Cross-disorder genomic structural equation modeling reveals common genetic basis of neuroimmune diseases

Abstract The genetic architecture underlying neuroimmune syndrome-related traits remains poorly characterized. We employed genomic structural equation modeling (genomic SEM) alongside comprehensive post-GWAS analytical frameworks to identify causal single nucleotide polymorphisms (SNPs) associated with phenotypic variance independent of measured traits, revealing 33 genome-wide significant loci. Multi-tissue transcriptome-wide association analyses were conducted across tissue, cellular, and genomic regulatory elements to characterize susceptibility gene signals and regulatory components with high relevance to neuroimmune syndrome GWAS. We subsequently leveraged extensive human disease datasets to determine neuroimmune syndrome-associated risk factors and explored potential therapeutic targets through plasma proteomics and drug target prioritization analyses. Additionally, summary statistics-based polygenic scoring assessed chromosomal contributions to neuroimmune syndrome risk. Our investigation represents the first comprehensive genetic architecture mapping of neuroimmune syndromes through GWAS of a latent, unmeasured phenotype, providing unprecedented insights into shared genetic mechanisms underlying these complex disorders.