Our ALS Consortium – a partnership of clinicians, basic scientists, geneticists, and computational biologists from 31 institutions across 5 countries – establishes a framework to apply whole genome sequencing (WGS) and functional genomics to the study of ALS. Because ALS-causing mutations tend to be of moderate impact and are relatively rare in the population (reviewed in Al-Chalabi et al. 2017), identification of new mutations requires several thousand samples, which need to be obtained from multiple sites (even the busiest ALS clinics see only 200-400 patients per year). To enable broad data sharing, we centralize the administration of a widespread, highly federated program. We developed and disseminate key elements for Informed Consent Forms and IRB protocols, disseminate common data elements to harmonize clinical phenotyping across all participating centers, and centralize administration and operations to ensure smooth coordination between sites. Currently, the ALS consortium has sequenced 3440 whole genomes and 1210 RNA samples. Data are shared both within our consortium and with other consortia, and novel analytical tools are applied to mine these data for ALS-associated mutations. These efforts have already led to the identification of novel ALS-associated mutations such as in KIF5A (Nicolas et al. (2018).
Broadly stated, the goals of this consortium are the following:
– Integrate whole genome sequencing with RNA sequencing to interrogate relationships between mutations, gene expression and disease mechanisms
– Integrate genomic data with histopathology and clinical data on postmortem tissue to study molecular mechanisms of disease spread
– Use our partners’ clinical phenotyping efforts to sequence well-stratified patient cohorts, to eventually identify mutations that are associated with different forms of the disease, or gene variants that can modify the presentation of the disease and could be further studied to identify pathways for the targeted development of therapies
– Create and maintain a data warehouse for genomic data that can be broadly accessed by the academic community
Consortium data is also being deposited in MetroNome, NYGC’s clinical genomics database.
ALS CONSORTIUM COORDINATION
We developed and disseminate key elements for Informed Consent Forms and IRB protocols, provide common data elements to harmonize clinical phenotyping across all participating centers, in order to centralize administration and operations to ensure smooth coordination between sites. Data are shared both within our consortium and with other consortia, and novel analytical tools are applied to mine these data for ALS-associated mutations.
Such broad sharing and collaborative efforts are ultimately geared towards making the best use of sequencing data. Comparing clinical profiles to genomic profiles can enable us to determine whether specific mutations are associated with specific clinical outcomes – this may ultimately make truly “personalized” medicine possible.