Answer ALS: A Large-Scale Resource for Sporadic and Familial ALS Combining Clinical Data with Multi-Omics Data from Induced Pluripotent Cell Lines

Abstract

Answer ALS is a comprehensive multi-omics approach to ALS to ascertain, at a population level, the various clinical-molecular- biochemical subtypes of sporadic ALS. This national program enrolled 1046 ALS and ALS/FTD patients along with a cohort of 100 matched control patients followed longitudinally over at least one year. A smartphone-based app was employed to collect deep clinical data including fine motor activity, speech, breathing and linguistics/cognition. Analytics of the speech patterns revealed a strong correlation between clinical progression indices and speech. In parallel, blood-derived iPS motor neurons were generated from each patient and the cells underwent multi-omics analytics including whole genome sequencing, RNA transcriptomics, ATAC-Seq and proteome along with quality assurance standards. HIPPA compliant cloud data bases were employed to store all data. There are more than 6 billion clinical and molecular data points per patient generated in the program. The program was designed, and patient consented, to be open access to all clinical, biological and molecular data as well as public release of all generated iPS cell lines. A web portal is available to academics as well as commercial researchers. The ultimate intent of this data is for the generation of Integrated clinical and biological signatures using bioinformatics, statistics and computational biology to establish patterns that may lead to a better understanding of the underlying mechanisms of disease including subgroup identification. Overall, this community based clinical and science program provides for the identification of distinct reliably identifiable subgroups among the sporadic and familial patients and the great utility in iPS based approaches to disease pathophysiology and therapy discovery. Although the data is ALS centric, given the large number of both ALS and control data sets, it would also be enormously useful to others studying frontotemporal dementia, Alzheimer’s, Parkinson’s disease and others.

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

“…We next extended our search for putative ALS-associated SARM1 GoF alleles to the Answer ALS project database consisting of WGS data for 706 ALS patients and 92 matched controls (Rothstein, 2020). Some of the Project MinE DF1 variants were independently found in this new, non-overlapping dataset, including one occurrence of the strong NADase GoF Δ229-235 SARM1 allele in a patient, but we also found three new patient-associated alleles and one new control-associated allele encoding changes within the ARM domain or just N-terminal to it (encompassing amino acids 29-397) (Figure 1 and Table 2).…”

“…Having thus identified a total of eight different SARM1 alleles encoding SARM1 variants with confirmed or probable NADase GoF, we next asked whether any of these alleles were specifically seen in patients in two other independent motor nerve disorder databases, the Answer ALS project database (Rothstein, 2020) and the GENESIS database (Gonzalez et al, 2015). We found four further occurrences of patients heterozygous for the D226-232 or R267W SARM1 alleles in these databases, three of them ALS patients (two D226-232 and one R267W) and the other an HSP patient (D226-232) (Table 1).…”

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

“…We next extended our search for putative ALS-associated SARM1 GoF alleles to the Answer ALS project database consisting of WGS data for 706 ALS patients and 92 matched controls (Rothstein, 2020). Some of the Project MinE DF1 variants were independently found in this new, non-overlapping dataset, including one occurrence of the strong NADase GoF 229-235 SARM1 allele in a patient, but we also found three new patient-associated alleles and one new control-associated allele encoding changes within the ARM domain or just N-terminal to it (encompassing amino acids 29-397) (Figure 1 and Table 2).…”

“…Here, we have identified a number of rare alleles specific to ALS patients in Project MinE initiative data freeze 1 (Project MinE ALS Sequencing Consortium, 2018;van der Spek et al, 2019) and the Answer ALS project (Rothstein, 2020) encoding missense substitutions and in-frame microdeletions in the auto-inhibitory ARM domain of SARM1 that confer substantial pro-degenerative NADase gain-of-function (GoF). A number of these GoF alleles were subsequently identified in additional ALS patients and in HSP or other motor nerve disorder patients in other databases but, crucially, were not seen at all in any individuals in the control groups.…”

Novel Genetic Signatures Associated With Sporadic Amyotrophic Lateral Sclerosis

“…Participants were provided with a global unique identifier (NeuroGUID) and were monitored every 3 months for an entire year. All of the methods employed in this study were performed in accordance with the relevant guidelines and regulations, including the Declaration of Helsinki ( Berry et al, 2001 ; Rothstein et al, 2020 ).…”