Previous studies, including the large Genome Wide Association Study from the UMC Utrecht that was published in the leading scientific journal Nature Genetics in 2016, showed that rare DNA variants contribute to the onset of ALS. It has, however, proven difficult to examine these rare variants using traditional methods. With support from Project MinE, researchers from the UMC Utrecht performed one of the largest rare variant studies in ALS to date using an ‘exome chip’.

The array was designed years ago to facilitate large-scale experiments, focussing on rare variants in the protein-coding regions (also called the ‘exome’) of our DNA. This ‘exome chip’ includes 240,000 (primarily rare) DNA-variants. Recently, researchers from the UMC Utrecht used the exome chip to perform one of the largest rare variant studies in ALS to date, with support from Project MinE. The study analysed genetic material from 7,350 patients and healthy controls from six European countries: Belgium, Germany, Ireland, Spain and The Netherlands. The results of these analyses were recently published in the scientific journal Scientific Reports.

Although no new ALS-variants or -genes were discovered in this study, important new insights in the disease were obtained. The study confirms that mutations in the NEK1-gene indeed confer an increased risk of ALS.

None of the other (rare) variants or genes captured on the exome chip are large-effect variants associated with ALS. Furthermore, additional analyses did not reveal an increased DNA-wide burden of unique rare variants in ALS patients compared to healthy controls.

An identical analysis previously performed in patients with schizophrenia did show an increased burden in patients compared to healthy controls. This underlines the notion that, despite the partial genetic overlap between ALS and schizophrenia (also published previously with support from project MinE), the genetic underpinnings of schizophrenia and ALS are likely quite different. These insights help with the design of future studies of rare variants associated with ALS, and with studies of their relation to other (neurological or neuropsychiatric) diseases.

Given that the study did not implicate new genetic risk genes for ALS, the analyses reaffirm the need for large scale, international collaborative studies of rare variants in ALS. In order to further facilitate large scale rare variant analyses, summary data are made publicly available on the Project MinE website.