Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

Does nature have joints worth carving? A discussion of taxometrics, model-based clustering and latent variable mixture modeling.

Taxometric procedures, model-based clustering and latent variable mixture modeling (LVMM) are statistical methods that use the inter-relationships of observed symptoms or questionnaire items to investigate empirically whether the underlying psychiatric or psychological construct is dimensional or categorical. In this review we show why the results of such an investigation depend on the characteristics of the observed symptoms (e.g. symptom prevalence in the sample) and of the sample (e.g. clinical, population sample). Furthermore, the three methods differ with respect to their assumptions and therefore require different types of a priori knowledge about the observed symptoms and their inter-relationships. We argue that the choice of method should optimally match and make use of the existing knowledge about the data that are analyzed.

Genome-wide analyses of borderline personality features.

The heritability of borderline personality (BP) features has been established in multiple twin and family studies. Using data from the borderline subscale of the Personality Assessment Inventory Borderline Features Scale (PAI-BOR) collected in two Dutch cohorts (N=7125), the Netherlands Twin Register and The Netherlands Study of Depression and Anxiety, we show that heritability of the PAI-BOR total score using genome-wide single-nucleotide polymorphism (SNPs) is estimated at 23%, and that the genetic variance is substantially higher in affect instability items compared with the other three subscales of the PAI-BOR (42.7% vs non-significant estimates for self-harm, negative relations and identity problems). We present results from a first genome-wide association study of BP features, which shows a promising signal on chromosome 5 corresponding to SERINC5, a protein involved in myelination. Reduced myelination has been suggested as possibly having a role in the development of psychiatric disorders characterized by lack of social interaction. The signal was confirmed in a third independent Dutch cohort drawn from the Erasmus Rucphen Family study (N=1301). Our analyses were complemented by investigating the heterogeneity that was implied by the differences in genetic variance components in the four subscales of the PAI-BOR. These analyses show that the association of SNPs tagging SERINC5 differs substantially across the 24 items of the PAI-BOR. Further, using reverse regression we showed that the effects were present only in subjects with higher scores on the PAI-BOR. Taken together, these results suggest that future genome-wide analyses can benefit substantially by taking into account the phenotypic and genetic heterogeneity of BP features.

Investigating Group Differences on Cognitive Tests Using Spearman's Hypothesis: An Evaluation of Jensen's Method.

Jensen has posited a research method to investigate group differences in cognitive tests. This method consists of first extracting a general intelligence factor by means of exploratory factor analysis. Secondly, similarity of factor loadings across groups is evaluated in an attempt to ensure that the same constructs are measured. Finally, the correlation is computed between the loadings of the tests on the general intelligence factor and the mean differences between groups on the tests. This part is referred to as a test of "Spearman's Hypothesis", which essentially states that differences in g account for the main part of differences in observed scores. Based on the correlation, inferences are made with respect to group differences in general intelligence. The validity of these inferences is investigated and compared to the validity of inferences based on multi-group confirmatory factor analysis. For this comparison, population covariance matrices are constructed which incorporate violations of the central assumption underlying Jensen's method concerning the existence of g and/or violations of Spearman's Hypothesis. It is demonstrated that Jensen's method is quite insensitive to the violations. This lack of specificity is observed consistently for all types of violations introduced in the present study. Multi-group confirmatory factor analysis emerges as clearly superior to Jensen's method.

Memory formation during general anesthesia for emergency cesarean sections.

BACKGROUND: Occurrence of explicit memory (i.e., conscious recall) has been reported especially after surgical procedures in which anesthesia is considered to be "light." In addition, previous research has shown that implicit memory (e.g., improved memory test performance in absence of conscious recall) decreases with increasing hypnotic state. The current study investigated explicit and implicit memory during emergency cesarean sections with consistently light levels of hypnotic state. METHOD: Words were presented via headphones, and the bispectral index was recorded throughout surgery. Memory for the presented words was tested after recovery with a word-stem completion test. Using both parts of the process dissociation procedure allowed separation of explicit and implicit memory. In the "inclusion" part of the process dissociation procedure, patients are asked to complete word stems, if possible, with the corresponding words recalled from the intraoperative presentation. In the "exclusion" part, patients are instructed to avoid the words presented intraoperatively and to use other words instead. In the absence of recall, patients are asked to use the first word that comes to mind. RESULTS: The mean bispectral index during word presentation was 76.3 (+/-3.0). On average, the 24 patients were able to make correct inclusion-exclusion decisions: In the inclusion part, hit rates (i.e., the probability of responding with a word presented during surgery) were higher than base rates (0.37 vs. 0.31), whereas in the exclusion part hit rates were lower (0.23 vs. 0.28). Importantly, the patients made these inclusion-exclusion decisions without being able to consciously recall the words presented during surgery. CONCLUSIONS: This study shows that if words are presented at relatively light levels of anesthesia, patients are able to control their inclusion-exclusion decisions. This weak form of explicit memory can occur in the absence of conscious recall.

Awareness and different forms of memory in trauma anaesthesia.

Awareness during surgery and memory for perioperative events may have substantial psychological consequences for the patient. The risk of awareness during trauma surgery is higher than during most elective procedures due to the fact that administration of adequate concentrations of anaesthetics is not always feasible. As a consequence, the risk of memory formation might be increased. The present review discusses different forms of memory, and the possibilities and limitations of awareness and memory prevention.

Dependence of explicit and implicit memory on hypnotic state in trauma patients.

BACKGROUND: It is still unclear whether memory of intraoperative events results entirely from moments of inadequate anesthesia. The current study was designed to determine whether the probability of memory declines with increasing depth of the hypnotic state. METHOD: A list of words was played via headphones during surgery to patients who had suffered acute trauma. Several commonly used indicators of anesthetic effect, including the bispectral index, were recorded during word presentation. First, these indicators served as predictors of the memory performance in a postoperative word stem completion test. Second, general memory performance observed in the first part was separated into explicit and implicit memory using the process dissociation procedure, and then two models of memory were compared: One model assumed that the probability of explicit and implicit memory decreases with increasing depth of hypnotic state (individual differences model), whereas the other assumed equal memory performance for all patients regardless of their level of hypnotic state. RESULTS: General memory performance declined with decreasing bispectral index values. None of the other indicators of hypnotic state were related to general memory performance. Memory was still significant at bispectral index levels between 60 and 40. A comparison of the two models of memory resulted in a better fit of the individual differences model, thus providing evidence of a dependence of explicit and implicit memory on the hypnotic state. Quantification of explicit and implicit memory revealed a significant implicit but no reliable explicit memory performance. CONCLUSIONS: This study clearly indicates that memory is related to the depth of hypnosis. The observed memory performance should be interpreted in terms of implicit memory. Auditory information processing occurred at bispectral index levels between 60 and 40.