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.

需要考虑多种遗传相关性状的功能基因组方法。在这里，我们开发并验证了全转录组结构方程模型（T-SEM），这是一种多变量方法，用于研究跨遗传重叠性状的组织特异性基因表达的影响。 T-SEM 允许对跨越性状群的广泛维度的影响进行建模，同时防止当基因表达的影响特定于性状子集时可能出现的误报。我们应用 T-SEM 来研究七种不同认知特征 ( N = 11,263–331,679) 共享的生物学机制，如遗传共享的一般维度 (g) 所索引。我们鉴定了 184 个其组织特异性表达与g相关的基因，其中包括在任何组织类型的个体认知特征的单变量分析中未鉴定的 10 个基因，以及其表达解释了g和不同亚簇之间遗传共享的重要部分的 3 个基因。的精神疾病。我们继续应用分层基因组 SEM 来识别 28 个功能类别中g的富集。这包括索引蛋白质截短变异不耐受（PI）基因和特定神经元细胞类型交叉的类别，我们还发现这些类别因g和精神障碍因素之间的遗传协方差而丰富。