M42 a Transcriptome-Wide Association Study of Mismatch Negativity (original) (raw)

2019, European Neuropsychopharmacology

tomic Wide Analysis, and eQTL mapping, as well as more recently developed methods that integrate GWAS and eQTL data via mendelian randomization [SMR] and linkage methods [HEIDI] (PMID 29500431& 27019110). Available, brainspecific eQTL databases included GTEXv7, BrainEAC, Com-monMind, ROSMAP, and PsychEncode. Intersecting credible genes were then annotated against multiple chemoinformatic databases (DGI, KI, and a review on 'druggability' (PMID 28356508)). Results: A total of 239 independent cognition-associated loci (39 novel) were identified by MTAG, encompassing 652 Bonferroni-significant genes identified in the MAGMA analysis. Incorporating brain-specific expression data, TWAS and eQTL mapping yielded 444 genes and 588 genes, respectively. By contrast, the more conservative SMR approach identified 166 cognitive genes, while the use of the HEIDI test permitted the identification of additional TWASnominated genes that did not demonstrate direct causal effects. Of the genes nominated by any method, 81 were identified as 'Tier 1' candidates, which included efficacy targets of approved small molecules and clinical-phase drug candidates. Of these, 14 were consistently supported by MAGMA, TWAS, eQTL mapping, SMR, and HEIDI analysis. Discussion: Converging results across multiple data analytic approaches suggest that the following genes-ALMS1,