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

A wide range of comorbidities have been observed with neuropsychiatric disorders, of which sleep disturbances are one of the most common. Chronotype, a self-reported measurement of an individuals preference for earlier or later sleep timing, is a proxy sleep measure that has been linked to neuropsychiatric disorders (NPDs). By investigating how chronotype influences risk for neuropsychiatric disorders and, vice versa, how risk for neuropsychiatric disorders influences chronotype, we may identify modifiable risk factors for each phenotype. By investigating the specific genetic mechanisms that are common to the risk of evening chronotype and the risk of NPDs, we may gain further understanding of the relationship and causal direction in these phenotypes. Here we use Mendelian randomisation (MR), a method used to explore causal effects, to 1) study the causal relationships between neuropsychiatric disorders and chronotype and 2) characterise the genetic components of these phenotypes. Firstly, we investigated if a causal role exists between six 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. We also used colocalization to validate that the same variant is causal for gene expression and each outcome. We identified that the evening chronotype is causal for increased risk of schizophrenia and autism spectrum disorder and, in the opposite direction, that insomnia and schizophrenia are causal for a tendency towards evening chronotype. We identified twelve eQTLs where gene expression changes in brain or blood were causal for one of the tested phenotypes (bipolar disorder, chronotype and schizophrenia). These findings provide important evidence for the complex, bidirectional relationship that exists between these sleep and neuropsychiatric disorders, and use gene expression data to identify causal roles for genes at associated loci. Author SummarySleep disturbances are commonly observed features of neuropsychiatric disorders. Chronotype, a behavioural manifestation of an individuals preference for early or late sleep timing i.e. morning chronotype means a preference for earlier sleep and wake times, has been used as a behavioural marker of underlying circadian function. Here, we used data from the largest genetic studies available to test the causal relationship between chronotype and risk for neuropsychiatric disorders. We found that individuals with the evening chronotype have greater risk for schizophrenia or autism spectrum disorder. In the other direction, we found insomnia or schizophrenia diagnosis is causal for a tendency towards evening chronotype. We searched for DNA variants that influence chronotype or risk for neuropsychiatric disorders through alterations of gene expression in blood and brain tissues. We found twelve DNA variants with a significant effect on chronotype or risk of either bipolar disorder or schizophrenia. These results demonstrate that sleep and neuropsychiatric disorders have a complex bidirectional relationship and that the causal role of some genes is due to variants that alter gene expression.