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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

IntroductionSingapore has a strong and well-established tobacco control policy, but smoking rates among young Singaporeans remain relatively high. In other countries, tobacco companies have used menthol to encourage smoking among young people. Singapore still permits the sale of menthol tobacco products and little is known about the tobacco industry's internal strategy and motivation for marketing menthol tobacco in Singapore.MethodsTobacco industry documents analysis using the Truth Tobacco Industry Documents Library. Findings were triangulated with Euromonitor market data on menthol tobacco in Singapore, and trend data on smoking prevalence in Singapore from the First National Morbidity Survey, Labour Force Survey, National Health Survey, and National Health Surveillance Survey.ResultsMenthol tobacco products became popular among young Singaporeans in the early 1980s, largely due to a health-consciousness trend among young people and the misperception that menthol tobacco products were "safer." Philip Morris, in an attempt to compete with R.J. Reynolds for starter smokers, developed and launched several menthol brands designed to appeal to youth. While many brands initially failed, as of February 2018, menthol tobacco products comprise 48% of Singapore's total tobacco market.ConclusionsMenthol is key to the tobacco industry's strategy of recruiting and retaining young smokers in Singapore. Banning the sale of menthol tobacco products will be an important part of preventing smoking in Singapore's younger generation.

Background and aimsCannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants.MethodsA twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals.ResultsThe twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P  0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant.ConclusionAge at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

BackgroundThe United Nations Global Compact (UNGC), a UN initiative to engage corporations in supporting the UN's mission, sets out principles that companies should follow for more ethical business practices. Since its inception in 2000, at least 13 tobacco companies, subsidiaries and tobacco industry affiliates joined the UNGC. In a September 2017 integrity review, the UNGC Board excluded from UNGC participation companies who derive revenue from tobacco production or manufacturing.ObjectiveTo determine, from the tobacco industry's perspective, tobacco companies' motives for joining the UNGC.MethodTobacco industry documents search using the Truth Tobacco Industry Documents Library, and search of published reports and documents on the tobacco industry and the UNGC.ResultsTobacco companies sought to join the UNGC for two reasons: (1) to improve their reputation, in keeping with other corporate social responsibility efforts; (2) to gain proximity to UN agencies and weaken the WHO's influence, part of an overall strategy to undermine the WHO Framework Convention on Tobacco Control.ConclusionsExcluding tobacco manufacturers from UNGC participation is an important step to limit the tobacco industry's ability to influence the UN and promote its image and, by extension, its deadly products. It is important to monitor enforcement of this policy and resist the engagement of tobacco industry front groups, such as industry-funded foundations, with the UNGC.

The manufacture, use, and marketing of tobacco present a serious threat to children's right to health. This makes the Convention on the Rights of the Child a potentially powerful tobacco-control tool and the United Nations Children's Fund (UNICEF), which oversees the convention's implementation, a potential leader in tobacco control. UNICEF actively supported tobacco control initiatives in the late 1990s, but since the early 2000s UNICEF's role in tobacco control has been minimal. Using the Truth Tobacco Industry Documents library, an online collection of previously secret tobacco industry documents, we sought to uncover information on the tobacco industry's ties with UNICEF. We found that from 1997 to 2000, when UNICEF was actively promoting tobacco control to support children's rights, the tobacco industry saw children's rights and UNICEF as potentially powerful threats to business that needed to be closely monitored and neutralized. The industry then positioned itself as a partner with UNICEF on youth smoking prevention initiatives as a way to avoid meaningful tobacco control measures that could save children's lives. After UNICEF's corporate engagement guidelines were loosened in 2003, tobacco companies successfully engaged with UNICEF directly and via front groups, including the Eliminating Child Labour in Tobacco Growing Foundation. This was part of an overall tobacco industry strategy to improve its corporate image, infiltrate the United Nations, and weaken global tobacco-control efforts. As part of its mission to protect children's rights, UNICEF should end all partnerships with the tobacco industry and its front groups.

The health risks associated with e-cigarette use in pregnancy are mostly unknown. Guidelines by the World Health Organization and national health agencies warn women against using e-cigarettes in pregnancy; however, in the UK, a recent multiagency guideline takes a different approach by not discouraging e-cigarette use in pregnancy. Furthermore, e-Voke™ , an e-cigarette, has been approved for use in pregnancy in the UK. We analyze United Nations human rights treaties to examine how they might inform best practice recommendations for e-cigarette use in pregnancy. These treaties oblige Parties to adopt policies that protect children's and women's right to health, appropriate pregnancy services, and health education. We argue that clinical practice guidelines related to use of e-cigarettes in pregnancy should consider both evidence and human rights principles, and ensure that healthcare providers and patients are given clear, accurate messages about the known and potential risks associated with e-cigarette use in pregnancy.

BackgroundFour studies previously indicated that the effect of malaria infection during pregnancy on the risk of low birthweight (LBW;

PurposeThe Maternal Malaria and Malnutrition (M3) initiative has pooled together 13 studies with the hope of improving understanding of malaria-nutrition interactions during pregnancy and to foster collaboration between nutritionists and malariologists.ParticipantsData were pooled on 14 635 singleton, live birth pregnancies from women who had participated in 1 of 13 pregnancy studies. The 13 studies cover 8 countries in Africa and Papua New Guinea in the Western Pacific conducted from 1996 to 2015.Findings to dateData are available at the time of antenatal enrolment of women into their respective parent study and at delivery. The data set comprises essential data such as malaria infection status, anthropometric assessments of maternal nutritional status, presence of anaemia and birth weight, as well as additional variables such gestational age at delivery for a subset of women. Participating studies are described in detail with regard to setting and primary outcome measures, and summarised data are available from each contributing cohort.Future plansThis pooled birth cohort is the largest pregnancy data set to date to permit a more definite evaluation of the impact of plausible interactions between poor nutritional status and malaria infection in pregnant women on fetal growth and gestational length. Given the current comparative lack of large pregnancy cohorts in malaria-endemic settings, compilation of suitable pregnancy cohorts is likely to provide adequate statistical power to assess malaria-nutrition interactions, and could point towards settings where such interactions are most relevant. The M3 cohort may thus help to identify pregnant women at high risk of adverse outcomes who may benefit from tailored intensive antenatal care including nutritional supplements and alternative or intensified malaria prevention regimens, and the settings in which these interventions would be most effective.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

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

Emerging evidence suggests that schizophrenia (SZ) susceptibility involves variation at genetic, epigenetic and transcriptome levels. We describe an integrated approach that leverages DNA methylation and gene expression data to prioritize genetic variation involved in disease. DNA methylation levels were obtained from whole blood of 260 SZ patients and 250 unaffected controls of which a subset with gene expression data was available. By assessing DNA methylation and gene expression in cases and controls, we identified 432 CpG sites with differential methylation levels that are associated with differential gene expression. We hypothesized that genetic factors involved in these methylation levels may be associated with the genetic risk of SZ susceptibility. To test this hypothesis, we used results from the Psychiatric Genomics Consortium SZ genome-wide association study (GWAS). We observe an enrichment of SZ-associated SNPs in the mQTLs of which the associated CpG site is also correlated with differential gene expression in SZ. While this enrichment was already apparent when using nominal significant thresholds, enrichment was even more pronounced when applying more stringent significance levels. One locus, previously identified as susceptibility locus in a SZ GWAS, involves SNP rs11191514:C>T, which regulates DNA methylation of calcium homeostasis modulator 1 that is also associated with differential gene expression in patients. Overall, our results suggest that epigenetic variation plays an important role in SZ susceptibility and that the integration of analyses of genetic, epigenetic and gene expression profiles may be a biologically meaningful approach for identifying disease susceptibility loci, even when using whole blood data in studies of brain-related disorders.

The aim of this study was to investigate the effectiveness of infection control measures to prevent transmission of SARS-CoV-2 within a professional sports team using whole genome sequencing. Prospective cohort study. 74 players and staff members of a Dutch professional male football team were followed from August 2020 until May 2021. A set of health and safety measures were introduced and all participants underwent regular SARS-CoV-2 RNA testing. All positive samples were subsequently sequenced (Nanopore sequencing) to assess whether infections were acquired within the training center or in the community. Throughout the study period, 13 participants tested positive for SARS-CoV-2. The phylogenetic analysis revealed 2 clusters (of 2 and 3 cases respectively), indicating that 3/13 cases (23%) acquired infection from another player or staff member. The first cluster was diagnosed upon enrolment, thus transmission had occurred prior to the implementation of health and safety protocols. Finally, 4 cases were diagnosed prior to symptom onset, emphasizing that frequent testing leads to early detection and isolation. These data show that a combination of regular testing and basic control measures can prevent outbreaks of COVID-19 in a professional sports team. Whole genome sequencing is an important tool to distinguish between infections introduced from the community and infections transmitted between athletes. [ABSTRACT FROM AUTHOR]

To investigate which preventive measures runners use when preparing for a half- or full-marathon and whether the use of these measures at baseline and during the preparation-period differs between runners who sustained no/non-substantial running-related injuries (NSIRs) or substantial running-related injuries (SIRs). Prospective cohort study. 16-week period before the Utrecht Marathon. Runners who subscribed for the half- or full-marathon. The occurrence of RRIs was registered every 2-weeks, using the Dutch version of the Oslo Sport Trauma Research Center (OSTRC) questionnaire on Health Problems. The OSTRC was used to differentiate between runners with SIRs (question 2/3 score>12) and NSIRs (question 2/3 score<13). The use of different preventive measures, was registered every 4-weeks. 51.6% of the runners reported at least one RRI in the 12-months prior to this study (history of RRIs). The SIRs with a history of RRIs more often asked for running shoe advice than NSIRs with a history of RRIs (67.9%vs43.4%, P < 0.05); 18.9% of the SIRs with a history of RRIs used supportive materials for knee and/or ankle versus 0% of NSIRs with a history of RRIs (P < 0.05). SIRs with a history of RRIs might be using their preventive measures for symptom reduction or secondary prevention. • 51.6% of the runners reported at least one RRI in the 12-months prior to this study (history of RRIs). • 44.1% of the runners had ≥ 1 moderate or severe RRI during the preparation period (substantially injured runners). • When preparing for a half or full marathon runners use various preventive measures. • 60% of all runners used at least one additional preventive measure during the study period. • Substantially injured runners with a history of RRIs more often used certain preventive measures. [ABSTRACT FROM AUTHOR]