New rare gene variants tied to ALS risk in large international genetic analysis
Study suggests genetic contributors in about a quarter of patients
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New rare genetic variants are linked to ALS, expanding understanding of genetic contributors.
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About a quarter of ALS cases have an identifiable genetic contributor.
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Findings support broader use of genetic testing to help guide research and treatment development.
A large-scale genetic analysis has identified several new rare mutations linked to amyotrophic lateral sclerosis (ALS), with findings suggesting that about a quarter of patients have an identifiable genetic contributor to their disease, according to a new study.
The results, which come from an analysis of nearly 18,000 people with ALS and more than 200,000 without the disease, identified several new genes associated with ALS risk, including YKT6, HTR3C, GBGT1, and KNTC1, and strengthened evidence for several others.
Findings also point to a broader genetic architecture than previously understood, where multiple rare variants may cumulatively increase disease risk.
Study highlights broader genetic contribution to ALS risk
“This study appreciably increases our knowledge of what causes [ALS], showing that it has a significant genetic component in about a quarter of people with the disease, regardless of family history,” Ammar Al-Chalabi, PhD, professor at King’s College London, in the U.K., and study author, said in a university news story.
“That means everyone presenting with symptoms should be offered genetic testing, and this increased knowledge improves the chances of developing an effective treatment,” Al-Chalabi said.
The study, “Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis,” was published in Nature Genetics.
ALS is broadly divided into two main types. Familial ALS, which accounts for about 10% of cases, occurs when the disease runs in a person’s family, suggesting an inherited genetic factor. Sporadic ALS, which makes up the majority of cases, occurs in people with no family history of the disease.
Yet, not all cases of familial ALS have a known genetic cause, and research suggests a substantial genetic component to sporadic ALS. This indicates rare variants — uncommon DNA changes that are hard to detect — may be the missing genetic component in many of these cases.
Advances in DNA sequencing technology have made it possible to study ALS genetics across the entire genome in both familial and sporadic cases. This approach has led to the discovery of new ALS-related genes, including TBK1, NEK1, and KIF5A.
Large dataset enables detection of rare ALS-linked genetic variants
Because some genetic variants are extremely rare or have only a modest effect, detecting them requires analyzing genetic data from tens of thousands of people.
To that end, scientists from 22 research groups worldwide pooled and standardized their genetic data. They analyzed the segments of genes that carry instructions for proteins, known as the exome, from 17,919 people with ALS and 200,703 people without ALS.
The analysis identified several new genes that contribute to ALS risk. One of the strongest new findings involved a gene called YKT6, with a variant consistently linked to ALS in the main study group and confirmed in a separate replication group.
Three other genes, HTR3C, GBGT1, and KNTC1, also showed strong and consistent signals. In addition, the study strengthened evidence for three genes, ARPP21, DNAJC7, and CFAP410, that had previously been linked to ALS, but with limited data.
Within the ARPP21 gene, researchers found two high-risk variants. One, called p.P563L, had previously been seen in a small number of families from the U.K. and Spain. In this study, the association with ALS was confirmed and identified in patients from several other countries. The mutation was also associated with earlier disease onset and a faster disease course. A second variant in the same gene, p.P747L, had never been described in the literature.
While the association of three genes (UNC13C, KIF4A, and CAPN2) with ALS was inconclusive, they are related to other known ALS genes and remain candidates for further study.
About a quarter of ALS cases tied to identifiable genetic contributors
Across all genes and variants examined, a known or suspected genetic risk factor was identified in 26.9% of ALS patients, regardless of whether the disease runs in the family.
Researchers noted that the data supported an “additive, oligogenic” model of ALS, meaning that several genetic variants may cumulatively increase ALS risk, rather than one single variant being solely responsible.
“The assembly of the largest exome sequencing dataset for ALS to date … enabled the discovery of rare variant contributions to ALS,” the researchers concluded. “The identification of several new genes, alongside the confirmation of genes with previous limited evidence, collectively provides a compelling set of potential new targets for translational ALS research.”
