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Integrating findings from genome-wide association studies with molecular datasets can help develop insight into the underlying functional mechanisms responsible for trait-associated genetic variants. We have applied the principles of Mendelian randomization to investigate whether brain-derived gene expression ( n  = 1194) may be responsible for mediating the effect of genetic variants on eight cognitive and psychological outcomes (attention-deficit hyperactivity disorder, Alzheimer’s disease, bipolar disorder, depression, intelligence, insomnia, neuroticism and schizophrenia). Transcriptome-wide analyses identified 83 genes associated with at least one outcome ( P  Bonferroni  &lt; 6.72 × 10 −6 ), with multiple trait colocalization also implicating changes to brain-derived DNA methylation at nine of these loci. Comparing effects between outcomes identified the evidence of enrichment, which may reflect putative causal relationships, such as an inverse relationship between genetic liability towards schizophrenia risk and cognitive ability in later life. Repeating these analyses in whole blood ( n  = 31 684), we replicated 58.2% of brain-derived effects (based on  P  &lt; 0.05). Finally, we undertook phenome-wide evaluations at associated loci to investigate pleiotropic effects with 700 complex traits. This highlighted pleiotropic loci such as  FURIN  [initially implicated in schizophrenia risk ( P  = 1.05 × 10 −7 )], which had evidence of an effect on 28 other outcomes, as well as genes which may have a more specific role in disease pathogenesis [e.g.  SLC12A5  which only provided evidence of an effect on depression ( P  = 7.13 × 10 −10 )]. Our results support the utility of whole blood as a valuable proxy for future studies analysing molecular datasets, but also suggest that conducting analyses in a tissue-specific manner may be more comprehensive.

Multi-omics analyses of cognitive traits and psychiatric disorders highlight brain-dependent mechanisms