Neuropsychiatric disorders, chronotype and sleep: A narrative review of GWAS findings and the application of Mendelian randomization to investigate causal relationships

Abstract

Genome-wide association studies (GWAS) have been important for characterizing the genetic component and enhancing our understanding of the biological aetiology of both neuropsychiatric disorders and sleep-related phenotypes such as chronotype, which is our preference for morning or evening time. Mendelian randomization (MR) is a post-GWAS analysis that is used to infer causal relationships between potential risk factors and outcomes. MR uses genetic variants as instrumental variants for exposures to study the effect on outcomes. This review details the main results from GWAS of neuropsychiatric disorders and sleep-related phenotypes, and the application of MR to investigate their bidirectional relationship. The main results from MR studies of neuropsychiatric disorders and sleep-related phenotypes are summarized. These MR studies have identified 37 causal relationships between neuropsychiatric disorders and sleep-related phenotypes. MR studies identified evidence of a causal role for five neuropsychiatric disorders and symptoms (attention deficit hyperactivity disorder, bipolar disorder, depressive symptoms, major depressive disorder and schizophrenia) on sleep-related phenotypes and evidence of a causal role for five sleep-related phenotypes (daytime napping, insomnia, morning person, long sleep duration and sleep duration) on risk for neuropsychiatric disorders. These MR results show a bidirectional relationship between neuropsychiatric disorders and sleep-related phenotypes and identify potential risk factors for follow-up studies.

Keywords: Mendelian randomization; chronotype; genome-wide association studies; neuropsychiatric disorders; sleep.

FIGURE 1

Genetic correlation results indicating shared biology of neuropsychiatric disorders and sleep‐related phenotypes. Symmetric heatplot displaying genetic correlations where those denoted by ‘*’ are significant at p < 0.05 after Bonferroni correction for all tests. L5 timing is the midpoint of the least active 5 h of each day. M10 timing is the timing of the most active 10 h of each day. This was generated using genome‐wide association studies (GWAS) data from European ancestry individuals from GWASatlas. GWASatlas ID and year of publication (brackets) are included for each phenotype. Results are clustered by degree of genetic correlation.

FIGURE 2

Mendelian randomisation concept and design. (A) Comparison of randomized controlled trial and MR study design. During a randomized controlled trial (RCT), study participants are randomly assorted during study design into two groups and an exposure (e.g., a treatment) is applied to one group to understand the extent to which it influences risk for the outcome. Outcomes (e.g., depression) are compared between both groups and any difference is considered to be due to the exposure treatment. Some treatments such as a set sleep duration are impractical and unethical. Alternatively, MR can be used for any genetically‐based traits. During MR, SNP alleles are assigned as instrumental variants (IVs) to assign groups. One group represents the exposure‐risk allele (e.g. carriers of alleles associated with short sleep duration) and one group with the other non‐risk allele. Outcomes are compared between both groups and any difference is considered to be due to the genetically‐based exposure. (B) Schematic diagram of MR study design and assumptions. During an MR analysis, the effect estimates for genetic instruments are extracted from genome‐wide association studies data and used to approximate the effect of the exposure on the outcome. The study design of MR is dependent on three core assumptions—(1) the genetic instruments are robustly associated with the exposure, (2) genetic instruments have no association with outcome that is not mediated through the risk factor and (3) genetic instruments are not directly associated with the outcome.

FIGURE 3

Mendelian randomisation analysis for neuropsychiatric disorders and sleep‐related phenotypes. Results outlined in this figure were compiled from all MR analyses which investigate causal relationships between neuropsychiatric disorders and sleep‐related phenotypes. Bold headers indicate the exposure category. Column ‘SNPs’ indicates the number of genetic instruments used for the exposure. Each point represents the odds ratio and confidence intervals. Where necessary, beta values were converted to odds ratios. The size of each point is proportional to the inverse standard error, meaning that larger points are indicative of more precise estimates. The p‐value is as reported in the original study. Odds ratios below 1 indicate that the exposure/risk factor is protective for the outcome, while odds ratios above 1 indicate that the exposure/risk factor increases risk for the outcome.