Exploring the Genetic Link Between Suboptimal Sleep Durations and Depression in Older Adults

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Sleep is a fundamental aspect of human health, with suboptimal sleep durations being a significant concern, particularly for older adults. Short-sleep, typically defined as less than 5-6 hours per night, and long-sleep, typically more than 8-10 hours per night, are sleep patterns that have been associated with various health issues.

Alongside depression, they contribute substantially to the public health burden among older adults. This article delves into the complex relationship between suboptimal sleep durations and depression, emphasizing the genetic underpinnings and the implications for the aging population.

Understanding the Context

Depression prevalence tends to increase with age but plateaus in adults aged 55-74. Simultaneously, older adults often experience a decline in their optimal sleep duration as they age. Given the global phenomenon of an aging population, there is an urgent need for a deeper understanding of the mechanisms behind the connection between suboptimal sleep durations and the onset of depression in older adults.

Suboptimal Sleep and Depression: A Bidirectional Relationship

Clinical and epidemiological research has demonstrated a strong link between suboptimal sleep durations and depression, with evidence of longitudinal associations working in both directions. Some studies suggest that short-sleep and long-sleep patterns precede the onset of depression, while others propose that depression can lead to the development of suboptimal sleep durations. These inconsistencies may stem from various methodological constraints, such as differences in measuring sleep and depression, the use of cross-sectional designs, small sample sizes, and diverse participant characteristics.

One noteworthy study on bidirectionality found that sleep disorders are more consistent predictors of depression than the reverse over a 20-year period. However, the absence of genetic information could contribute to the uncertainty surrounding the directionality of the relationship between suboptimal sleep durations and depression in adults.

Genetics and Suboptimal Sleep Durations

While environmental factors play a significant role in the development of suboptimal sleep durations and depression, these traits also have a strong genetic component. Twin studies have shown that genetic differences account for approximately 40% of the variance in sleep duration and around 35% for depression. Recent advances in genetics have introduced polygenic scores (PGS), which provide insights into the genetic basis of traits.

PGSs are calculated based on the total number of trait-associated alleles, known as single-nucleotide polymorphisms (SNPs), across the genome. They are weighted by their respective effect sizes, as estimated through genome-wide association analysis. SNP heritability differs from traditional twin studies. For instance, a study found narrow sense heritability for overall sleep duration to be 9.8%, while short-sleep was 7.9%, and long-sleep was 4.7%. PGSs are valuable tools for investigating whether suboptimal sleep durations and depression share an underlying genetic basis.

Aims of the Study

The study discussed in this article aims to explore the genetic links between suboptimal sleep durations and depression in older adults using a large and well-defined sample of the UK population. Over an average course of 8 years, the research seeks to achieve two main objectives:

  • Investigate the role of polygenic predisposition to overall sleep duration, short-sleep, and long-sleep in the development of depression.
  • Examine the role of polygenic predisposition to depression in overall sleep duration and the onset of short-sleep and long-sleep.

Methodology

To account for the variation in thresholds defining short-sleep and long-sleep, the study utilized a meta-analysis of prospective studies to establish the thresholds as <5-7 hours for short-sleep and >8-9 hours for long-sleep. Given the stronger predictive power of sleep disorders on future depression, the hypothesis is that there is a significant unidirectional association between polygenic predisposition to sleep durations and the onset of depression over an average 8-year period.

Discussion

This study represents a significant advancement in the field of sleep research by employing a polygenic predisposition approach to explore the relationship between suboptimal sleep durations and depression in a large population-representative sample of older adults. The findings shed light on the genetic underpinnings of this complex relationship and have important implications for understanding the mental and physical health of aging populations.

Genetic Predisposition and Depression

The study reveals that genetic predisposition to short-sleep is strongly associated with the onset of depression over an average 8-year period among older adults. However, genetic predisposition to overall sleep duration and long-sleep did not show a significant relationship with the onset of depression. These findings suggest that different underlying mechanisms contribute to the relationship between depression and the development of suboptimal sleep durations in older adults.

These results challenge a previous Mendelian randomization (MR) study, which found no causal relationship between short sleep (or overall or long sleep duration) and depression. The discrepancy might be attributed to the definitional cut-off point for short-sleep, which was <7 hours in the previous study compared to ≤5 hours in the present study. Nevertheless, the genetic predisposition for short-sleep has a clear and robust connection with depression in older adults, consistent with twin studies and genetic correlations observed between short-sleep and depression in adults aged 40-69.

Several potential mechanisms underlie the association between short-sleep and depression, including electroencephalogram abnormalities, circadian rhythm disruptions, and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. These findings emphasize the clinical and public health importance of understanding the genetic factors involved in short-sleep and its relationship to depression in older adults.

Long-Sleep and Depression

In agreement with previous meta-analytic results, the study shows that self-reported long-sleep is a risk factor for the onset of depression during an 8-year follow-up in older adults. Conversely, overall phenotypic sleep duration was negatively associated with depression, aligning with earlier research. However, these relationships were not replicated in the genetic analyses, nor in two MR studies focused on overall sleep duration. This discrepancy may be attributed to the strength of the genetic instruments used in the present study.

The absence of associations between genetic predisposition to overall sleep duration and long-sleep with the onset of depression suggests that other factors drive the relationship between sleep duration and depression in older adults. Inflammation and metabolic abnormalities are posited as potential factors that could contribute to increased long-sleep and depression. These findings highlight the complex interplay of various factors in the relationship between sleep duration and depression.

Short-Sleep vs. Long-Sleep

The study supports the growing consensus that short-sleep is more strongly associated with depression than long-sleep, a pattern that holds true across the lifespan. Different molecular mechanisms likely underlie these associations at either end of the sleep duration spectrum. Genetic correlations between short-sleep and long-sleep were negative, further suggesting distinct genetic underpinnings for these two sleep patterns.

Despite robustly replicated common variants of sleep duration in the Vaccinia Related Kinase 2 (VRK2) and Paired Box 8 (PAX8) genes, there may be unidentified markers with large effects driving the risk for long-sleep. The genetic basis of sleep duration is known to be pleiotropic, with the presence of the same single-nucleotide polymorphisms but different risk alleles resulting in diverse outcomes. This genetic complexity may explain the differences observed between polygenic risk for short-sleep and long-sleep in the onset of depression.

Depression and Sleep Duration

Interestingly, genetic predisposition to depression did not show significant associations with overall sleep duration, short-sleep, or long-sleep. These genetic findings align with previous research that suggests depression is a risk factor for the development of short-sleep and is negatively associated with overall sleep duration. However, depression did not precede long-sleep, which contradicts observational evidence indicating that depression has a curvilinear association with sleep duration.

Future studies should consider testing causal sequences using Mendelian randomization for the observed polygenic associations, which could provide further insights into the complex interplay between genetic predisposition, depression, and sleep duration.

In conclusion, this study represents a significant step forward in understanding the genetic basis of the relationship between suboptimal sleep durations and depression in older adults. These findings have the potential to inform future research and interventions aimed at improving the mental and physical health of aging populations. Understanding the complex interplay of genetic and environmental factors in this relationship is crucial for developing targeted and effective preventive and therapeutic strategies.


reference link : https://www.nature.com/articles/s41398-023-02622-z

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