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  • 1
    In: Addiction, Wiley, Vol. 113, No. 11 ( 2018-11), p. 2073-2086
    Abstract: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi‐substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. Methods A twin‐based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome‐wide association meta‐analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. Results The twin‐based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19–60%]. Shared and unique environmental factors explained 39% (95% CI = 20–56%) and 22% (95% CI = 16–29%). The genome‐wide association meta‐analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium‐transporting ATPase gene ( ATP2C2) at P   〈  5E‐08. All five SNPs are in high linkage disequilibrium (LD) ( r 2   〉  0.8), with the strongest association at the intronic variant rs1574587 ( P  = 4.09E‐09). Gene‐based tests of association identified the ATP2C2 gene on 16q24.1 ( P  = 1.33e‐06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2 , which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP‐based heritability for age at first cannabis use was non‐significant. Conclusion Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.
    Type of Medium: Online Resource
    ISSN: 0965-2140 , 1360-0443
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2002997-4
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  • 2
    In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, Wiley, Vol. 165, No. 8 ( 2014-12), p. 654-664
    Abstract: 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 (N = 169–6,078). Initial findings showed a positive relationship of cannabis usage (OR = 2.070, P  = 0.007, N = 406 (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. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc.
    Type of Medium: Online Resource
    ISSN: 1552-4841 , 1552-485X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 2143866-3
    SSG: 12
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