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Marta Di Forti, Conrad Iyegbe,
Hannah Sallis,
Anna Kolliakou,
M Aurora Falcone,
Alessandra Paparelli,
Miriam Sirianni,
Caterina La Cascia,
Simona A Stilo,
Tiago Reis Marques,
Rowena Handley,
Valeria Mondelli,
Paola Dazzan,
Carmine Pariante,
Anthony S David,
Craig Morgan,
John Powell,
Robin M Murray
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ABSTRACT: Cannabis use is associated with an increased risk of psychosis. One study has suggested that genetic variation in the AKT1 gene might influence this effect.
In a case-control study of 489 first-episode psychosis patients and 278 control subjects, we investigated the interaction between variation at the AKT1 rs2494732 single nucleotide polymorphism and cannabis use in increasing the risk of psychosis.
The rs2494732 locus was not associated with an increased risk of a psychotic disorder, with lifetime cannabis use, or with frequency of use. We did, however, find that the effect of lifetime cannabis use on risk of psychosis was significantly influenced by the rs2494732 locus (likelihood ratio statistic for the interaction = 8.54; p = .014). Carriers of the C/C genotype with a history of cannabis use showed a greater than twofold increased likelihood of a psychotic disorder (odds ratio = 2.18 [95% confidence interval: 1.12, 4.31]) when compared with users who were T/T carriers. Moreover, the interaction between the rs2494732 genotype and frequency of use was also significant at the 5% level (likelihood ratio = 13.39; p = .010). Among daily users, C/C carriers demonstrated a sevenfold increase in the odds of psychosis compared with T/T carriers (odds ratio = 7.23 [95% confidence interval: 1.37, 38.12]).
Our findings provide strong support for the initial report that genetic variation at rs2494732 of AKT1 influences the risk of developing a psychotic disorder in cannabis users.
Biological psychiatry 07/2012; 72(10):811-6. · 8.93 Impact Factor
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Petroula Proitsi,
Michelle K Lupton,
Suzanne J Reeves,
Gillian Hamilton,
Nicola Archer,
Belinda M Martin, Conrad Iyegbe,
Paul Hollingworth,
Brian Lawlor,
Michael Gill,
Carol Brayne,
David C Rubinsztein,
Michael J Owen,
Julie Williams,
Simon Lovestone,
John F Powell
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ABSTRACT: Genetic association studies investigating the association between genes of serotonergic and dopaminergic systems and behavioral and psychological symptoms in dementia (BPSD) are contradictory. We have utilized 1008 probable Alzheimer's disease (AD) patients from the UK and used the 12-item Neuropsychiatric Inventory. We applied a multiple indicators-multiple causes (MIMIC) approach to investigate the effect of 11 polymorphisms on the 4 behavioral subphenotypes "psychosis", "moods", "agitation", and "behavioural dyscontrol". Significant associations were observed between the serotonin transporter gene (SERT) polymorphism STin2 and "psychosis"; the dopamine transporter gene (DAT) 3' variable number tandem repeats (VNTR) and "agitation"; and the dopamine receptor 4 (DRD4) VNTR and "moods" factors. Direct associations were identified between the dopamine receptor 3 (DRD3) BalI polymorphism and depression; the dopamine receptor 1 (DRD1) and dopamine transporter gene 3' VNTR polymorphisms and aberrant motor behavior; the DRD4 VNTR and sleep disturbances; and the SERT gene VNTR 5HTTLPR and apathy items. Significant interactions observed between polymorphisms suggested epistatic effects and interactions between polymorphisms and medications highlighted potential treatment response. This multiple indicators multiple causes (MIMIC) model efficiently captured the complexity of the interrelations between genetic variation, behavioral symptoms, and clinical variables.
Neurobiology of aging 04/2012; 33(4):791-803. · 5.94 Impact Factor
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ABSTRACT: Four strains of mice were inoculated intracerebrally with a primary isolate of bovine spongiform encephalopathy (BSE) and the cloned mouse-adapted scrapie strain ME7. Clinical prion disease diagnosis was made at the appearance of three or more neurological symptoms and their persistence for 3 consecutive weeks and confirmed by neuropathological criteria. For BSE, incubation periods were profoundly different between the sexes in all four mouse strains, being longer in the females. In contrast, ME7 scrapie incubation times were similar between the sexes. Our results indicate that sex-specific processes are involved in the course of primary BSE transmission. Research into this phenomenon may provide clues to the prophylaxis of BSE and have possible implications for new variant Creutzfeldt-Jakob disease in humans.
Intervirology 02/2002; 45(1):56-8. · 2.34 Impact Factor
