Iain Smith

The functional GRM3 Kozak sequence variant rs148754219 affects the risk of schizophrenia and alcohol dependence as well as bipolar disorder

We previously reported that a Kozak sequence variant in the metabotropic glutamate receptor 3 gene (GRM3), rs148754219, is associated with bipolar disorder (BP) and affects gene transcription and translation (Kandaswamy et al., 2013). A marker near GRM3, rs12704290, is one of the top hits and reached genome-wide significance in a recently reported genome-wide association study of schizophrenia (SZ) (Ripke et al., 2014), and markers for GRM3 have also been reported to demonstrate association with alcohol dependence syndrome (ADS) (Levey et al., 2014). In our original sample, considering patients successfully genotyped for rs148754219, 19 out of 1062 BP cases and only four out of 932 controls were heterozygous [odds ratio (OR)=4.2 (1.4–12.3), P=0.005]. We have genotyped this variant in additional controls and cases diagnosed with BP, SZ and ADS with the same ancestry. Patients were assessed by trained clinicians as described previously (Kandaswamy et al., 2013; Way et al., 2014). Allele counts were compared and significance was tested using Fisher’s exact test. Thirteen out of 934 additional BP cases and three out of 377 additional controls were heterozygous [OR=1.8 (0.49–6.2), P=not significant]. Combined with the originally reported results (Kandaswamy et al., 2013), 32 out of 1964 BP cases and seven out of 1309 controls were heterozygous [OR=3.0 (1.3–6.8), P=0.003]. Out of 1235 SZ cases 16 were heterozygous and were compared with the total control sample [OR=2.4 (0.99–5.8), P=0.03]. Out of 1514 ADS cases 18 were heterozygous and one was homozygous for the variant allele [OR=2.5 (1.0–5.9), P=0.03]. If all case cohorts (BP, SZ and ADS) are combined together, there would be one homozygote and 66 heterozygotes out of 4971 cases compared with the seven heterozygotes out of 1309 controls [OR=2.7 (1.2–5.8), P=0.004]. Previous work has supported the view that some genetic risk factors may be common to different psychiatric diagnoses (Lydall et al., 2011; Lee et al., 2013). Although the individual results are of questionable significance, the magnitude and direction of effect are consistent across all the cohorts and thus suggest the possibility that this rare variant may have a direct, functional effect on the risk of developing any of these three disorders. Because of its rarity, large sample sizes would be needed to confirm these results. Doing this would be worthwhile because if this finding is confirmed it could provide molecular insight into a mechanism involving GRM3 leading to increased risk of mental disorders and could provide a basis for further functional and therapeutic studies.

Genetic variants in or near ADH1B and ADH1C affect susceptibility to alcohol dependence in a British and Irish population.

Certain single nucleotide polymorphisms (SNPs) in genes encoding alcohol dehydrogenase (ADH) enzymes confer a significant protective effect against alcohol dependence syndrome (ADS) in East Asian populations. Recently, attention has focused on the role of these SNPs in determining ADS risk in European populations. To further elucidate these associations, SNPs of interest in ADH1B, ADH1C and the ADH1B/1C intergenic region were genotyped in a British and Irish population (ADS cases n = 1076: controls n = 1027) to assess their relative contribution to ADS risk. A highly significant, protective association was observed between the minor allele of rs1229984 in ADH1B and ADS risk [allelic P = 8.4 × 10−6, odds ratio (OR) = 0.26, 95 percent confidence interval, 0.14, 0.49]. Significant associations were also observed between ADS risk and the ADH1B/1C intergenic variant, rs1789891 [allelic P = 7.2 × 10−5, OR = 1.4 (1.2, 1.6)] and three non‐synonymous SNPs rs698, rs1693482 and rs283413 in ADH1C. However, these associations were not completely independent; thus, while the ADH1B rs1229984 minor allele association was independent of those of the intergenic variant rs1789891 and the three ADH1C variants, the three ADH1C variants were not individually independent. In conclusion, the rare ADH1B rs1229984 mutation provides significant protection against ADS in this British and Irish population; other variants in the ADH gene cluster also alter ADS risk, although the strong linkage disequilibrium between SNPs at this location precluded clear identification of the variant(s) driving the associations.

Hair testing for `ecstasy' (MDMA) in volunteer Scottish drug users

The aim of the study was to compare self reported “ecstasy” use with the results of the analysis of hair harvested from the same users. Subjects were recruited by multisite chain‐referral sampling within the 1994–95 “dance scene” in Glasgow. One hundred subjects donated hair after completing a lengthy interviewer‐administered questionnaire. Overall gross concordance between self reported “ecstasy” use and discovery of MDMA (or related compounds) in analysed hair did not surpass 59%, and no relationship had a Cohens kappa of more than 0.08. Within the positive concordant dataset (n = 52), scatter was considerable, with no correlation being significant, and none more strongly positive than −0.0518. The results presented here indicate that, as far as MDMA is concerned, if judged by self‐report, hair does not reach a level of apparent accuracy that would permit its use as a general population estimator. However, hair testing is probably more reliable than self‐report, and its accuracy could be verified independently if large‐scale inter‐ and intra‐laboratory comparative research is conducted.

Lack of allelic association between markers at the DRD2 and ANKK1 gene loci with the alcohol-dependence syndrome and criminal activity

and ANKK1 gene loci with the alcohol-dependence syndrome and criminal activity Katherine Kasiakogia-Worlley, Andrew McQuillin, Gregory John Lydall, Shamir Patel, Girija Kottalgi, Priyanthi Gunwardena, Raquin Cherian, Harsih Rao, Audrey Hillman, Nallananathan Gobikrishnan, Ewen Douglas, Sherhzad Yameen Qureshi, Sameer Jauhar, David Ball, Aideen O’Kane, Lynne Owens, Alex Dedman, Sally Isobel Sharp, Radhika Kandaswamy, Irene Guerrini, Allan D. Thomson, Iain Smith, Karim Dar, Marsha Yvonne Morgan and Hugh Malcolm Douglas Gurling

The temperance movement - in 100 words

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Addiction and Art

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Social Behaviour and Network Therapy for Alcohol Problems

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On Speed: The Many Lives of Amphetamine

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Management of Alcohol Korsakoff Syndrome

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