Henry R. Kranzler

The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk.

Eleven single-nucleotide polymorphisms (SNPs) spanning OPRD1 were examined in 1063 European Americans (EAs) (620 cases with substance dependence (SD), including 557 with alcohol dependence (AD), 225 with cocaine dependence (CD) and 111 with opioid dependence (OD), and 443 controls). Nominally significant associations (P<0.05) of five SNPs with SD were observed; only the association of the non-synonymous variant G80T with OD remained significant after correction for multiple testing using SNPSpD. Haplotype analyses with six tag SNPs indicated that a specific haplotype GCAACT, which harbors G80T G-allele and C921T C-allele, was significantly associated with AD (χ2=14.82, degrees of freedom (d.f.)=1, P<0.001), CD (χ2=9.19, d.f.=1, P=0.002) and OD (χ2=20.68, d.f.=1, P<0.001). Logistic regression analyses, with sex and age being considered, demonstrated that this haplotype had a risk effect on AD (P=0.03, β=1.86, odds ratio (OR)=6.43) and especially on OD (P<0.001, β=3.92, OR=50.57). Moreover, seven SNPs covering OPRK1 were examined in the majority of the above subjects (390 cases, including 327 AD, 177 CD and 97 OD subjects, and 358 controls). Although no significant differences in allele, genotype or haplotype frequency distributions were seen between cases and controls, a specific OPRK1 haplotype, GGCTTCT, was significantly associated with AD (χ2=8.12, d.f.=1, P=0.004). Logistic regression analyses also revealed its risk effect on AD (P=0.009, β=1.06, OR=2.90). Population stratification artifact was not observed in the sample. Taken together, our findings supported a positive association between OPRD1 variants and SD, and a positive haplotypic association between OPRK1 and AD in EAs.

Validity of Psychiatric Diagnoses in Patients With Substance Use Disorders: Is the Interview More Important Than the Interviewer?

Although structured diagnostic interviews are increasingly being used in substance abuse treatment settings, there has been limited systematic evaluation of their ability to enhance reliability and validity of psychiatric diagnoses. The present report provides data on the concurrent, discriminant, and predictive validity of current substance use disorders and common comorbid diagnoses in a sample of 100 substance abuse patients. Diagnoses formulated primarily by masters-level clinicians in the usual course of their duties were compared with diagnoses formulated by research technicians using a semistructured interview. Results indicated that the validity of clinician diagnoses was good for substance use disorders, moderate for personality disorders, and poor for anxiety disorders and major depression. Greater validity was observed for substance abuse diagnoses formulated by research technicians using the semistructured interview. Based on these findings, we conclude that psychiatric diagnosis in substance abuse patients may be improved by adding elements of structured interviews to the clinicians usual assessment.

Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.

We conducted a 1000 Genomes–imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17u2009074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10−9 across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08–1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10−4). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28u2009998, odds ratio=1.06 and 95% confidence interval=1.00–1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single ‘cigarettes per day’ item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.

Reduction of alcohol drinking in young adults by naltrexone: a double-blind, placebo-controlled, randomized clinical trial of efficacy and safety.

OBJECTIVEnNaltrexone, an opioid antagonist, may facilitate reduction in drinking among young adults. We compared the efficacy and safety of naltrexone administered daily plus targeted dosing with placebo to reduce drinking in young adults who engage in heavy drinking.nnnMETHODnA randomized, double-blind, placebo-controlled study was conducted in an outpatient research center in March 2008-January 2012. Participants were aged 18-25 years and reported ≥ 4 heavy drinking days in the prior 4 weeks. Interventions included naltrexone 25 mg daily plus 25 mg targeted (at most daily) in anticipation of drinking (n = 61) or daily/targeted placebo (n = 67). All participants received a personalized feedback session and brief counseling every other week. Primary outcomes were percent heavy drinking days and percent days abstinent over the 8-week treatment period. Secondary outcomes included number of drinks per drinking day and percentage of days with estimated blood alcohol concentration (BAC) levels ≥ 0.08 g/dL.nnnRESULTSnOf 140 randomized patients, 128 began treatment, comprising the evaluable sample. During treatment, percent heavy drinking days (naltrexone: mean = 21.60, SD = 16.05; placebo: mean = 22.90, SD = 13.20) (P = .58) and percent days abstinent (naltrexone: mean = 56.60, SD = 22.52; placebo: mean = 62.50, SD = 15.75) (P = .39) did not differ by group. Naltrexone significantly reduced the number of drinks per drinking day (naltrexone: mean = 4.90, SD = 2.28; placebo: mean = 5.90, SD = 2.51) (P = .009) and percentage of drinking days with estimated BAC ≥ 0.08 g/dL (naltrexone: mean = 35.4, SD = 28.40; placebo: mean = 45.7, SD = 26.80) (P = .042). There were no serious adverse events. Sleepiness was more common with naltrexone.nnnCONCLUSIONSnNaltrexone did not reduce frequency of drinking or heavy drinking days, but reduced secondary measures of drinking intensity. While effects were modest, the risk-benefit ratio favors offering naltrexone to help young adult heavy drinkers reduce the amount of alcohol they drink.nnnTRIAL REGISTRATIONnClinicalTrials.gov identifier: NCT00568958.

Confirmation and fine mapping of the chromosome 1 alcohol dependence risk locus

Two previous large genetic linkage studies in the US population have implicated an area in chromosome 1p to contain a susceptibility gene for alcohol dependence. The 1-LOD support interval of the linkage signal spans about 30u2009cM and contains >30u2009000u2009000 DNA base pairs (bp) and 700 predicted genes. In order to reduce the size of the candidate area and potentially identify novel candidate genes within this region, we fine-mapped this area using closely spaced short tandem repeat (STR) markers and the transmission disequilibrium test (TDT) in small nuclear families. The subjects were 87 European-American families including one or more alcohol-dependent offspring (93 children and 174 parents). The initial marker set consisted of 30 STR markers, spanning the Marshfield map interval between 101.48 and 130.73u2009cM. Using the TDTPHASE program, we identified three markers in the distal part of this region (125–126u2009cM), which showed evidence of transmission disequilibrium. On the basis of this result, an additional 12 STR markers were genotyped in this region; some of these markers provided additional evidence for linkage disequilibrium. The strongest evidence for transmission disequilibrium was obtained at the marker D1S406 (P=0.005, 126.16u2009cM), with supporting evidence from three neighboring STR markers D1S424 (126.16u2009cM, P=0.01), D1S2804 (126.16u2009cM, P=0.04), and D1S2776 (126.16u2009cM, P=0.02), which are all located within a <350u2009000u2009bp interval. These findings suggest that a gene (or genes) causing susceptibility to alcohol dependence resides near location 126.16u2009cM on chromosome 1. In addition, these results provide independent confirmation of the linkage finding regarding the identification of at least one gene in this region increasing the risk for alcohol dependence.

Evaluating the role of a galanin enhancer genotype on a range of metabolic, depressive and addictive phenotypes

There is a large body of pre‐clinical and some clinical data to link the neuropeptide galanin to a range of physiological and pathological functions that include metabolism, depression, and addiction. An enhancer region upstream of the human GAL transcriptional start site has previously been characterised. In‐vitro transfection studies in rat hypothalamic neurons demonstrated that the CA allele was 40% less active than the GG allele in driving galanin expression. Our hypothesis was to investigate the effect of this galanin enhancer genotype on a range of variables that relate to the known functions of the galaninergic system in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort of young adults (Nu2009=u2009169–6,078). Initial findings showed a positive relationship of cannabis usage (ORu2009=u20092.070, Pu2009=u20090.007, Nu2009=u2009406 (individuals who had used cannabis at least once within the last 12 months, total sample size 2731) with the GG haplotype, consistent with the previous published data linking galanin with an increased release of dopamine. As our sample size was relatively small we replicated the analysis in a larger cohort of 2,224 African Americans and 1,840 European Americans, but no discernible trend across genotypes was observed for the relationship with cannabis usage. Further, we found no association of the galanin enhancer genotype with any of the other pathophysiological parameters measured. These findings emphasise that preclinical data does not always predict clinical outcomes in cohort studies, noting that association studies are subject to multiple confounders.