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 x 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.
Sustained Virologic Response (SVR) in Prior PegInterferon/ribavirin (PR) treatment failures after retreatment with boceprevir (BOC) + PR: The PROVIDE study interim results [Meeting Abstract]
Background: Patients in P/R control arms of BOC Phase II/III studies who did not achieve SVR could receive BOC + P/R in PROVIDE. This interim analysis examines preliminary efficacy and safety of BOC + P/R in patients who failed prior P/R treatment. Methods: BOC (800 mg TID) was given with P 1.5 mcg/kg/week and weight-based R (600-1400 mg/ day) BID for up to 44 weeks. If > 2 weeks had elapsed since end of treatment (EOT) in the previous study, P/R was given for 4 weeks before adding BOC. Analyses included patients who received >=1 BOC dose. Denominators for on-treatment response included patients who reached the specific time point or discontinued, while those for SVR included all who reached end of follow-up, discontinued, or failed treatment. Results: 67% of 168 enrolled patients were male, 84% Caucasian, mean age 52 years, mean body mass index (BMI) 27.9 kg/m2, 77% high viral load (>800,000 IU/mL; mean log10 6.26); 10% cirrhotic; 61% HCV subtype 1a. SVR was achieved in 40% of prior null responders (<2 log10 decline in HCV RNA at TW12 in prior study) and 68% of partial responders/ relapsers; 78% (38/49) of prior null responders and 24% (26/107) of partial responders/relapsers had <1 log10 decline in HCV RNA after P/R lead in. Overall SVR was 47% in patients with <1 log10 decline with 36% SVR rates in prior null versus 65% partial responders/relapsers. 68% of patients with >=1 log decline achieved SVR (55% prior null; 70% prior partial responders/relapsers) and 7% discontinued due to adverse events. (Table Presented) Conclusions: BOC + P/R achieved high SVR rates regardless of prior response to P/R. Degree of interferon responsiveness after P/R lead in correlated with prior response and could help predict SVR for prior null responders. The safety profile was comparable to that previously reported for BOC + P/R