To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Physical activity and sleep duration are established risk factors for many diseases, but their aetiology is poorly understood, partly due to relying on self-reported evidence. Here we report a genome-wide association study (GWAS) of device-measured physical activity and sleep duration in 91,105 UK Biobank participants, finding 14 significant loci (7 novel). These loci account for 0.06% of activity and 0.39% of sleep duration variation. Genome-wide estimates of ~ 15% phenotypic variation indicate high polygenicity. Heritability is higher in women than men for overall activity (23 vs. 20%, p = 1.5 × 10−4) and sedentary behaviours (18 vs. 15%, p = 9.7 × 10−4). Heritability partitioning, enrichment and pathway analyses indicate the central nervous system plays a role in activity behaviours. Two-sample Mendelian randomisation suggests that increased activity might causally lower diastolic blood pressure (beta mmHg/SD: −0.91, SE = 0.18, p = 8.2 × 10−7), and odds of hypertension (Odds ratio/SD: 0.84, SE = 0.03, p = 4.9 × 10−8). Our results advocate the value of physical activity for reducing blood pressure.

Stroke, a leading cause of long-term disability and death worldwide, has a heritable component. Recent gene discovery efforts have expanded the number of known single-gene disorders associated with stroke and linked common variants at approximately 35 genetic loci to stroke risk. These discoveries have highlighted novel mechanisms and pathways implicated in stroke related to large artery atherosclerosis, cardioembolism, and small vessel disease, and defined shared genetic influences with related vascular traits. Further, genetics has successfully established causal relationships with risk factors and holds promise for prioritizing targets for exploration in clinical trials. Genome-wide polygenic scores enable the identification of high-risk individuals before the emergence of vascular risk factors. Challenges ahead include a better understanding of rare variants and ancestral differences for integration of genetics into precision medicine, integration with other omics data, uncovering the genetic factors that govern stroke recurrence and stroke outcome and, ultimately, the conversion of genetic discoveries to novel therapies.