Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Intelligence is highly heritable(1) and a major determinant of human health and well-being(2). Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.Peer reviewe

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Author Correction:Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article

Cohort Profile: Burden of Obstructive Lung Disease (BOLD) study

The Burden of Obstructive Lung Disease (BOLD) study was established to assess the prevalence of chronic airflow obstruction, a key characteristic of chronic obstructive pulmonary disease, and its risk factors in adults (≥40 years) from general populations across the world. The baseline study was conducted between 2003 and 2016, in 41 sites across Africa, Asia, Europe, North America, the Caribbean and Oceania, and collected high-quality pre- and post-bronchodilator spirometry from 28 828 participants. The follow-up study was conducted between 2019 and 2021, in 18 sites across Africa, Asia, Europe and the Caribbean. At baseline, there were in these sites 12 502 participants with high-quality spirometry. A total of 6452 were followed up, with 5936 completing the study core questionnaire. Of these, 4044 also provided high-quality pre- and post-bronchodilator spirometry. On both occasions, the core questionnaire covered information on respiratory symptoms, doctor diagnoses, health care use, medication use and ealth status, as well as potential risk factors. Information on occupation, environmental exposures and diet was also collected

Sea Traffic Management – Concepts and Components

This paper gives an overview of all components making up the Sea Traffic Management (STM) concept. STM builds upon information sharing in the whole maritime transport chain, where informationis shared as early as possible about intentions and reached states. Sea System Wide Information Management will provide an infrastructure for a regulated and federated approach to informationsharing. The functional sub-concepts are described: Strategic Voyage Management, Dynamic Voyage Management, Flow Management and Port Cooperative Decision Making. We will elaborate on how they complement each other and which benefits each of them has in regards to safety, environment and efficienc

A health promotion intervention to improve lifestyle choices and health outcomes in people with psychosis:a research programme including the IMPaCT RCT

Background: People with psychotic disorders have reduced life expectancy largely because of physical health problems, especially cardiovascular disease, that are complicated by the use of tobacco and cannabis. / Objectives: We set out to (1) chart lifestyle and substance use choices and the emergence of cardiometabolic risk from the earliest presentation with psychosis, (2) develop a pragmatic health promotion intervention integrated within the clinical teams to improve the lifestyle choices and health outcomes of people with psychosis and (3) evaluate the clinical effectiveness and cost-effectiveness of that health promotion intervention. / Design: We performed a longitudinal cohort study of people presenting with their first episode of psychosis in three mental health trusts and followed up participants for 1 year [work package 1, physical health and substance use measures in first episode of psychosis (PUMP)]. We used an iterative Delphi methodology to develop and refine a modular health promotion intervention, improving physical health and reducing substance use in psychosis (IMPaCT) therapy, which was to be delivered by the patient’s usual care co-ordinator and used motivational interviewing techniques and cognitive–behavioural therapy to improve health choices of people with psychosis (work package 2). We then conducted a multicentre, two-arm, parallel-cluster, randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of using the intervention with people with established psychosis (work package 3: IMPaCT randomised controlled trial) in five UK mental health trusts. The work took place between 2008 and 2014. / Participants: All people aged between 16 and 65 years within 6 months of their first presentation with a non-organic psychosis and who were proficient in English were eligible for inclusion in the PUMP study. Participants in the work package 2 training development were staff selected from a range of settings, working with psychosis. Participants in the phase 3 Delphi consensus and manual development comprised three expert groups of (1) therapists/researchers recruited from the local and national community, (2) clinicians and (3) service users, each of whom took part in two iterative review and feedback sessions. For work package 3, IMPaCT randomised controlled trial, care co-ordinators in participating community mental health teams who were permanently employed and had a minimum of four eligible patients (i.e. aged between 18 and 65 years with a diagnosis of a psychotic disorder) on their caseload were eligible to participate. In studies 1 and 3, patient participants were ineligible if they were pregnant or had a major illness that would have had an impact on their metabolic status or if they had a significant learning disability. All participants were included in the study only after giving written confirmed consent. / Main outcome measures: Cardiometabolic risk markers, including rates of obesity and central obesity, and levels of glycated haemoglobin (HbA1c) and lipids, were the main outcomes in work package 1 (PUMP), with descriptive data presented on substance use. Our primary outcome measure for the IMPaCT randomised controlled trial was the physical or mental health component Short Form questionnaire-36 items quality-of-life scores at 12 months. / Results: Obesity rates rose from 18% at first presentation with psychosis to 24% by 1 year, but cardiometabolic risk was not associated with baseline lifestyle and substance use choices. Patterns of increase in the levels of HbA1c over the year following first presentation showed variation by ethnic group. We recruited 104 care co-ordinators, of whom 52 (with 213 patients) were randomised to deliver IMPaCT therapy and 52 (with 193 patients) were randomised to deliver treatment as usual, in keeping with our power calculations. Of these 406 participants with established psychosis, 318 (78%) and 301 (74%) participants, respectively, attended the 12- and 15-month follow-ups. We found no significant effect of IMPaCT therapy compared with treatment as usual on the physical or mental health component Short Form questionnaire-36 items scores at either time point in an intention-to-treat analysis [physical health score (‘d’) –0.17 at 12 months and –0.09 at 15 months; mental health score (‘d’) 0.03 at 12 months and –0.05 at 15 months] or on costs. Nor did we find an effect on other cardiovascular risk indicators, including diabetes, except in the case of high-density lipoprotein cholesterol, which showed a trend for greater benefit with IMPaCT therapy than with treatment as usual (treatment effect 0.085, 95% confidence interval 0.007 to 0.16; p = 0.034). / Limitations: Follow-up in work package 1 was challenging, with 127 out of 293 participants attending; however, there was no difference in cardiometabolic measures or demographic factors at baseline between those who attended for follow-up and those who did not. In work package 3, the IMPaCT randomised controlled trial, care co-ordinators struggled to provide additional time to their patients that was devoted to the health promotion intervention on top of their usual clinical care contact with them. / Conclusions: Cardiometabolic risk is prominent even soon after first presentation with psychosis and increases over time. Lifestyle choices and substance use habits at first presentation do not predict those who will be most cardiometabolically compromised 1 year later. Training and supervising care co-ordinators to deliver a health promotion intervention to their own patients on top of routine care is not effective in the NHS for improving quality of life or reducing cardiometabolic risk. / Future work: Further work is needed to develop and evaluate effective, cost-effective and affordable ways of preventing the emergence of and reversing existing cardiometabolic risk indicators in people with psychosis. / Trial registration: Current Controlled Trials ISRCTN58667926