Association of CNR1 genotypes with changes in neurocognitive performance after eighteen-month treatment in patients with first-episode psychosis

Abstract

Introduction: We analyzed the association of cannabinoid receptor CNR1 genotypes with changes in neurocognitive performance in patients with first-episode psychosis (FEP) after 18 months of treatment. Our secondary aim was to analyze the association of CNR1 genotypes with changes of perceived levels of stress. Methods: We enrolled a sample of 159 patients with FEP from two Croatian psychiatric hospitals between 2014 and 2017. Patients were assessed at baseline and after 18 months. We analyzed the associations of changes in neurocognitive test results and the perceived levels of stress with CNR1 polymorphic loci (rs7766029 and rs12720071) in 121 patients. Results: In the analysis adjusted only for baseline neurocognitive test scores, carriers of rs7766029 CC genotype had significantly (with false discovery rate, FDR < 15%) higher improvement in verbal memory (Wechsler, Wechsler 30 0) and attention (Digit span F) compared with other participants. In such analysis, rs12720071 carriers of AG genotype had significantly (FDR < 15%) higher improvement in executive functions (Block design), but lower improvement in language functions than AA carriers. In the fully adjusted analysis for age, sex, cannabis use and negative symptoms, only the association of rs7766029 genotypes with the change in the Weschler 30 0 score was significant (FDR < 15%). In the analysis adjusted only for the baseline neurocognitive tests' scores, both rs7766029 and rs12720071 genotypes were significantly associated with the change in perceived levels of stress (FDR < 15%). In the fully adjusted analysis, only the association with rs7766029 genotype remained significant. Conclusions: The rs7766029 CNR1 variants may moderate changes in neurocognitive performance as well as in perceived levels of stress of patients with FEP over time.

Endocannabinoid System Components as Potential Biomarkers in Psychiatry

“…In addition, in 65 FEP patients, TT genotype of the CNR1 rs2023239 polymorphism was associated with a better improvement of negative and positive symptoms (292). Similarly, in another group of patients with FEP, carriers of rs7766029 CC genotype presented significantly higher improvement in verbal memory and attention while carriers of rs12720071 AG genotype showed a better improvement in executive functions (293). Furthermore, minor alleles of CNR1 polymorphisms rs6928499, rs1535255, and rs2023239 might be associated with a lower risk to develop antipsychotic-induced metabolic syndrome.…”

<strong>Bias, Confounding, Multiplicity and <em>Researchers&rsquo; Degrees of Freedom</em> Combined with Segmented Publications are not Likely to Provide Accurate Estimates of Reality: A Case Study of Two Candidate-Gene Association Reports in the First Episode Psychosis Patients</strong>

“…The two reports (Rojnic Kuzman, et al, 2019a, Bosnjak Kuharic, et al, 2020 are segmented publications from one study, which raises both scientific and ethical issues(Supak Smolcic, 2013), but the focus here is on three other points: bias/confounding, a phenomenon named researchers degrees of freedom (Gelman and Loken, 2013) and multiplicity, as these are the key determinants rendering the reported estimates highly unlikely to be accurate, thus making them meaningless (or misleading). While we have no option but to observe in samples and, hence, inevitably have to deal with error due to a chance (sampling error), inaccurate estimates are due to bias/confounding.…”

“…The two papers presented "first discoveries" of effects of individual candidate genes on complex traits in a setting with vaguely suggested mechanistic plausibility in FEP patients. The sample was actually too small for the purpose with a vague reference to sample size calculation (Rojnic Kuzman, et al, 2019a, Bosnjak Kuharic, et al, 2020: it seems that it was not planned in respect to any specific of the many outcome measures and did not account for the (expected) distribution of patients across the targeted SNPs (i.e., subsets by genotypes across different genes), and particularly not for any relevant interaction, but rather in respect to detection of a relatively large effect (declared as Cohen's g of 0.53) in any pairwise comparison.…”

“…Report 1 (Rojnic Kuzman, et al, 2019a) Positive and negative syndrome scale (PANSS), General Assessment of Functioning (GAF) scale and Holmes-Rahe Stress Inventory and 20 cognitive tests were assessed at baseline and 18 months later. All patients were genotyped for a single nucleotide polymorphism (SNP) in the gene encoding the cannabinoid receptor type 1 (CNR1) -CNR1 A>G (rs12720071); 112/121 were genotyped also for CNR1 C>T (rs7766029).…”

“…Of notion: a) it was not explained why the two SNPs in LD were evaluated separately; b) treatments delivered between baseline and end-of-study or those in use at the time of re-testing, and a number of other potential confounders were never mentioned nor included in the analysis; c) it remained unclear to which contrasts reported coefficients referred and why "stress" was listed among neurocognitive tests if considered a secondary objective; d) it remained unclear how many p-values were submitted to the FDR adjustment and why; and why FDR-adjusted p-values <0.15 should be perceived as relevant (i.e., likely not associated with falsely rejected nulls). Further data (Table 3 in Rojnic Kuzman, et. al., 2019a) referred to rs12720071 and reported on stress and two cognitive tests -none "flagging" an independent association with the variant allele carriage vs. wild type (wt) subjects.…”