Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2 , 3 and etiologically related 4 , 5 behaviors that have been resistant to gene discovery efforts 6 – 11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

52% Yes, a signiicant crisis 3% No, there is no crisis 7% Don't know 38% Yes, a slight crisis 38% Yes, a slight crisis 1,576 RESEARCHERS SURVEYED M ore than 70% of researchers have tried and failed to reproduce another scientist's experiments, and more than half have failed to reproduce their own experiments. Those are some of the telling figures that emerged from Nature's survey of 1,576 researchers who took a brief online questionnaire on reproducibility in research. The data reveal sometimes-contradictory attitudes towards reproduc-ibility. Although 52% of those surveyed agree that there is a significant 'crisis' of reproducibility, less than 31% think that failure to reproduce published results means that the result is probably wrong, and most say that they still trust the published literature. Data on how much of the scientific literature is reproducible are rare and generally bleak. The best-known analyses, from psychology 1 and cancer biology 2 , found rates of around 40% and 10%, respectively. Our survey respondents were more optimistic: 73% said that they think that at least half of the papers in their field can be trusted, with physicists and chemists generally showing the most confidence. The results capture a confusing snapshot of attitudes around these issues, says Arturo Casadevall, a microbiologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. "At the current time there is no consensus on what reproducibility is or should be. " But just recognizing that is a step forward, he says. "The next step may be identifying what is the problem and to get a consensus. "

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.