Trait#63: Seasonal Affective Disorder
Monday, April 20, 2020. Author FitnessGenes
Monday, April 20, 2020. Author FitnessGenes
As we discovered in previous traits, our circadian clock system syncs our sleep / wake cycle, secretion of hormones, fluctuation in body temperature and other circadian rhythms with patterns of light and darkness caused by the Earth’s 24-hour rotation.
Patterns of light and darkness also vary according to what season we’re in. Generally speaking, there are more hours of daylight in spring and summer and fewer in autumn (fall) and winter months.
These seasonal changes in light and darkness are tracked by our circadian clock system, which, in response, adjusts the timings of various biological processes. On this note, it’s estimated that the activity of at least a quarter of all our genes changes according to season. For example, we tend to burn more fat in summer compared to winter because the expression of our lipoprotein lipase gene (which encodes an enzyme that breaks down triglycerides in adipose tissue) is seasonally regulated by our circadian clock system. Similarly, seasonal changes in the production of hormones cause differences in our reproductive activity throughout the year.
Our circadian clock system also significantly influences the activity of brain networks that regulate our mood.
In this respect, many of us show seasonal variation or “seasonality” in our mood. For example, the graph below shows that several “non-seasonals” experience mild fluctuations in mood throughout the year. Depending on our genetics, however, some of us may be more liable to develop depressive symptoms on a seasonal basis. As the graph below demonstrates, “seasonals” experience greater changes in mood and energy according to season.
This trait specifically looks at your risk of seasonal affective disorder (SAD) – a condition characterised by depressive episodes that recur at the same time each year (most commonly during winter).
Variants of genes that regulate our circadian clock system, as well as genes involved in the activity of brain circuits that process mood, can increase our risk of SAD.
Seasonal affective disorder (SAD) is a mental health condition whereby symptoms of depression occur annually at the same time each year.
Symptoms of SAD include:
For most people with SAD, these depressive symptoms tend to begin in late autumn (fall) and early winter, while disappearing during the spring and summer. Given this pattern of symptoms, the more common type of SAD is often known as ‘winter depression.’
With regards to the list of symptoms above, people with autumn (fall) / winter-onset SAD more characteristically tend to experience:
More rarely, symptoms of SAD may appear in spring and summer, disappearing in autumn and winter. In contrast to those whose symptoms get worse in winter, people with spring / summer-onset SAD tend to experience:
IMPORTANT: If you are suffering from any of the above symptoms, you are strongly advised to consult your GP or other qualified healthcare professional. They will be able to fully assess you and guide you on the best treatment options.
The underlying causes of SAD are not yet clear. Research to date, however, points to three main potential mechanisms:
According to this theory, seasonal changes in light patterns cause disruption to the timings of the circadian clock system. In particular, certain circadian rhythms (i.e. biological processes which follow a 24-hour cycle) may become out of sync with your sleep/wake cycle, leading to alterations in mood and behaviour.
Serotonin (5-HT) is a key neurotransmitter (nerve signalling molecule) in the brain, particularly in brain networks that regulate mood, emotion, sleep and food intake.
Several lines of research suggest that a reduction in serotonin levels and lower activity within serotonergic brain networks may underlie SAD. For example, post-mortem studies of SAD patients show that samples of their brain tissue contain much less serotonin in winter compared to summer.
Furthermore, carbohydrate ingestion – one of the characteristic symptoms of SAD – is thought to be a compensatory behaviour to raise serotonin levels. Similarly, SSRI (selective serotonin reuptake inhibitor) medication and bright light therapy, both of which can relieve symptoms of SAD, are demonstrated to increase serotonergic activity in the various brain networks.
Melatonin is commonly referred to as our ‘sleep hormone.’ During the night, production of melatonin increases, which makes us feel sleepy. The graph below shows how levels of melatonin in the blood plasma rise and peak at night-time.
Studies have shown that people with SAD tend to produce more melatonin and for longer durations at night in winter. This may be responsible for the feelings of tiredness and lethargy that characterise SAD.
Many of these proposed mechanisms for SAD are likely to be linked to one another. For example, disruption to the circadian clock system may cause melatonin production to be out of sync with the normal sleep/wake cycle. Melatonin is also produced from serotonin, so imbalances of one hormone may affect the other.
In this trait, we analyze gene variants related to the activity of your circadian clock system and brain circuits that use serotonin.
Your genetic seasonal affective disorder (SAD) risk trait analyzes several different gene variants related to the function of your circadian clock system.
As detailed in the Clock genes and your sleep cycle blog, your circadian clock system works through a complex mechanism whereby so-called “Clock genes” are switched on and off in a cyclical fashion.
Variants of Clock genes, which include CLOCK, PER1, PER2, PER3, CRY1, CRY2, NPAS2 and ARNTL, may alter the timings of the circadian clock system, which in turn increases the risk of SAD. For example, studies suggest that certain variants of the PER3 gene may disrupt the timings of circadian rhythms and shorten the period of sleep / wake cycle (i.e. the time to complete one full cycle). The same PER3 gene variants have been linked to an increased risk of SAD.
In addition to regulating the timing of circadian rhythms, Clock genes also the affect expression of several other genes involved in the function of wider brain networks. Such brain networks include those that regulate mood and use the neurotransmitters dopamine, serotonin and noradrenaline to send nerve signals.
For example, the PER2 gene alters the expression and activity of the MAO-A enzyme that degrades serotonin, noradrenaline and dopamine. By changing nerve activity within brain networks that rely on these neurotransmitters, variants of Clock genes can affect mood and alter your risk of developing SAD. In this respect, studies suggest that inheriting certain PER2 (as well as NPAS2 and ARNTL) gene variants is associated with a greater likelihood of SAD.
Another key gene related to the functioning of the circadian clock system is OPN4 - the melanopsin gene.
Melanopsin is a light-sensitive pigment found in the retinas of our eyes. The main function of melanopsin is to signal “daytime” to our master clock (located in the SCN of the brain), thereby allowing us to sync or ‘entrain’ circadian rhythms to daily patterns of light and darkness.
This process relies on a pathway between the retina and the SCN (suprachiasmatic nucleus) called the retino-hypothalamic tract.
Variants of the OPN4 gene may disrupt this pathway and thereby interfere with the entrainment of our circadian clock system. On this note, studies have linked certain OPN4 gene variants with an increased risk of SAD.
Your SAD risk trait also looks at your ZBTB20 gene. This gene likely plays a role in your circadian clock system, although more research is required to elucidate its precise function.
We do know that mice lacking the ZBTB20 gene have disruptions to their circadian rhythms, are less active in the evening, and have difficulty entraining circadian rhythms to patterns of light and dark.
In humans, certain variants of the ZBTB20 gene are thought to increase the risk of SAD. For example, a SNP (Single Nucleotide Polymorphism) in the ZBTB20 gene (rs139459337) has been linked to a 1.63 times higher risk of SAD.
As explained in the Serotonin Synthesis blog, serotonin (5-HT) is a key neurotransmitter used to relay nerve signals in brain networks that regulate mood, emotion, sleep and appetite. Such serotonergic brain networks connect widespread regions within the brain, such as our limbic system (a collection of linked structures deep within the brain that process emotional stimuli), frontal cortex (which is plays a role in higher-order functions such as decision-making and planning) and brainstem centres (that regulate, among other things, food intake).
Changes in neural activity within these serotonergic networks are thought to contribute to the symptoms of SAD. For example, a neuroimaging study using PET (Positron Emission Tomography) found that women with SAD had different patterns of brain activity in serotonergic networks compared to those without SAD. Crucially, these differences in brain activity were only apparent in winter.
Perhaps unsurprisingly, variants of genes that play a role in serotonergic activity have also been linked to SAD. In this respect, certain variants of the 5HTR2A gene, which codes for the serotonin 2A receptor, are significantly more common in people with SAD. For example, a SNP (Single Nucleotide Polymorphism) in the 5HTR2A gene (given the code rs731779) creates two different gene variants or alleles: ‘G’ and ‘T’. Those with two copies of the G allele (i.e. people with the GG genotype) were 6 times more like to have either winter or summer-onset SAD.
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