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Identification of Genetic Factors Contributing to ALS

The identification of the genetic causes of ALS is necessary to further understand the cellular pathways involved in neurodegeneration and contribute towards establishing targets for therapeutic intervention. Our laboratory has a proven history of identifying genes contributing to ALS using a variety of approaches. Lab efforts were instrumental towards the identification of FUS as a causative gene for familial ALS (FALS) using a combination of linkage analysis, homozygosity mapping and high-throughput Sanger sequencing. Through our long-standing interest in novel technologies, our laboratory employed exome capture and next-generation sequencing to identify mutations in the profilin 1 (PFN1) as a cause of FALS.

As a result of collaborations with leaders in ALS genetic research, our lab now contains the largest collection of FALS exome data in existence consisting of 1,376 FALS derived from 11 countries. We have focused on using rare variant burden analysis (RVB) of exome sequencing results on this cohort to identify novel genes for FALS. In brief, RVB compares the combined frequency of rare variants within all genes in a case-control cohort. Candidate associations are identified by significant differences after multiple test correction. Through our efforts, we identified mutations in the TUBA4A gene, which encodes the Tubulin, Alpha 4A protein, are associated with FALS. To our knowledge, this study represents the first successful application of rare variant burden analysis for the discovery of a novel disease gene.

Currently, our laboratory continues to work towards the identification of additional novel ALS genes through various approaches and taking full advantage of our collection of FALS exome data. This includes further expanding this cohort and developing novel methodologies based on RVB. We have improved RVB by developing a training session for the analysis with known ALS genes. This innovative method had led us to the identification of NEK1, which is a risk factor that is observed in ~3% of ALS patients. Our lab has also been involved in whole genome sequencing (WGS) our extensive FALS cohort. We anticipate that the results of this WGS will reveal novel non-coding regions of the genome contributing to ALS.

Our lab has become more focused in the genetic factors contributing to sporadic ALS (SALS). In contrast to FALS, SALS cases represents the vast majority of all ALS cases (~90%). Based on the lack of a family history and supported by heritability studies, the genetic contribution of SALS is lower compared to FALS. As a result, it presents a difficult challenge to identify genetic factors contributing to SALS. In fact, it is anticipated that the identification of rare risk factors for SALS will require the WGS of tens of thousands of cases and controls. Such an endeavor is well beyond the capabilities (scientifically and financially) of a single laboratory. As a result of this limitation, the ALS scientific community created Project MinE, with a goal to WGS the DNA from 15,000 ALS cases and 7,500 controls. Our efforts have thus far resulted in the WGS of nearly 11,000 samples. Currently, Project MinE has reached nearly one-half of its goal of 22,500 WGS in total. Again, it is our hope that the findings from this effort will advance our efforts to further understand the pathogenesis of ALS.

It is anticipated that the investigation of ALS genetics will continue to be a major focus of our laboratory for the foreseeable future. There are still many unexplored areas of ALS genetics and we anticipated that we will be successful in our endeavors. Such areas will include the role of non-coding regions, indels, copy number variations, genetic/environment interactions and epigenetic factors in the pathogenesis of ALS. Given the complexity of the future ALS genetic efforts, many of these genetic projects will likely be performed in continued collaboration with other leaders in ALS genetics. Project MinE is a prime example of such collaborative effort.