Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Abstract

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1

Comparison of imputation accuracy. (a,b) Aggregate r2 values between imputed and sequenced genotypes on chromosome 20 are shown when using different reference panels for imputation. Allele frequencies were calculated from the Dutch samples included in the Genome of the Netherlands (GoNL) cohort. The highest imputation accuracy was achieved when imputing from the merged custom and 1000 Genomes Project (1000GP) panel. The difference in accuracy was most pronounced for low-frequency alleles (frequency 0.5–10%) in ALS cases from both the Netherlands (a) and the UK (b).

Figure 2

Meta-analysis and LMM associations. (a) Manhattan plot for the meta-analysis results. This approach yielded four genome-wide-significant associations. The associated SNP in C21orf2 is a nonsynonymous variant not found to be associated in previous GWAS. (b) Manhattan plot for the LMM results. This analysis yielded three loci in addition to those identified by meta-analysis with associations that reached genome-wide significance (MOBP, LOC101927815 and SCFD1). The association for SNPs in the previously identified ALS risk gene TBK1 approached genome-wide significance (P = 6.6 × 10−8). As the C21orf2 SNP was removed from a Swedish stratum because of MAF <1%, this SNP was tested separately, but it is presented here together with all SNPs with MAF >1% in all strata. LOC101927815 is shown in gray because the association for this locus could not be replicated. Loci are labeled by the name of the nearest gene. The dotted lines correspond to the significance threshold of P = 5 × 10−8.

Figure 3

Partitioned heritability. (a) Heritability estimates for each chromosome were significantly correlated with chromosome length (P = 4.9 × 10−4). (b) For ALS, there was a clear trend where more heritability was explained by the low-frequency alleles. This effect was still observed when, for a fair comparison between ALS and a previous study partitioning heritability for schizophrenia (SCZ) using identical methods22, SNPs present in HapMap 3 (HM3) were included. Error bars correspond to standard errors.