Mendelian randomization analysis using GWAS and eQTL data to investigate the relationship between chronotype and neuropsychiatric disorders and their molecular basis.

Chronotype is a proxy sleep measure that has been associated with neuropsychiatric disorders. By investigating how chronotype influences risk for neuropsychiatric disorders and vice versa, we may identify modifiable risk factors for each phenotype. Here we used Mendelian randomization (MR), to explore causal effects by (1) studying the causal relationships between neuropsychiatric disorders and chronotype and (2) characterizing the genetic components of these phenotypes. Firstly, we investigated if a causal role exists between five neuropsychiatric disorders and chronotype using the largest genome-wide association studies (GWAS) available. Secondly, we integrated data from expression quantitative trait loci (eQTLs) to investigate the role of gene expression alterations on these phenotypes. Evening chronotype was causal for increased risk of schizophrenia and autism spectrum disorder and schizophrenia was causal for a tendency toward evening chronotype. We identified 12 eQTLs where gene expression changes in brain or blood were causal for one of the phenotypes, including two eQTLs for SNX19 in hippocampus and hypothalamus that were causal for schizophrenia. These findings provide important evidence for the complex, bidirectional relationship that exists between a sleep-based phenotype and neuropsychiatric disorders, and use gene expression data to identify causal roles for genes at associated loci.