Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci.

We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P=1.17 × 10(-31); AAs: Arg369Cys, P=6.33 × 10(-17)) and ADH1C in AAs (Thr151Thr, P=4.94 × 10(-10)), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P=2.63 × 10(-11)), PDLIM5 in EAs (P=2.01 × 10(-8)), and METAP in AAs (P=3.35 × 10(-8)). We also identified a novel GWS association (1.17 × 10(-10)) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits.

Association of functional DBH genetic variants with alcohol dependence risk and related depression and suicide attempt phenotypes: results from a large multicenter association study.

OBJECTIVE: Dopamine-beta-hydroxylase (DBH) metabolizes the conversion of dopamine to noradrenaline. DBH, located on chromosome 9q34.2 has variants with potential functional consequences which may be related to alterations of neurotransmitter function and several psychiatric phenotypes, including alcohol dependence (AD), depression (MD) and suicidal behavior (SA). The aim of this association study in a large multicenter sample of alcohol-dependent individuals and controls is to investigate the role of DBH SNPs and haplotypes in AD risk and associated phenotypes (AD with MD or SA). METHOD: 1606 inpatient subjects with DSM-IV AD from four addiction treatment centers and 1866 control subjects were included. Characteristics of AD, MD and SA were obtained using standardized structured interviews. After subjects were genotyped for 4 DBH polymorphisms, single SNP case-control and haplotype analyses were conducted. RESULTS: rs1611115 (near 5') C-allele and related haplotypes were significantly associated with alcohol dependence in females. This association with female alcohol dependence also accounts for the significant relationship between this variant and comorbid conditions and traits. CONCLUSIONS: This study presents evidence for a potentially functional DBH variant influencing the risk for alcohol dependence while other comorbid conditions are not independently influenced by this SNP. However, the study also supports the possible role of the dopamine system in the etiology of female alcohol dependence.

[Indicators of course of inpatient therapy in offenders with substance dependency]. / Indikatoren für den Verlauf einer stationären Behandlung bei Straftätern mit Substanzmittelabhängigkeit.

The objective of this review is to summarise the recent state of research on intake criteria for forensic psychiatry in Germany. Therefore, a systematic literature review was conducted on the legal basis of paragraph 64 of the German Penal Code for forensic psychiatry. Although the patients were very heterogeneous, relatively robust indicators were identified that may yield an unsuccessful therapy outcome. A younger age, previous delinquency, absence of an educational and vocational qualification, and personality disorders are the most robust indicators adversely affecting therapy in German forensic psychiatric institutions.

No association of alcohol dependence with HOMER 1 and 2 genetic variants.

Several lines of evidence indicate that alterations of the central cortico-accumbens glutamate pathway are involved in the development and maintenance of alcohol- and substance-use disorders. The HOMER protein family is encoded by 3 genes HOMER (1-3) which are components of the excitatory postsynaptic density complex and function to modulate synaptic activity by the regulation of glutamate signaling. HOMER 1 and 2 have been reported to contribute to chronic alcohol-induced long-term neurochemical changes in the endogenous reward system. Data from animal models suggest a potential role of the Homer protein family in the development of alcohol and substance use. The aim of this study is to assess potential associations between HOMER 1 and 2 genetic variants in a larger sample of alcohol-dependent individuals and unrelated controls. Five genetic variants of HOMER 1 and 3 of HOMER 2 were genotyped in a multi-site sample of 1,923 German healthy controls and 2,039 alcohol-dependent subjects. Neither single SNP nor haplotype analysis could detect significant associations with alcohol dependence (AD) and related phenotypes. While most of the HOMER 1 and 2 SNPs are in low-to-moderate linkage disequilibrium, three major haplotypes of HOMER 1 and 4 haplotypes of HOMER 2 are present in the majority of alcohol-dependent and control subjects. In conclusion, our results suggest that single SNPs, respectively, haplotypes of the HOMER 1 and 2 genes are unlikely to play a major role in the pathophysiology of AD.

[The impact of attachment styles and ADHD on alcohol dependence]. / Einfluss unsicherer Bindungsstile und ADHS auf Alkoholabhängigkeit.

BACKGROUND: Insecure attachment (IA) and attention-deficit/hyperactivity disorder (ADHD) are discussed as risk factors for increased alcohol intake and the development of alcoholism. METHODS: Among a sample of 517 consecutively admitted German inpatients with alcohol dependence we investigated the contribution of IA to alcoholism phenotypes, taking into consideration comorbid ADHD. RESULTS: IA was significantly associated with increased alcohol consumption, increased frequency of withdrawal symptoms, increased frequency of physical or psychological problems that are likely to have been worsened by alcohol, and reduced social activities because of alcohol use. ADHD has no significant effect on these parameters. CONCLUSIONS: IA developed as a result of social interactions during childhood long before alcohol dependence. The results point to an important effect of IA on the severity and acceleration of alcohol dependence. Therefore, it might be helpful to improve efforts in primary prevention and psychotherapy of alcohol dependence by considering the specific needs of subjects with an IA.

Nutraceuticals: miracle or meme?

Nutraceuticals, widely becoming adopted as a catchall term to refer to vitamins, minerals, herbs, and various other supplements, continue to gain popularity among large segments of the population, despite little proof of any benefit of most of these compounds.

In vivo molecular imaging biomarkers: clinical pharmacology's new "PET"?

Medicine, including the pharmaceutical and biotechnology industries as well as many clinical practitioners, has recognized the importance of using molecular imaging biomarkers, including those labeled in such a way as to be imaged by positron emission tomography (PET), as tools for predicting outcomes in drug development and creating opportunities for "personalized" medicine, for diagnosing early-stage disease, and for the follow-up of the effectiveness of treatment.(1) However, only one important and widely used PET biomarker is currently approved by the Food and Drug Administration (FDA). If the technology is so important, we can ask why there is such a limitation to the availability of these biomarkers.

Is the Dx for welfare Rx?

Welfare recipients in the United States are three times as likely to suffer from depression and anxiety as average Americans. Although affordable pharmacotherapy options are readily available in more affluent parts of society, welfare programs are ineffective in facilitating diagnosis and therapy that could help the affected improve their lives and even ultimately become gainfully employed and off taxpayer-supported welfare programs. To the benefit of all, more "bang for the buck" is within reach with common pharmacotherapy, but the question remains: who will wake up and champion the obvious?

Endothelium-dependent gender differences in the response of the rat aorta.

Segments of rat aortic arch were studied to determine the existence of sexual dimorphism. The influence of the endothelium in mediating gender differences in contractility (maximum tension, Tmax) and sensitivity (ED50) to prostaglandin F2 alpha was measured. This was done in both intact and denuded vascular ring preparations which were dissected from adult male and female rats. Group I comprised untreated male and female rats; Groups II and III were treated with testosterone (10 mg/kg i.m.) or 17 beta-estradiol (2.5 mg/kg i.m.), respectively, on days 1, 3 and 6 and sacrificed on day 7. Intact vascular ring preparations from untreated females were significantly less sensitive (P less than .01) and less contractile (P less than .025) than those from the males. After the intimal surface of the aortic arch rings was rubbed the rings from females exhibited a significant increase in Tmax. However, in vessels from males endothelial denudation had no effect on either Tmax or ED50. Testosterone treatment of female rats significantly increased Tmax (P less than .01) and decreased the ED50 (P less than .01) when compared to rings from untreated females. Testosterone treatment did not significantly affect either parameter in vessels from females which had been rubbed. Testosterone treatment also had no significant effect in either intact or rubbed vessels from males. Estrogen treatment significantly increased the Tmax (P less than .05) of intact vessels from females and had no effect on other vessel segments. Thus, the gender difference in Tmax may relate to an attenuating effect of the endothelium on contractility in the rings from females.(ABSTRACT TRUNCATED AT 250 WORDS)