Working group 2 will provide a standardized means of performing quality control and analyses for project MinE.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that predominantly affects the upper and lower motor neurons and, to a variable extent, extramotor systems, such as temporal circuits and behavioral and executive frontal circuits. Patients with ALS become progressively weaker over months to years, until death from neuromuscular respiratory failure, typically 2–5 years after the first symptoms. The only available drug, Riluzole, is marginally effective in extending the lifespan of ALS patients by 3-6 months. ALS can affect people of any age and is the most common neurodegenerative disease of midlife, although the peak age of onset is ~70 years. The cumulative lifetime risk of ALS is ~1 in 300. The incidence of ALS is 1– 2 per 100,000 person–years but the point prevalence is only 5 per 100,000 people because of the very poor prognosis.
Five to ten percent of patients have ‘familial’ ALS (fALS), with at least one other first- or second-degree relative also affected with ALS. The remainder of patients is considered to have sporadic ALS (sALS), although the exact definition of fALS is unclear. Twin studies have shown that there is a considerable contribution of ALS genes to risk of 61%. The classical view is to distinguish familial ALS (fALS) as Mendelian disease from sALS as complex genetic disease with many small effect genetic risk factors interacting with environmental factors. However, recent evidence suggest that the classical etiologic distinction between fALS and sALS is no longer tenable: mutations in ALS genes (e.g. SOD1, FUS, TARDBP, C9orf72) do occur in sALS, and there appears to be a a disproportionate large contribution from low-frequency genetic variants in all ALS as opposed to the contribution of thousands of common variants in common diseases such as schizophrenia. These observations have led to the start of Project MinE with the primary goal to systematically look for an increased burden of rare genetic variation in all ALS.
The aim of the analysis and association testing working group is to provide a standardized method for:
Alignment and genotype calling will be performed in such a way as to allow for joint analysis of diverse data sets (e.g., WGS data as well as externally-collected whole-exome sequencing (WES) data) and performed with open-source softwares so as to allow external collaborators and consortia with additional sequence data (generated separately from the Project MinE effort) to also contribute their data to the effort.
Additionally, the working group will provide a standardized means of performing quality control on the data, and to perform single-variant and gene-based association testing.
Chair / The Netherlands
Co-chair / USA