Research has shown that ALS has a strong genetic component. Genetic risk factors have been found in the SOD1, TARDBP, FUS and C9orf72 genes in familial ALS cases, while other genetic risk loci — specific spots in a person’s DNA (genome) — were identified in sporadic ALS cases. However, the link between risk loci and ALS remains largely unexplored.
The most recent and largest genome-wide association study (GWAS) in ALS showed a disproportionate contribution from low-frequency, rarer gene variants to the overall disease susceptibility. Because existing GWAS approaches focus mainly on the more common mutations (frequency over 1%), addressing rarer variants is a “pressing need,” the authors stated.
Researchers started a large-scale whole-genome sequencing study called Project MinE, which aims to evaluate the global, full spectrum of genetic variations in ALS.
The project hopes to collect information from at least 15,000 ALS patients and 7,500 matched controls to identify new loci linked to ALS risk, while also providing a public dataset for future genetic research in rare diseases such as ALS.
Project MinE is a collaborative effort by researchers from 16 countries. The study’s large scale is necessary to detect rare gene variants, the authors said.
In the project’s pilot phase, conducted in 1,264 cases and 611 controls collected in the Netherlands, the investigators explored the analytic challenges faced by rare variants in studies such as Project MinE.
The analysis was made up of 1,169 unrelated Dutch-ancestry cases and 608 ancestrally-matched controls. A total of 42,200,214 single nucleotide variants (SNVs) — which are variations in a single nucleotide, the building clocks of DNA — were found.
Importantly, 69% of these SNVs were rare, and most were not found in publicly available datasets.
“This observation reflects population-specific variants and the growing number of rare variants that will continue to be discovered as sequencing is performed in increasingly larger samples around the globe,” the researchers wrote.
Models predicted the birthplace of individuals in the Netherlands with high accuracy, which increased when including rarer variants. This finding illustrates “the strong geographical clustering [grouping] of rare variants,” the authors said. However, no variants reached genome-wide significance when analyzing their association with ALS traits.
The results also revealed that including controls from publicly-available datasets can lead to analytical challenges and must be approached with “extreme rigor,” the researchers said.
“With a global collaboration in place, a wealth of genetic variation being generated, and new methods for sequence data constantly in development, Project MinE will be the largest and most complete study of ALS genetics to date,” they wrote.
In prior reports from Project MinE, scientists showed that mutations in the NEK1 gene are the most common genetic causes of ALS in North American and European patients, and that rare variants of functionally related genes can interact to promote disease progression.