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Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS-frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries.Methods: We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10(-7)Findings: After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10(-6); odds ratio [OR] 1·39, 95% CI 1·21-1·59) and rs2814707 (p=3·32×10(-6); 1·38, 1·20-1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10(-10); OR 1·22, 95% CI 1·15-1·30) and rs2814707 (p=4·72×10(-10); 1·22, 1·15-1·30) were associated with ALS.Interpretation: We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS-frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS-frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene. [ABSTRACT FROM AUTHOR]

With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10-5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. Individuals with ALS rapidly progress to paralysis and die from respiratory failure within 3 to 5 years after symptom onset. Epidemiological factors explain only a modest amount of the risk for ALS. However, there is growing evidence of a strong genetic component to both familial and sporadic ALS risk. The International Consortium on Amyotrophic Lateral Sclerosis Genetics was established to bring together existing genome-wide association cohorts and identify sporadic ALS susceptibility and age at symptom onset loci. Here, we report the results of a meta-analysis of the International Consortium on Amyotrophic Lateral Sclerosis Genetics genome-wide association samples, consisting of 4243 ALS cases and 5112 controls from 13 European ancestry cohorts from across the United States and Europe. Eight genomic regions provided evidence of association with ALS, including 9p21.2 (rs3849942, odds ratio [OR] = 1.21; p = 4.41 × 10(-7)), 17p11.2 (rs7477, OR = 1.30; p = 2.89 × 10(-7)), and 19p13 (rs12608932, OR = 1.37, p = 1.29 × 10(-7)). Six genomic regions were associated with age at onset of ALS. The strongest evidence for an age of onset locus was observed at 1p34.1, with comparable evidence at rs3011225 (R(2)(partial) = 0.0061; p = 6.59 × 10(-8)) and rs803675 (R(2)(partial) = 0.0060; p = 6.96 × 10(-8)). These associations were consistent across all 13 cohorts. For rs3011225, individuals with at least 1 copy of the minor allele had an earlier average age of onset of over 2 years. Identifying the underlying pathways influencing susceptibility to and age at onset of ALS may provide insight into the pathogenic mechanisms and motivate new pharmacologic targets for this fatal neurodegenerative disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD., Methods: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios., Results: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD., Interpretation: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD., (Copyright © 2011 American Neurological Association.)