Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study

Abstract

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.

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

“…A common founder was originally proposed for Finnish FALS cases based on a 42-SNP haplotype. 8 A subsequent meta-analysis of genome-wide association study data from five European 94A_8 97A_24 96A_24 93A_6 84X_2 39X_113 32X_1 38X_3 40X_4 108X_1 33X_1 107X_6 26X_7 101A_18 107A_52 26A_12 39A_371 33A_24 40A_74 2A_111 4A_14 67A_25 115A_147 53A_109 76A_10 70A_8 118A_201 119A_17 10A_196 16A_8 58A_10 72A_5 77A_15 78A_797 Identifiers with an X contain the expanded HREM allele (highlighted in red). Digits after the underscore indicate the number of chromosomes in which the haplotype was observed.…”

“…5,6 Genome-wide association studies in sporadic and familial ALS demonstrated highly significant association with single-nucleotide polymorphisms (SNPs) across a 170-Kb region at 9p21.2. [7][8][9][10][11] A massive GGGGCC hexanucleotide repeat expansion mutation (HREM) has recently been identified within intron 1 of C9ORF72 as the pathogenic mutation responsible for familial and sporadic ALS and FTD in these cases. 12,13 Here we describe HREM mutation frequencies in ALS in five European populations.…”

Genetics of Amyotrophic Lateral Sclerosis

“…ITPR2 has a role in glutamate-mediated neurotransmission, regulation of calcium concentration and apoptosis. However, the ITPR2 association has not been found in a replication study and in subsequent GWAS (Chiò et al, 2009;Fernández-Santiago et al, 2011;Laaksovirta et al, 2010;Shatunov et al, 2010;Van Es et al, 2009c). Variation in the dipeptidyl-peptidase 6 (DPP6) gene was found to be significantly associated with sALS in a GWAS performed in a combined GWA data set from the USA and the Netherlands (Van Es et al, 2008).…”

A Major Genetic Factor at Chromosome 9p Implicated in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD)

“…Next, data of the first GWAS in FTLD-TDP were suggestive for association of five SNPs (rs774352, rs774351, rs3849942, rs2814707, rs774359) on chromosome 9p21, in the same LD block . Subsequently, a Finnish and a British independent ALS GWAS identified genome-wide significance with SNPs rs3849942, rs2814707, rs774359, rs2225389 (Laaksovirta et al, 2010) and with SNPs rs3849942, rs2814707, rs903603 (Shatunov et al, 2010) respectively, all in the same locus at chromosome 9p21. The Finnish study defined a 42-SNP haplotype associated with increased risk of ALS in the Finnish population, located in a 232 kb LD block which overlaps with the previously reported 80 kb LD block (van Es et al, 2009) and the 106.5 kb LD block of the UK study (Shatunov et al, 2010).…”

“…The minimally linked region in all these families is about 3.6 Mb in size containing five known protein-coding genes. Moreover, several recent genome-wide association studies (GWAS) in ALS populations from different European origins showed the presence of a major genetic risk factor for ALS at the same chromosome 9p region (Laaksovirta et al, 2010;Shatunov et al, 2010;van Es et al, 2009). The Finnish study narrowed the associated region to a 232 kb linkage disequilibrium (LD) block containing three known genes (MOBKL2B, IFNK, C9orf72) and suggested the presence of a major risk gene with high penetrance (Laaksovirta et al, 2010).…”