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

Abstract

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.

The circadian system: A neglected player in neurodevelopmental disorders

“…Using participants from the UK Biobank, genome-wide association analyses revealed that evening chronotype is positively correlated to increased SZ risk while morning chronotype is negatively correlated to SZ (Jones et al, 2016;Jones et al, 2019;Lane et al, 2016). Additionally, mendelian randomisation analyses revealed a causal effect of chronotype on SZ and ASD (Crinion et al, 2024;Sun et al, 2022). Studies using experience sampling methodology (ESM), a technique used to capture interdaily and intradaily variations of a behaviour of interest based on a daily diary, primarily looked at the predictive power of sleep disturbances on psychotic symptoms such as paranoia (Hennig & Lincoln, 2018;Mulligan et al, 2016;Waters et al, 2011).…”