Sleep a Potential Treatment Target for Schizophrenia?

A new analysis reveals a bidirectional relationship between sleep patterns and schizophrenia, leading researchers to suggest that sleep may be a potential treatment target for the disorder.

Applying a Mendelian randomization (MR) approach, the investigators selected genetic variants from a meta-analysis of genome-wide association studies (GWAS) conducted using data from UK Biobank and 23andMe. They found that morning diurnal preference was associated with a lower risk for schizophrenia. In contrast, long sleep duration and daytime napping were associated with a higher risk for schizophrenia.

Conversely, genetically predicted schizophrenia was negatively associated with morning diurnal preference and short sleep duration, whereas it was positively associated with daytime napping and longer sleep duration.

“Our MR study revealed that morning diurnal preference was associated with a lower risk of schizophrenia; in addition, our results provided clues for the causal relationship between long sleep duration and a higher risk of schizophrenia, between daytime napping and a higher risk of schizophrenia, write the investigators, led by Zhen Wang of the Department of Cardiovascular Surgery, School of Medicine, First Affiliated Hospital of Zhejiang University, Hangzhou, China. “Therefore, sleep traits were identified as a potential treatment target for patients with schizophrenia,” they add.

The study was published online on June 15 in BMC Psychiatry.

Underrecognized Therapeutic Target

About 80% of patients with schizophrenia experience widespread sleep abnormalities. However, sleep continues to be an “underrecognized therapeutic target in clinical practice,” the investigators note. They point out that most meta-analyses suggest “potential causal associations between sleep dysfunction and schizophrenia. However, they add, causality is “difficult to confirm.”

MR “uses genetic variants as instrumental variables to investigate the causal association between exposures and outcomes.” The researchers consider MR as a “natural randomized controlled trial” because genetic variants are randomly inherited.

Therefore, they add, MR offers an “alternative approach to explore the potential causal relationship between an exposure and an outcome when RCTs are not feasible” and are useful for investigating the bidirectional causal relationship between sleep traits and schizophrenia.

Exposures and Outcomes

The sleep traits that the researchers examined included morning diurnal, long and short sleep duration, daytime sleepiness, daytime napping, and insomnia.

The researchers obtained genetic summary statistics for exposures and outcomes by selecting variants from a meta-analysis of GWAS conducted using data from the UK Biobank and 23andMe.

Although they used summary statistics from European individuals in the UK Biobank (n = 449,734), the genetic loci that they included in some of the analyzes were taken from both data sources.

Genetic loci identified in the meta-analysis and used by the researchers in the current study are listed below. Shift workers and those with chronic and psychiatric disorders or other poor health were excluded from some of the analyses.

Sleep trait

Genetic loci (n)

Morning diurnal preference

340

Habitual sleep duration

78

Short (<7 h) and long (≥ 9h) sleep durations

27

Daytime napping

123

Daytime sleepiness

42

Insomnia

57

Sensitivity analyzes showed that these genetic associations were “largely independent” of known risk factors for sleep disturbances, such as insomnia, caffeine intake, chronotype, and additional lifestyle and clinical considerations.

The researchers extracted genetic variants from a large meta-analysis of GWAS (n = 77,096 European ancestry participants; 33,640 cases, 43,456 controls), from which 108 schizophrenia-associated genetic loci were identified.

The investigators removed single nucleotide polymorphisms (SNPs) with effect sizes greater in the outcome than in the exposure and then matched sleep-related SNPs to schizophrenia-related SNPs. If no matching SNP was available for an outcome, they selected a proxy.

The final number of SNPs used as variables is in the table below.

Characteristic

Independent SNPs (n)

Morning diurnal preference

316

Sleep duration

74

Short sleep duration

26

Long sleep duration

7

Daytime napping

105

Daytime sleepiness

40

Insomnia

52

The researchers selected 105 SNPs for schizophrenia as the exposure.

After excluding SNPs without proxies, they arrived at 315 instrumental variables for diurnal preference, 101 SNPs for schizophrenia, and 100 SNPs when the outcome was daytime napping.

Consistent Associations

Odds ratios for the association between sleep patterns and schizophrenia are found in the table below.

Genetically predicted sleep trait (association with schizophrenia risk)

Odds ratio (95% CI)

P value

Morning diurnal preference (lower risk)

.839 (.777-.907)

9.86 x 10-6

Sleep duration (higher risk)

1.562 (1.311-1.861)

6.08 x 10-7

Short sleep duration (no higher risk)

1.046 (0.908–1.206)

.533

Long sleep duration (higher risk)

1.404 (1.190-1.656)

5.58 x 10–5

Daytime napping (higher risk)

2.051 1.590-2.647

3.28 x 10-8

Daytime sleepiness (no higher risk)

1.766 (1.055-2.957)

.031

Insomnia (no higher risk)

.776 (.550-1.096)

.150

The findings remained, even after correcting for outliers and after a multivariable analysis that adjusted for other sleep traits.

Odds ratios for the association between genetically predicted schizophrenia and sleep patterns are in the table below.

Sleep trait (association with schizophrenia)

Odds ratio (95% CI)

P value

Morning diurnal preference (negative)

.984 (.977-.992)

2.9 x 10-5

Increased sleep duration (positive)

1.026 (1.020-1.032)

3.4 x 10-16

Higher odds of daytime napping (positive)

1.010 (1.007-1.014)

4.2 x 10-9

Daytime sleepiness (no association)

1.001 (.998-1.0040

.564

Insomnia (no association)

1.002 (.998-1.005)

.383

There “has been increasing interest in the distinct opinion that sleep abnormalities play a possible causal role in the outbreak and persistence of schizophrenia,” the authors note.

However, because traditional observational studies are affected by confounding factors and biases, these studies could not clarify whether sleep abnormalities causally influence the risk of schizophrenia. Based on this setting, the MR study can confirm the causality of sleep traits in schizophrenia because of its characteristics,” they conclude.

‘Premature Conclusion’

Commenting for Medscape Medical NewsFabio Ferrarelli, MD, PhD, associate professor of psychiatry and director of the Sleep and Schizophrenia Program, University of Pittsburgh School of Medicine, Pennsylvania, noted that “despite not being part of the clinical criteria used to diagnose schizophrenia, altered sleep patterns are commonly reported by these patients and objectively assessed in these individuals both in the clinical and the research settings.”

Strengths of this study include the large sample size and the bidirectionality of the associations examined, including sleep traits and risk for schizophrenia and vice versa, noted Ferrarelli, who was not involved with the study.

However, he cautioned, “the directionality shown here does not prove causality, but simply that the association is reciprocal. Additionally, what was examined here was the genetic risk for schizophrenia, not the genetic alterations present in individuals with the disorder. Thus, the conclusion that sleep traits were identified as a potential treatment target for patients with schizophrenia is premature.”

No funding was obtained for this study. The authors and Ferrarelli declare no relevant financial relationships.

BMC Psychiatry. Published online June 15, 2022. Full text

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her story).

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