The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one third of familial ALS cases of outbred European descent making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

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.

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.

Introduction The genetic etiology of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well-suited location for a genome-wide association study of ALS, as the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. Methods We performed a genome-wide association study of 442 Finnish patients diagnosed with ALS, and 521 Finnish control subjects using Illumina genome-wide genotyping arrays. DNA was collected from patients attending an ALS specialty clinic that receives referrals from neurologists throughout Finland, whereas the control samples were obtained from a population-based study of elderly Finnish individuals. Individuals known to carry D90A alleles of the SOD1 gene (n = 40) were included in the final analysis as positive controls to determine if our GWAS was able to detect an association signal at this locus. Findings We identified two association peaks that exceeded genome-wide significance. One of these was located on chromosome 21q22 (rs13048019, p = 2·58×10−8) that corresponded to the known autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232kb block of linkage disequilibrium (rs3849942, p = 9·11×10−11) in a region of chromosome 9p that has been previously identified by linkage studies of ALS families. Within this region, we defined a 42-SNP haplotype that significantly increased risk of developing ALS (p = 4·2×10−33 among familial cases, odds ratio = 21·0, 95% CI = 11·2–39·1), and which overlapped with an association locus recently reported for fronto-temporal dementia (FTD). Based on the 93 familial ALS cases included in the analysis, population attributable risk percent for the chromosome 9p21 locus was 37.9% (95% CI, 27·7 – 48·1%), and for D90A homozygosity was 25·5% (95% CI, 16·9 – 34·1%). Interpretation In summary, we present evidence that the chromosome 9p21 ALS-FTD locus is a major cause of familial ALS in the Finnish population.