Genome-wide association study identifies a novel locus for cannabis dependence.

Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry.

Fast beta (20-28 Hz) electroencephalogram (EEG) oscillatory activity may be a useful endophenotype for studying the genetics of disorders characterized by neural hyperexcitability, including substance use disorders (SUDs). However, the genetic underpinnings of fast beta EEG have not previously been studied in a population of African-American ancestry (AA). In a sample of 2382 AA individuals from 482 families drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a genome-wide association study (GWAS) on resting-state fast beta EEG power. To further characterize our genetic findings, we examined the functional and clinical/behavioral significance of GWAS variants. Ten correlated single-nucleotide polymorphisms (SNPs) (r2>0.9) located in an intergenic region on chromosome 3q26 were associated with fast beta EEG power at P<5 × 10-8. The most significantly associated SNP, rs11720469 (ß: -0.124; P<4.5 × 10-9), is also an expression quantitative trait locus for BCHE (butyrylcholinesterase), expressed in thalamus tissue. Four of the genome-wide SNPs were also associated with Diagnostic and Statistical Manual of Mental Disorders Alcohol Dependence in COGA AA families, and two (rs13093097, rs7428372) were replicated in an independent AA sample (Gelernter et al.). Analyses in the AA adolescent/young adult (offspring from COGA families) subsample indicated association of rs11720469 with heavy episodic drinking (frequency of consuming 5+ drinks within 24 h). Converging findings presented in this study provide support for the role of genetic variants within 3q26 in neural and behavioral disinhibition. These novel genetic findings highlight the importance of including AA populations in genetics research on SUDs and the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53.

Several studies have identified genes associated with alcohol-use disorders (AUDs), 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 to identify novel genes affecting risk for alcohol dependence (AD). 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 (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.

ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry.

A coding variant in alcohol dehydrogenase 1B (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 the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.24, 0.48) on 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 significantly protective effect. This variant has the strongest effect on risk for alcohol dependence compared with any other tested variant in European populations.

Genome-wide association study of conduct disorder symptomatology.

Conduct disorder (CD) is one of the most prevalent childhood psychiatric conditions, and is associated with a number of serious concomitant and future problems. CD symptomatology is known to have a considerable genetic component, with heritability estimates in the range of 50%. Despite this, there is a relative paucity of studies aimed at identifying genes involved in the susceptibility to CD. In this study, we report results from a genome-wide association study of CD symptoms. CD symptoms were retrospectively reported by a psychiatric interview among a sample of cases and controls, in which cases met the criteria for alcohol dependence. Our primary phenotype was the natural log transformation of the number of CD symptoms that were endorsed, with data available for 3963 individuals who were genotyped on the Illumina Human 1M beadchip array. Secondary analyses are presented for case versus control status, in which caseness was established as endorsing three or more CD symptoms (N = 872 with CD and N = 3091 without CD). We find four markers that meet the criteria for genome-wide significance (P<5 × 10(-8)) with the CD symptom count, two of which are located in the gene C1QTNF7 (C1q and tumor necrosis factor-related protein 7). There were six additional SNPs in the gene that yielded converging evidence of association. These data provide the first evidence of a specific gene that is associated with CD symptomatology. None of the top signals resided in traditional candidate genes, underscoring the importance of a genome-wide approach for identifying novel variants involved in this serious childhood disorder.

The association of polygenic risk for schizophrenia, bipolar disorder, and depression with neural connectivity in adolescents and young adults: examining developmental and sex differences.

Neurodevelopmental abnormalities in neural connectivity have been long implicated in the etiology of schizophrenia (SCZ); however, it remains unclear whether these neural connectivity patterns are associated with genetic risk for SCZ in unaffected individuals (i.e., an absence of clinical features of SCZ or a family history of SCZ). We examine whether polygenic risk scores (PRS) for SCZ are associated with functional neural connectivity in adolescents and young adults without SCZ, whether this association is moderated by sex and age, and if similar associations are observed for genetically related neuropsychiatric PRS. One-thousand four-hundred twenty-six offspring from 913 families, unaffected with SCZ, were drawn from the Collaborative Study of the Genetics of Alcoholism (COGA) prospective cohort (median age at first interview = 15.6 (12-26), 51.6% female, 98.1% European American, 41% with a family history of alcohol dependence). Participants were followed longitudinally with resting-state EEG connectivity (i.e., coherence) assessed every two years. Higher SCZ PRS were associated with elevated theta (3-7 Hz) and alpha (7-12 Hz) EEG coherence. Associations differed by sex and age; the most robust associations were observed between PRS and parietal-occipital, central-parietal, and frontal-parietal alpha coherence among males between ages 15-19 (B: 0.15-0.21, p < 10-4). Significant associations among EEG coherence and Bipolar and Depression PRS were observed, but differed from SCZ PRS in terms of sex, age, and topography. Findings reveal that polygenic risk for SCZ is robustly associated with increased functional neural connectivity among young adults without a SCZ diagnosis. Striking differences were observed between men and women throughout development, mapping onto key periods of risk for the onset of psychotic illness and underlining the critical importance of examining sex differences in associations with neuropsychiatric PRS across development.

Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence.

Alcohol dependence frequently co-occurs with cigarette smoking, another common addictive behavior. Evidence from genetic studies demonstrates that alcohol dependence and smoking cluster in families and have shared genetic vulnerability. Recently a candidate gene study in nicotine dependent cases and nondependent smoking controls reported strong associations between a missense mutation (rs16969968) in exon 5 of the CHRNA5 gene and a variant in the 3'-UTR of the CHRNA3 gene and nicotine dependence. In this study we performed a comprehensive association analysis of the CHRNA5-CHRNA3-CHRNB4 gene cluster in the Collaborative Study on the Genetics of Alcoholism (COGA) families to investigate the role of genetic variants in risk for alcohol dependence. Using the family-based association test, we observed that a different group of polymorphisms, spanning CHRNA5-CHRNA3, demonstrate association with alcohol dependence defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) criteria. Using logistic regression we replicated this finding in an independent case-control series from the family study of cocaine dependence. These variants show low linkage disequilibrium with the SNPs previously reported to be associated with nicotine dependence and therefore represent an independent observation. Functional studies in human brain reveal that the variants associated with alcohol dependence are also associated with altered steady-state levels of CHRNA5 mRNA.

Evoked brain potentials as indicators of decision-making.

The effects of decision-making processes on evoked brain potentials recorded at the vertex were studied in human subjects. Significantly different visual evoked potentials to the same physical stimulus were obtained in trails that resulted in different behavioral decisions. The results suggest that certain characteristics of evoked potentials may perhaps be used as indicators of specific behavioral outcomes.

Event-related brain potentials in boys at risk for alcoholism.

Recent neurophysiological findings have demonstrated that abstinent chronic alcoholics manifest deficits in event-related brain potentials. To explore possible biological antecedents of alcoholism the present study examined boys at high risk for alcoholism. Event-related brain potentials were recorded from biological sons of alcoholic fathers and matched control boys. Differences in the P3 component of the potentials were obtained between the high-risk and control subjects.

Auditory brainstem potentials in chronic alcoholics.

Auditory brainstem potentials were recorded from abstinent chronic alcoholics and control subjects. The latencies of peaks II, III, IV, and V were significantly delayed in the alcoholic patients compared to control subjects. Brainstem transmission time was longer in alcoholics than in controls. This study provides systematic evidence that chronic alcohol abuse results in brainstem deficits suggesting possible demyelination of auditory tracts.

Evoked potential correlates of expected stimulus intensity.

The electrophysiological responses to a flash of medium intensity have different wave shapes in trials in which the occurrence of bright stimuli or dim stimuli is expected. When a bright or dim stimulus is signaled, the potentials evoked by the medium stimulus resemble the responses evoked by a real bright or dim flash.

A sex-adjusted and age-adjusted genome screen for nested alcohol dependence diagnoses.

Alcohol dependence is a complex disorder with a substantial genetic contribution to susceptibility. The Collaborative Study on the Genetics of Alcoholism is a multi-site study whose purpose is to detect, localize, and characterize genes contributing to this susceptibility. Previous linkage analyses of the trait of alcohol dependence in Collaborative Study on the Genetics of Alcoholism have used affected sib-pair methods with a dichotomous phenotype definition. In contrast, the analysis in this paper uses a sex-adjusted and age-adjusted multiple threshold liability model. The use of such a model, in that it includes unaffected as well as as affected subjects and in that it utilizes the differential severity of a diagnosis scale, should heuristically be more powerful than a straight affected sib-pair analysis. Three regions of interest are found on chromosome 1 (lod 5.17), chromosome 4 (lod 3.46), and chromosome 8 (lod 4.31). The region on chromosome 1 near the marker D1S532 is in the region previously reported as linked to alcohol dependence and correlated phenotypes in this dataset. The region on chromosome 4 near the alcohol dehydrogenase gene cluster has been reported to be linked to alcohol dependence in other studies, as well as to the alcohol consumption phenotype 'Maximum Number of Drinks in a 24-Hour Period' in this dataset. The region on chromosome 8 near the marker D8S1988 is homologous to a section of rat chromosome 5 to which an alcohol consumption phenotype has been linked.

Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism.

BACKGROUND: Alcoholism and substance dependence frequently co-occur. Accordingly, we evaluated the familial transmission of alcohol, marijuana, and cocaine dependence and habitual smoking in the Collaborative Study on the Genetics of Alcoholism. METHODS: Subjects (n=1212) who met criteria for both DSM-III-R alcohol dependence and Feighner definite alcoholism and their siblings (n=2755) were recruited for study. A comparison sample was also recruited (probands, n=217; siblings, n=254). Subjects were interviewed with the Semi-Structured Assessment for the Genetics of Alcoholism. The familial aggregation of drug dependence and habitual smoking in siblings of alcohol-dependent and non-alcohol-dependent probands was measured by means of the Cox proportional hazards model. RESULTS: Rates of alcohol, marijuana, and cocaine dependence and habitual smoking were increased in siblings of alcohol-dependent probands compared with siblings of controls. For siblings of alcohol-dependent probands, 49.3% to 50.1% of brothers and 22.4% to 25.0% of sisters were alcohol dependent (lifetime diagnosis), but this elevated risk was not further increased by comorbid substance dependence in probands. Siblings of marijuana-dependent probands had an elevated risk of developing marijuana dependence (relative risk [RR], 1.78) and siblings of cocaine-dependent probands had an elevated risk of developing cocaine dependence (RR, 1.71). There was a similar finding for habitual smoking (RR, 1.77 in siblings of habitual-smoking probands). CONCLUSIONS: Alcohol, marijuana, and cocaine dependence and habitual smoking are all familial, and there is evidence of both common and specific addictive factors transmitted in families. This specificity suggests independent causative factors in the development of each type of substance dependence.

Late positive component amplitude in schizophrenics and alcoholics in two different paradigms.

Abstinent alcoholics, unmedicated schizophrenics, and controls were tested in two paradigms designed to elicit the late positive component. Experiment A used frequent stimuli of differing incentive value and Experiment B used infrequent stimuli of differing perceptual discriminability. Alcoholics and schizophrenics showed late positive components that were significantly reduced in amplitude compared to controls. The patient groups were similar in their late component amplitudes. Control subjects showed a substantially wider response range than the patient groups. The narrow response range in both patient groups was manifested in diminished late component amplitudes to both stimuli in both experiments. The intraclass correlation coefficient of late component amplitudes for both patient groups was significantly greater than that of the controls.

Event-related potential index of semantic mnemonic dysfunction in abstinent alcoholics.

BACKGROUND: The objective of the study was to expand the investigation of the match/mismatch mnemonic impairment in the semantic domain in sober alcoholics. METHODS: Event-related potentials (ERPs) were recorded from 28 healthy adults and 36 sober alcoholics in a category (either animals or fruits/vegetables) match/nonmatch S1-S2 paradigm. RESULTS: There was a significant interaction of ERP amplitude (c3) between groups (controls vs. alcoholics) and stimulus conditions (category match vs. nonmatch) at the posterior brain regions; the c3 component was smaller for the category match than for nonmatch trials in controls, with the absence of such c3 differences in alcoholics. There were no significant ERP differences between the two groups in processing the sample stimuli. The ERPs c2) elicited by the animal category were larger than those for the vegetable category in both groups. The alcoholics showed prominent suppressed activation of left temporooccipital brain regions under both matching and nonmatching conditions, as demonstrated by the current source density maps. The alcoholics were also slower and less accurate than the controls in judging both category matching and nonmatching stimuli, while neither of the two groups demonstrated shorter response times to the matching stimuli. CONCLUSIONS: These data suggest that alcoholics are less efficient in the semantic mnemonic match/nonmatch process, and are less likely to be deteriorated in the stage of forming the template for such match/nonmatch comparisons.

Auditory P3a assessment of male alcoholics.

BACKGROUND: P3a amplitude differences between alcoholic and control groups have not been well defined. Because event-related potential (ERP) differences between these groups appear to be influenced by task difficulty, the present study employed a new auditory ERP paradigm, in which target/standard tone discriminability was difficult, with infrequent nontarget stimuli used to elicit the P3a. METHODS: A total of n = 27 male alcoholics and n = 25 male controls were assessed using a three-tone discrimination paradigm, in which the discriminability between the target and standard was difficult, with easily discriminable infrequent nontarget tones also presented. A P3a component with a centro-frontal maximum to the rare nontargets and a P3b with a parietal maximum amplitude to the target stimulus were obtained. Current Source Density (CSD) maps were derived from the potential data and employed to assay topographical differences between subject groups. RESULTS: Alcoholics produced smaller P3a amplitudes than control subjects to the rare nontargets with no peak latency differences observed. The most prominent current sources are apparent more anteriorly for the nontarget compared to the target stimulus in both groups. There were more sources and sinks in the alcoholics than in the control subjects for P3a. A bootstrap analysis method showed that P3a CSD maps evinced distinct topographic distributions between alcoholics and control subjects in all brain regions. CONCLUSIONS: The lower P3a amplitude and weaker sources in alcoholics coupled with less topographic specificity in their CSD maps, suggests disorganized inefficient brain functioning. This global electrophysiological pattern suggests cortical disinhibition perhaps reflecting underlying CNS hyperexcitability in alcoholics.

Event-related potential evidence of dysfunction in automatic processing in abstinent alcoholics.

The preattentive automatic processing of 63 alcoholics and 27 controls was evaluated with an auditory inattentive event-related oddball paradigm. We examined the mismatch negativity and the N2-P3 complex. Results showed significantly greater amplitude for N2, P3 and the N2-P3 complex for controls but no individual lead (Fz, Cz, Pz) differences by group. A group-by-lead interaction was found for N2 and for the N2-P3 complex. There were no significant latency differences between groups; however, a significant age-by-group interaction effect on latency was greatest at the Cz electrode. Results reflect a possible aberration of automatic processing in alcoholics because of a defect in the mnemonic template necessary to match with an infrequent deviant stimuli. We also found suggestive evidence of a relative weakness of frontal cortical organization in alcoholics. Future studies are suggested that would help clarify these differences in alcoholics.

Neuroelectric correlates of response production and inhibition in individuals at risk to develop alcoholism.

P300 recordings were made from males at high risk (HR) for alcoholism and low-risk (LR) controls, participating in a visual go/no go reaction time paradigm. The go (button press) and no go (inhibit response) stimuli were large and small forms of the same letters. The LR group had significantly larger go than no go P300 amplitudes in the central, parietal, and temporal regions; the HR group manifested no response differences in any region. In the LR group compared to the HR group, both go and no go response amplitudes were larger over the entire head; no group differences in latencies were observed in any region. Surface energy magnitudes paralleled P300 amplitudes and were also larger in the LR group during both go and no go trials. Our findings indicate that HR individuals manifest widespread P300 amplitude deficits while performing a simple information-processing paradigm. These deficits, which may reflect genetic influences, preceded the onset of alcoholism and may function as a phenotypic marker for its development.

Auditory P3a deficits in male subjects at high risk for alcoholism.

BACKGROUND: Substantial evidence indicates that alcoholism is biologically mediated by a genetic predisposition. As the decreased P300 (P3b) event-related brain potential component does not recover with prolonged abstinence, it is unlikely to be related to drinking history but is more likely to be genetically influenced. This is supported by findings that P3b amplitudes are reduced in subjects at high-risk compared to low-risk for alcoholism. Although there are few studies of P3a in HR subjects, lower P3a amplitudes have been reported with a novel nontarget stimulus paradigm, as well as with a difficult three-stimulus visual paradigm. Using a similar three-tone auditory paradigm in which the discriminability between the target and standard tone is difficult, the P3a component can also be reliably elicited with a rare nontarget perceptually distinct stimulus. This technique was employed in young adult subjects at low-risk and high-risk for alcoholism. METHODS: A total of 17 low-risk and 24 high-risk male subjects were employed as subjects in an auditory paradigm that yielded a large amplitude P3a with a centro-frontal maximum to the nontarget and a robust low amplitude prolonged P3b with a parietal maximum amplitude to the target stimulus. Current source density maps were derived to assess topographic differences between low-risk and high-risk subjects. RESULTS: The high-risk group manifested significantly lower P3a amplitudes than the low-risk group at the frontal electrodes to rare nontarget stimuli. High-risk subjects also demonstrated a more disorganized current source density map for P3a compared to low-risk subjects. CONCLUSIONS: The reduction of P3a in the high-risk group may be due to cortical dysfunction including the frontal and prefrontal cortex. The lower P3a amplitude coupled with more disorganized current source density maps suggest inefficient brain functioning in high-risk subjects.

Electrophysiological evidence of memory impairment in alcoholic patients.

In a series of event-related potential (ERP) studies, we have consistently demonstrated an ERP component correlate of visual short-term memory. There have been frequent reports on the deficits of information encoding, retention, and retrieval in chronic alcoholics. In the present study, we investigated that the ERP mnemonic effects could be influenced by long-term alcohol abuse. ERP data were recorded from 48 controls and 77 alcoholics while the subjects performed a modified delayed matching to sample paradigm using a series of object pictures as stimuli. The alcoholics completed the task with more errors and longer response times than the controls. The major differences in the evoked potentials between the two groups are found at the temporo-occipital and frontal regions in the sample and nonmatching trials, and mostly prominent in the right hemisphere. The current study indicates that the ERP technique can be a useful tool to index short-term memory. The ERP mnemonic effect difference between the two groups may be a reflection of a working memory deficit caused by long-term alcohol abuse. Our data also suggest right hemisphere dysfunction in alcoholics, with deficits in information encoding.