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More Than Dozen Genetic Loci Linked to Amyotrophic Lateral Sclerosis Risk

NEW YORK — Researchers have identified more than a dozen genetic loci associated with amyotrophic lateral sclerosis risk, including ones that implicate autophagy in disease development.

For about 10 percent of ALS patients, there is a family history of disease, but for most patients, it is thought to be a complex disease with a heritability of between 40 percent and 50 percent. Through a genome-wide association study of nearly 30,000 ALS patients and more than 122,000 controls, a Utrecht University-led team of researchers has homed in on 15 genetic loci linked to ALS risk and traced those loci to likely causal rare variants and short tandem repeats.

As they reported in Nature Genetics, the researchers also conducted a Mendelian randomization analysis that further found a role for high cholesterol levels in ALS development. This, in combination with the GWAS findings, underscored a role for vesicle-mediated transport and autophagy in disease development.

"We show a causal role for cholesterol, which can be linked to impaired autophagy as common denominators of neuron-specific pathology that drive ALS susceptibility and serve as potential targets for therapeutic strategies," senior author Jan Veldink from Utrecht and colleagues wrote in their paper.

For their GWAS, the researchers combined data from 117 cohorts to conduct a meta-analysis of 27,205 individuals with ALS and 110,881 control individuals of European ancestry. This linked 12 genetic loci to disease risk. Nine of these loci were present in a further analysis of 2,407 ALS patients and 11,775 controls of Asian ancestry, while a cross-ancestry analysis uncovered three additional loci, for a total of 15 genetic loci associated with ALS risk.

The researchers then zeroed in on likely causal variants using summary-based Mendelian randomization analyses and a brain cortex-derived eQTL dataset. For three of the loci, they identified low-frequency coding variants as likely causal variants, while for another locus they traced the likely causal variant to a repeat expansion. At the same time, other loci pointed both common and rare variants in known ALS risk genes.

As previous studies had suggested, genetic correlations between ALS and other neurodegenerative conditions including Parkinson's disease, frontotemporal dementia, and Alzheimer's disease, the researchers examined whether any of these risk loci were shared across conditions. The Utrecht-led team noted these genetic correlations and, through colocalization analyses, uncovered shared signals at loci like MOBP-RPSA and UNC13A between ALS and progressive supranuclear palsy and frontotemporal dementia, respectively.

Meanwhile, the ALS risk loci were enriched for expression in brain tissue, and not in peripheral nervous tissue or muscle. This, the researchers noted, is similar to the expression pattern seen in Parkinson's disease but contrasts with what is observed in Alzheimer's disease. There further was enrichment for expression in neurons, particularly glutamatergic neurons. This, they added, suggested that neurodegeneration in ALS is governed by neuron-specific pathology, rather than inflammatory processes that are observed in Alzheimer's disease.

At the same time, the researchers noted that a coexpression network enrichment analysis indicated a role for vesicle-medicated transport and autophagy in ALS, and that a Mendelian randomization analysis found a causal relationship between high cholesterol levels and ALS. They added that recent studies have found a relationship between lipid metabolism and autophagy, indicating the two results could be related. They further suggested the effect of cholesterol levels on increased ALS risk could be mediated though impaired autophagy.