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.

Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid.

Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized ß=0.32, P=4.92 × 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (ß=0.21; P unadjusted=5.6 × 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.

Diabetic retinopathy screening in patients with diabetes mellitus in primary care: Incentives and barriers to screening attendance.

AIM: Although diabetic retinopathy (DR) screening is a basic component of diabetes care, uptake of screening programs is less than optimal. Because attendance rates and reasons for non-attendance in an unselected diabetes population are unknown, this study examines incentives and barriers to attend DR-screening. METHOD: Four focus groups provided patient-related themes concerning individual decision-making regarding attendance at DR-screening. A questionnaire measuring attendance rates and the influence of several factors was sent to 3236 diabetes patients (>18 years) in 20 Dutch general practices, of which 2363 (73%) responded. RESULTS: In the past 3 years, 81% of the patients had attended DR-screening. Patients not attending had lower levels of education, a more recent diagnosis of diabetes, and less frequently used insulin. There was no difference in DM types 1 and 2 patients regarding attendance. Patients attending more often visited health-care providers. Patients reported 'knowledge of detrimental effects of DR on visual acuity', 'sense of duty' and 'fear of impaired vision' as main incentives. The main barrier was the absence of a recommendation by the health-care provider. CONCLUSION: Knowledge about detrimental effects of DR on visual acuity and recommendation by health-care providers are important, possibly modifiable, factors in the attendance to DR screening.

Sequential versus conventional coronary artery bypass graft surgery in matched patient groups.

The relative merits of sequential bypass grafting were compared to those of conventional bypass grafting in 247 patients undergoing uncomplicated coronary artery bypass graft surgery. The duration of both ischemic arrest and cardiopulmonary bypass could be predicted on the basis of the number of end-to-side and side-to-side anastomoses. Multivariate regression showed that sequential grafting can be executed more quickly than conventional grafting because: 1. the suture time for side-to-side anastomoses is less than that for end-to-side (5 vs. 12 min) and, 2. fewer aortic anastomoses are required. The rate of perioperative myocardial infarction was similar in both groups. In 109 patients recatheterized at one year, both groups improved equally in functional class, there was no significant difference in mortality, and graft patency was similar in both groups. The principal advantage of sequential grafting therefore is a shorter duration of ischemic arrest and cardiopulmonary bypass, while graft patency and the overall benefit of surgery remains the same.