The New York Genome Center ALS Consortium resource integrates postmortem tissue transcriptomics and whole genome sequencing to empower biological discovery

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with substantial genetic and clinical heterogeneity that impedes therapeutic development. Large-scale multi-tissue genomic resources have transformed the study of neuropsychiatric and neurodegenerative diseases, but no equivalent resource exists for ALS. Here we present the full NYGC ALS Consortium dataset, combining whole-genome sequencing from 4,746 donors and bulk RNA-seq from 2,574 samples across 8 brain and spinal cord regions from 695 donors across the ALS disease spectrum. Our catalogue of small variants, structural variants, and short tandem repeats identified likely pathogenic mutations in 15.6% of ALS cases. Gene expression and mRNA splicing analysis across 5 major tissues reveals shared and region-specific features, highlighting microglial and T-cell dysregulation in the spinal cord. Mapping the genetic regulation of expression and splicing across tissues identified associations with 6 ALS risk loci, whereas allele-specific rare variant analysis detected expression effects for C9orf72 and OPTN . All data are immediately publicly available.