Transcriptome-wide and stratified genomic structural equation modeling identify neurobiological pathways shared...

Functional genomic methods are needed that consider multiple genetically correlated traits. Here we develop and validate Transcriptome-wide Structural Equation Modeling (T-SEM), a multivariate method for studying the effects of tissue-specific gene expression across genetically overlapping traits. T-SEM allows for modeling effects on broad dimensions spanning constellations of traits, while safeguarding against false positives that can arise when effects of gene expression are specific to a subset of traits. We apply T-SEM to investigate the biological mechanisms shared across seven distinct cognitive traits (N = 11,263-331,679), as indexed by a general dimension of genetic sharing (g). We identify 184 genes whose tissue-specific expression is associated with g, including 10 genes not identified in univariate analysis for the individual cognitive traits for any tissue type, and three genes whose expression explained a significant portion of the genetic sharing across g and different subclusters of psychiatric disorders. We go on to apply Stratified Genomic SEM to identify enrichment for g within 28 functional categories. This includes categories indexing the intersection of protein-truncating variant intolerant (PI) genes and specific neuronal cell types, which we also find to be enriched for the genetic covariance between g and a psychotic disorders factor.