The effect of the AKT1 gene and cannabis use on cognitive performance in healthy subjects.

BACKGROUND: Evidence suggests that the AKT1 gene may modulate the degree to which cannabis use induces cognitive alterations in patients with a psychotic disorder. AIM: To examine the interplay between AKT1 and cannabis use in terms of the cognitive performance of the general population. METHODS: Our sample consisted of 389 Spanish university students. Sustained attention was measured via the Continuous Performance Test-Identical Pairs, immediate and delayed verbal memory with the Logical Memory subtest of the Wechsler Memory Scale, and working memory with the Wisconsin Card Sorting Test. Lifetime cannabis use frequency was assessed and individuals were classified as cannabis users or non-users. Two single nucleotide polymorphisms of the AKT1 gene were genotyped and, according to previous studies, each subject was defined as a carrier of two, one or no copies of the haplotype (rs2494732(C)-rs1130233(A)). Multiple linear regressions were conducted to test the effect of the genetic variability and cannabis use (and their interaction) on cognitive performance. RESULTS: An effect of the AKT1 haplotype was found on attention scores: individuals with two copies of the haplotype performed better (ß=0.18, p<0.001 (adjusted for false discovery rate)), while neither cannabis nor the AKT1-cannabis interaction was associated with attention. No effect of AKT1, cannabis or the AKT1-cannabis interaction was found on verbal memory or working memory. CONCLUSIONS: Our study provides additional evidence that AKT1 modulates cognitive performance. However, in our non-clinical sample, the previously reported interaction between cannabis use and the AKT1 gene was not replicated.

Evidence of an epistatic effect between Dysbindin-1 and Neuritin-1 genes on the risk for schizophrenia spectrum disorders.

BACKGROUND: The interest in studying gene-gene interactions is increasing for psychiatric diseases such as schizophrenia-spectrum disorders (SSD), where multiple genes are involved. Dysbindin-1 (DTNBP1) and Neuritin-1 (NRN1) genes have been previously associated with SSD and both are involved in synaptic plasticity. We aimed to study whether these genes show an epistatic effect on the risk for SSD. METHODS: The sample comprised 388 SSD patients and 397 healthy subjects. Interaction was tested between: (i) three DTNBP1 SNPs (rs2619537, rs2743864, rs1047631) related to changes in gene expression; and (ii) an haplotype in NRN1 previously associated with the risk for SSD (rs645649-rs582262: HAP-risk C-C). RESULTS: An interaction between DTNBP1 rs2743864 and NRN1 HAP-risk was detected by using the model based multifactor dimensionality reduction (MB-MDR) approach (P=0.0049, after permutation procedure), meaning that the risk for SSD is significantly higher in those subjects carrying both the A allele of rs2743864 and the HAP-risk C-C. This interaction was confirmed by using a logistic regression model (P=0.033, OR (95%CI)=2.699 (1.08-6.71), R2=0.162). DISCUSSION: Our results suggest that DTNBP1 and NRN1 genes show a joint effect on the risk for SSD. Although the precise mechanism underlying this effect is unclear, the fact that these genes have been involved in synaptic maturation, connectivity and glutamate signalling suggests that our findings could be of value as a link to the schizophrenia aetiology.