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Novel ALS Susceptibility Variants Uncovered in Pair of Studies

NEW YORK (GenomeWeb) – An international team of researchers has linked new gene variants to amyotrophic lateral sclerosis risk.

In a pair of papers appearing in Nature Genetics today, a University Medical Center Utrecht- and University of Massachusetts Medical School-led team took both genome-wide association and gene burden analysis-based approaches to implicate variants in C21orf2, MOBP, SCFD1, and NEK1 in ALS susceptibility. As C21orf2 and NEK1 are both involved in cilial function and are linked to mitochondrial function, the researchers said these variants also hint at disease pathogenesis.

"Our results provide new and important insights into ALS etiopathogenesis and genetic etiology," UMass's John Landers and his colleagues said in one paper.

In the first paper, Utrecht's Jan Veldink and his colleagues developed a custom imputation reference panel using high-coverage whole-genome sequencing data from more than 1,800 cases and controls from the Netherlands. From this, they built a reference panel of some 18 million SNVs that, when they imputed into the Dutch ALS cases, improved the imputation accuracy for low-frequency variants, as compared to reference panels from the 1000 Genomes Project or Genome of the Netherlands study.

The researchers then used this merged reference panel to impute a dataset of 27 cohorts they had amassed that included 12,577 cases and 23,475 controls. After a meta-analysis, the researchers found four loci that reached genome-wide significance with ALS risk: the previously reported C9orf72, UNC13A, and SARM1, and the novel C21orf2. A linear mixed-model analysis further supported those four genome-wide significant associations while also implicating three additional loci at MOBP, SCFD1, and 8p23.2.

Veldink and his colleagues replicated three of the newly uncovered loci — C21orf2, MOBP, and SCFD1 — in a separate cohort of 2,579 cases and 2,767 controls.

Meanwhile, UMass's John Landers and his colleagues performed an exome-wide rare variant burden analysis to examine the frequency of rare variants in various genes in the exome. For this, they first trained their analysis based on 10 known ALS-associated genes before applying it to a cohort of 1,022 familial ALS cases and 7,315 controls.

They uncovered four genes — SOD1, TARDBP, UBQLN2, and FUS — with exome-wide significance when they restricted their analysis to variants with low minor allele frequencies that could be functionally characterized as deleterious. When they extended their analysis to all protein-coding genes, they identified a new gene —NEK1 — with exome-wide significant disease association.

At the same time, Landers and his colleagues sequenced the whole genomes of four ALS patients from an isolated Netherlands community and also uncovered four candidate disease variants — including one, p.Arg261His, in NEK1. In a further cohort of 6,172 sporadic ALS cases and 4,417 matched controls, the researchers noted an excess of minor alleles of NEK1 among cases, and further found NEK1 risk variants in about 3 percent of ALS cases.

Both C21orf2 and NEK1 could be traced to roles in cilia formation and mitochondrial function, the researchers noted in their papers. While Veldink and his colleagues noted the functional role of C21orf2 isn't well understood, they added that it is required for the formation and maintenance of primary cilia and it has been found in the mitochondria of immune cells. Likewise, Landers and his colleagues noted that NEK1 regulates the formation of nonmotile primary cilia as well as mitochondrial membrane permeability and DNA repair. It also is known to interact with other ALS-associated proteins like VAPB, ALS2, and FEZ1.

C21orf2, Veldink and his colleagues added, also interacts with protein product of NEK1. This led them to hypothesize that C21orf2 mutations may lead to cilia or mitochondria dysfunction or to poor DNA repair and thus to adult-onset disease.