte, Janet A.

Journal of Child and Adolescent Psychopharmacology 2009;19(2):101-109.

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

Results

Conclusions

doi:10.1089/cap.2008.007

PMCID: PMC2715008 PMID: 19364288

15. Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) Sample

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

16. A Risk Allele for Nicotine Dependence in CHRNA5 Is a Protective Allele for Cocaine Dependence

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

17. Variants in the Nicotinic Receptors Alter the Risk for Nicotine Dependence

The American journal of psychiatry 2008;165(9):1163-1171.

Objective

A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the α5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study is to replicate these findings in an independent dataset and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking.

Methods

Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid variant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influenced receptor function.

Results

A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across non-human species, but its frequency varied across human populations (0% in African populations to 37% in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown.

Conclusions

This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.

doi:10.1176/appi.ajp.2008.07111711

PMCID: PMC2574742 PMID: 18519524

18. A regulatory variation in OPRK1, the gene encoding the κ-opioid receptor, is associated with alcohol dependence

Human Molecular Genetics 2008;17(12):1783-1789.

Variations in OPRK1, which encodes the κ-opioid receptor, are associated with the risk for alcohol dependence. Sequencing DNAs with higher and lower risk haplotypes revealed an insertion/deletion (indel) with a net addition of 830 bp located 1986 bp upstream of the translation start site (1389 bp upstream of the transcription start site). We demonstrated that the upstream region extending from −1647 to −10 bp or from −2312 to −10 bp (relative to the translation start site) could function as a promoter in transient transfection assays. We then determined that the presence of the indel reduced transcriptional activity by half. We used a PCR assay to genotype individuals in 219 multiplex alcohol-dependent families of European American descent for the presence or absence of this indel. Family-based association analyses detected significant evidence of association of this insertion with alcoholism; the longer allele (with the indel), which had lower expression, is associated with higher risk for alcoholism. This indel is, therefore, a functional regulatory variation likely to explain at least part of the association of OPRK1 with alcohol dependence.

doi:10.1093/hmg/ddn068

PMCID: PMC2405904 PMID: 18319328

19. Delta and Theta oscillations as risk markers in Adolescent Offspring of Alcoholics

International journal of psychophysiology : official journal of the International Organization of Psychophysiology 2006;63(1):3-15.

Background

Visual P300 is consistently lower in alcohol dependent individuals, their offspring and subjects at risk. Delta and theta event related oscillations (ERO) are the major contributors to the P300 signal. The total and evoked power in delta and theta bands in the 300 to 700 millisecond post-stimulus window (corresponding to the zone of P3 maxima) was compared between adolescent offspring of alcoholics (high-risk) and age-matched normal controls (low-risk), to assess the utility of the risk markers.

Methods

EEG was recorded during the performance of visual oddball task. The S-Transform algorithm decomposed the EEG signals into different frequency bands and the group differences in total and evoked power in the oscillatory responses during the P300 time window (300 to 700 ms) were analyzed using a multivariate design. Similar analysis was performed on P300 peak amplitudes for the target.

Results

The high-risk group showed significantly lower parietal post-stimulus evoked and total power in the delta band for targets. A decrease in total power was seen centrally and parietally in theta band. The P300 peak amplitude in the parietal electrodes was also significantly lower in the high-risk group.

Conclusions

The decreased total theta power and total and evoked delta power for visual targets in high risk individuals may serve as an endophenotypic marker in the development of alcoholism and other disinhibitory disorders. The differences seen between the offspring of alcoholics and controls may have a cholinergic basis. The ERO measures appear to be more robust than the P300 amplitude in differentiating the groups.

doi:10.1016/j.ijpsycho.2006.10.00

PMCID: PMC2020838 PMID: 17129626

Offspring of Alcoholics; Endophenotype; Event-related Oscillations; Delta; Theta; P300

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