A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

Abstract

Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

Figure 1.

Manhattan plot of the international ALS meta-analysis. Scatter plot of chromosome position (x-axis) against –log₁₀ GWAS meta-analysis P-values (y-axis) from imputed data. The threshold of genome-wide significance (P = 5 × 10⁻⁸) is indicated as a horizontal red line. At locus 9p21.2, 18 SNPs close to Corf72 gene lie above the red line (most significant SNP is rs3849943 with P = 7.69 × 10⁻⁹). Locus 17q11.2 shows SNP rs34517613 (P = 1.11 × 10⁻⁸) to be significantly associated. SNP rs1788776 at 18q11.2 is very close to the threshold of significance with P = 7.67 × 10⁻⁸. Manhattan plot was produced using ggplot2 package in R.

Figure 2.

Regional association plots of the associated loci. LD structure of the three regions associated with ALS in the international GWAS meta-analysis. For each plot, the −log₁₀ P-values (left y-axis) of SNPs are shown according to their chromosomal positions (x-axis); the genetic recombination rates are shown on the right y-axis. −log₁₀ P-values are shown for both genotyped and imputed SNPs distributed in a 0.8-megabase genomic region. The top SNP of each region is indicated as a diamond, and SNPs colour reflects LD correlation (r²). (A) locus at 9p21, (B) 17q11.2 and (C) 18q11.2. LD plots were generated by LocusZoom v1.1.

Figure 3.

Heritability estimate across ALS-GWA studies. Heritability estimated in eight independent ALS cohorts. Forest plot shows heritability value and confidence interval (95%) calculated in each study at the reported prevalence of 5/100 000. Black boxes indicate the single studies, and box sizes are proportional to the sample (N). Grey bars specify lower and upper limit of 95% confidence interval.