van Winkel Ruud
Department of Psychiatry and Psychology, School of Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, the Netherlands.
Arch Gen Psychiatry. 2011 Feb;68(2):148-57. doi: 10.1001/archgenpsychiatry.2010.152. Epub 2010 Nov 1.
Individual differences exist in sensitivity to the psychotomimetic effect of cannabis; the molecular genetic basis underlying differential sensitivity remains elusive.
To investigate whether selected schizophrenia candidate single-nucleotide polymorphisms (SNPs) moderate effects of cannabis use.
Interactions between recent cannabis use, determined by urinalysis results, and 152 SNPs in 42 candidate genes were examined in 740 unaffected siblings of 801 patients with psychosis to examine genetic moderation of the association between Structured Interview for Schizotypy-Revised positive schizotypy and recent cannabis use (at-risk paradigm). The SNPs showing Bonferroni-adjusted association in the at-risk paradigm were used in a case-only analysis in the 801 patients, as well as in a case-sibling and case-control analysis (using 419 controls) focusing on genetic moderation of developmental effects of cannabis on later psychotic disorder.
The Netherlands and Flanders, Belgium.
Eight hundred one patients with psychosis and their 740 unaffected siblings.
Significant interaction between any of the selected SNPs and cannabis in the at-risk paradigm, followed by selective case-only, case-sibling, and case-control analyses.
In the unaffected siblings, 16 SNPs in 12 genes showed significant interaction at P < .05, 3 of which survived correction for multiple testing (P < .0003), situated in AKT1 (rs2494732 and rs1130233) and LRRTM1 (rs673871). Follow-up analysis supported AKT1 rs2494732 × cannabis interaction in the case-only (β = 0.20; P = .007), case-sibling (interaction P = .040), and case-control (interaction P = .057) analyses, with individuals with C/C genotypes having an approximately 2-fold odds of being diagnosed with a psychotic disorder when having used cannabis. In the unaffected siblings, the AKT1 × cannabis interaction explained 2.2% additional variance in schizotypy in the whole sample and 19.0% additional variance in the exposed siblings with recent cannabis use.
Genetic variation in AKT1 may mediate both short-term as well as longer-term effects on psychosis expression associated with use of cannabis, possibly through a mechanism of cannabinoid-regulated AKT1/GSK-3 signaling downstream of the dopamine D(2) receptor.
个体对大麻致幻效应的敏感性存在差异；导致这种差异敏感性的分子遗传基础仍不清楚。
研究选定的精神分裂症候选单核苷酸多态性（SNP）是否会调节大麻使用的影响。
通过尿液分析结果确定近期大麻使用情况，并在801例精神病患者的740名未患病同胞中检测42个候选基因中的152个SNP之间的相互作用，以检验精神分裂症分型修订版结构化访谈中阳性分型与近期大麻使用之间关联的基因调节作用（风险范式）。在风险范式中显示经Bonferroni校正有相关性的SNP，用于801例患者的病例单组分析，以及聚焦大麻对后期精神障碍发育影响的基因调节作用的病例-同胞和病例-对照分析（使用419名对照）。
荷兰和比利时的弗拉芒地区。
801例精神病患者及其740名未患病同胞。
在风险范式中，所选任何SNP与大麻之间的显著相互作用，随后进行选择性病例单组、病例-同胞和病例-对照分析。
在未患病同胞中，12个基因中的16个SNP在P < 0.05时显示出显著相互作用，其中3个在多重检验校正后仍有统计学意义（P < 0.0003），位于AKT1基因（rs2494732和rs1130233）和LRRTM1基因（rs673871）。后续分析在病例单组分析（β = 0.20；P = 0.007）、病例-同胞分析（相互作用P = 0.040）和病例-对照分析（相互作用P = 0.057）中均支持AKT1基因rs2494732与大麻的相互作用，即携带C/C基因型的个体在使用大麻后被诊断为精神障碍的几率约为2倍。在未患病同胞中，AKT1基因与大麻的相互作用在整个样本中额外解释了2.2%的分型变异，在近期使用过大麻的暴露同胞中额外解释了19.0%的分型变异。
AKT1基因的遗传变异可能介导大麻使用对精神病表达的短期和长期影响，可能是通过多巴胺D(2)受体下游大麻素调节的AKT1/GSK-3信号传导机制。
