ALS GWAS Summary Statistics 2021

Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci. When combined with 8,953 whole-genome sequenced individuals (6,538 patients, 2,415 controls) and a large cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

W.Rheenen, et al. Nature Genetics (2021)

The download link includes:

• GWAS summary statistics, cross-ancestry meta-analysis
• GWAS summary statistics, European-ancestry meta-analysis
• Rare-variant burden analysis summary statistics
• eQTL SMR summary statistics for eQTLGen and MetaBrain

Summary statistics can also be downloaded from IEU Open GWAS (https://gwas.mrcieu.ac.uk), accession number GCST90027163.

ALS GWAS Summary Statistics 2016

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

W. van Rheenen et al., Nature Genetics (2016)

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.

The download link includes:

• GWAS summary statistics, stratified meta-analysis
• GWAS summary statistics, pooled linear mixed model analysis