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Background: We investigated the association between cigarette smoking and risk of amyotrophic lateral sclerosis (ALS) in a pooled analysis of population-based case-control studies and explored the independent effects of intensity, duration and time-since-quitting., Methods: ALS cases and controls, matched by age, sex and region, were recruited in the Netherlands, Italy and Ireland (*Euro-MOTOR project). Demographics and detailed lifetime smoking histories were collected through questionnaires. Effects of smoking status, intensity (cigarettes/day), duration (years), pack-years and time-since-quitting (years) on ALS risk were estimated using logistic regression models, adjusting for age, sex, alcohol, education and centre. We further investigated effect modification of the linear effects of pack-years by intensity, duration and time-since-quitting using excess OR (eOR) models., Results: Analyses were performed on 1410 cases and 2616 controls. Pack-years were positively associated with ALS risk; OR=1.26 (95% CI: 1.03 to 1.54) for the highest quartile compared with never smokers. This association appeared to be predominantly driven by smoking duration (p trend =0.001) rather than intensity (p trend =0.86), although the trend for duration disappeared after adjustment for time-since-quitting. Time-since-quitting was inversely related to ALS (p trend <0.0001). The eOR decreased with time-since-quitting smoking, until about 10 years prior to disease onset. High intensity smoking with shorter duration appeared more deleterious than lower intensity for a longer duration., Conclusions: Our findings provide further support for the association between smoking and ALS. Pack-years alone may be insufficient to capture effects of different smoking patterns. Time-since-quitting appeared to be an important factor, suggesting that smoking may be an early disease trigger., Competing Interests: Competing interests: EB reports grants from UCB-PHARMA, personal fees from MA-Provider, grants from American ALS Association, grants from EISAI, grants from Shire. AC reports personal fees from Biogen, grants from Italfarmaco, personal fees from Roche, personal fees from Cytokinetics, personal fees from Mitsubishi Tanabe. OH has received speaking honoraria from Novartis, Biogen Idec, Sanofi Aventis and Merck-Serono; and has been a member of advisory panels for Biogen Idec, Allergen, Ono Pharmaceuticals, Novartis, Cytokinetics and Sanofi Aventis. LvdB serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen, Cytokinetics, Orion and Sarepta. SP, AEV, FD, JV, LP, GL, EP, JHV and RV report no potential conflicts of interest., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the association between physical activity (PA) and amyotrophic lateral sclerosis (ALS) in population-based case-control studies in three European countries using a validated and harmonised questionnaire., Methods: Patients with incident ALS and controls were recruited from five population-based registers in The Netherlands, Ireland and Italy. Demographic and data regarding educational level, smoking, alcohol habits and lifetime PA levels in both leisure and work time were gathered by questionnaire, and quantified using metabolic equivalent of task scores. Logistic regression models adjusting for PA-related factors were used to determine the association between PA and ALS risk, and forest plots were used to visualise heterogeneity between regions., Results: 1557 patients and 2922 controls were included. We found a linear association between ALS and PA in leisure time (OR 1.07, P=0.01) and occupational activities (OR 1.06, P<0.001), and all activities combined (OR 1.06, P<0.001), with some heterogeneity between regions: the most evident association was seen in the Irish and Italian cohorts. After adjustment for other occupational exposures or exclusion of patients with a C9orf72 mutation, the ORs remained similar., Conclusion: We provide new class I evidence for a positive association between PA and risk of ALS in a large multicentre study using harmonised methodology to objectively quantify PA levels, with some suggestions for population differences., Competing Interests: Competing interests: AEV, FD, HJW, RCHV and GL report no disclosures. JPKR reports grants from health research board, during the conduct of the study. EB reports grants from UCB-Pharma, grants from Shire, grants from EISAI, personal fees from Viropharma, grants from Italian Ministry of Health, grants from European Union, grants from Fondazione Borgonovo, grants from Associazione IDIC 15, outside the submitted work. AC reports personal fees from Biogen Idec, personal fees from Cytokinetics, grants from Italfarmaco, personal fees from Mitsubishi, outside the submitted work. OH reports grants from framework 7 EUROMOTOR project, grants from Health Research Board Ireland, grants from Science Foundation Ireland, during the conduct of the study; personal fees from ALS FTD Journal, outside the submitted work. JHV reports other from Vertex Pharmaceuticals, outside the submitted work. LHvdB reports grants from Netherlands ALS Foundation, grants from The Netherlands Organisation for Health Research and Development, during the conduct of the study; grants from Baxalta, grants from Prinses Beatrix Spierfonds, grants from European Community’s Health Seventh Framework Programme, outside the submitted work; LHvdB serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen and Cytokinetics and serves on the editorial board of amyotrophic lateral sclerosis and frontotemporal degeneration and the journal of neurology, neurosurgery and psychiatry., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process., Methods: We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995-2012), the Netherlands (2006-12), Italy (1995-2004), Scotland (1989-98), and England (2002-09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register., Findings: We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r(2)=0·95, Ireland r(2)=0·99, Italy r(2)=0·95, the Netherlands r(2)=0·99, and Scotland r(2)=0·97; overall r(2)=0·99. All five registers gave similar estimates of the linear slope ranging from 4·5 to 5·1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4·8 (95% CI 4·5-5·0), with similar estimates for men (4·6, 4·3-4·9) and women (5·0, 4·5-5·5)., Interpretation: A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues., Funding: UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The Netherlands Organisation for Health Research and Development (ZonMw); the Ministry of Health and Ministry of Education, University, and Research in Italy; the Motor Neurone Disease Association of England, Wales, and Northern Ireland; and the European Commission (Seventh Framework Programme)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is an unrelenting neurodegenerative condition characterized by adult-onset loss of motor neurons. Genetic risk factors have been implicated in ALS susceptibility. Copy number variants (CNVs) account for more inter-individual genetic variation than SNPs and have the capacity to alter gene dose and phenotype. We sought to identify the contribution both of commonly polymorphic CNVs and rare ALS-specific CNVs to sporadic ALS (SALS). Using high-density genome-wide data from 408 Irish individuals and 868 Dutch individuals and the QuantiSNP CNV-detection algorithm, we showed that no common CNV locus is significantly associated with ALS risk. However, we identified 39 recurrent CNV loci and 16 replicated ALS-specific gene dose alterations that occur exclusively in patients with ALS and do not occur in more than 11 000 previously identified CNVs in the Database of Genomic Variation. Ataxin genes and the hereditary haemochromatosis locus were implicated along with ENSG00000176605, an uncharacterized gene on chromosome 14. Our data support the hypothesis that multiple rare CNVs may contribute risk for SALS. Future work should seek to profile the contribution of CNVs located in regions not covered on the present SNP platforms.