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Amyotrophic lateral sclerosis (ALS) is a progressively fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord. In this study, we investigated gene expression changes in ALS via RNA sequencing in 380 postmortem samples from cervical, thoracic and lumbar spinal cord segments from 154 individuals with ALS and 49 control individuals. We observed an increase in microglia and astrocyte gene expression, accompanied by a decrease in oligodendrocyte gene expression. By creating a gene co-expression network in the ALS samples, we identified several activated microglia modules that negatively correlate with retrospective disease duration. We mapped molecular quantitative trait loci and found several potential ALS risk loci that may act through gene expression or splicing in the spinal cord and assign putative cell types for FNBP1, ACSL5, SH3RF1 and NFASC. Finally, we outline how common genetic variants associated with splicing of C9orf72 act as proxies for the well-known repeat expansion, and we use the same mechanism to suggest ATXN3 as a putative risk gene., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Structural variants (SVs), which are genomic rearrangements of more than 50 base pairs, are an important source of genetic diversity and have been linked to many diseases. However, it remains unclear how they modulate human brain function and disease risk. Here we report 170,996 SVs discovered using 1,760 short-read whole genomes from aged adults and individuals with Alzheimer's disease. By applying quantitative trait locus (SV-xQTL) analyses, we quantified the impact of cis-acting SVs on histone modifications, gene expression, splicing and protein abundance in postmortem brain tissues. More than 3,200 SVs were associated with at least one molecular phenotype. We found reproducibility of 65-99% SV-eQTLs across cohorts and brain regions. SV associations with mRNA and proteins shared the same direction of effect in more than 87% of SV-gene pairs. Mediation analysis showed ~8% of SV-eQTLs mediated by histone acetylation and ~11% by splicing. Additionally, associations of SVs with progressive supranuclear palsy identified previously known and novel SVs., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)