An investigation into the relationship between the OPN4 gene’s melanopsin and environmental light availability in contributing to Seasonal Affective Disorder.
Seasonal Affective Disorder (SAD), is a form of transient depression commonly linked to the shorter daylight hours and temperature changes associated with winter. SAD is pervasive although misrepresented within our society, and is believed to impact up to 5% of Americans annually (Torres, 2023). The most prominent symptoms of SAD are irregular sleeping patterns such as insomnia, lack of sleep, and hypersomnia, excessive sleep (Melrose, 2015). These effects are frequently compounded by increased daytime fatigue and unusual weight gain (Melrose, 2015). The prevailing clinical understanding of SAD partially revolves around decreased light availability catalyzing the overproduction of sleep hormones like melatonin which contribute to the lethargy sufferers experience (Melrose, 2015). This paper will investigate this by exploring the relationship between variants in photoreceptor proteins, their ability to effectively process light, and the environmental availability of light in the development of SAD.
While the cause of SAD is debated, research has pointed to difficulties with the eye’s ability to process and intake light, the downstream effect of a variant in the OPN4 gene. OPN4 is an 11.8 kilobase sequence located on chromosome 10 that codes for the melanopsin protein (Provencio et al., 2000). Melanopsin is a G-coupled receptor found on the membrane of ganglion cells in the human retina, the interior ocular tissue responsible for perceiving light and visual information (Michael Tri H, 2019). The retina is composed of multiple ganglion layers, collections of differentiated neurons with distinct functions. Specifically, OPN4 melanopsin works in intrinsically photosensitive retinal ganglion cells (ipRGCs), a unique subset that comprises less than 1% of retinal cells (Michael Tri H, 2019). Functionally, melanopsin is a photopigment, a transmembrane protein that initiates reaction sequences that moderate the release of neurotransmitters. This is achieved by a process called phototransduction, the signal transmission of a chemical light communicator through melanopsin into the ipRGC. These ligand molecules, chromophores, undergo a shape change when absorbing photons, the energy particles associated with light. This new form can bind to the melanopsin receptor, inducing a transformation in its structure. The conformational change in melanopsin introduces a tertiary shape change to its associated G-protein, powering the phosphorylation of its linked GDP to a higher energy GTP form (Yoshinori Shichida & Matsuyama, 2009). Finally, the activation of the G-protein triggers a cascade of secondary messengers such as PIP2 that amplify the chromophore signal throughout the ipRGC (Yoshinori Shichida & Matsuyama, 2009). The downstream response of this amplification is a depolarization of the ipRGC membrane, achieved by the opening of ligand-gated ion channels. These proteins, transporting Na+ into the cell while exporting K+ and Ca2+, raise the resting membrane potential and generate an action potential that innervates sections of the brain like the hypothalamus and the suprachiasmatic nucleus (SCN) (Michael Tri H, 2019). Thus, the initial input of light in the form of photon energy has been transformed to a chemical messenger which is transduced to trigger an electrical response in the brain.
As described previously, SAD is frequently attributed to circadian dysfunction, caused by imbalances in sleep-associated hormones (Melrose, 2015). Melanopsin’s activation of neural tissues plays a significant role in regulating the endocrine component of homeostatic circadian rhythms. This is through the production of melatonin, a hormone secreted by the pineal gland upon norepinephrine signals released from the anterior hypothalamus (Tan et al., 2023). Once produced, melatonin is rapidly distributed throughout the body in the bloodstream, having diffused into nearby capillaries. Functionally, melatonin works to communicate levels of visual light to the body, signaling a suppression or promotion of sleep-associated chemical processes (Tan et al., 2023). Given melatonin production is first initiated by phototransduction, melanopsin is a critical protein for the regulation of sleep. This understanding of melanopsin’s role formed a key component of my hypothesis, that the symptoms of SAD sufferers are the result of defective photoreceptors.
Under the thesis that the primary pathway of melatonin dysfunction is stunted melanopsins, I posited that carriers within the population would have a higher likelihood of experiencing SAD. In 2009, two missense SNP variants of OPN4, I394, and P10L, were discovered and sequenced. Among these, two alleles, “C” and “T” were identified (Roecklein et al., 2009). To investigate their possible connection to SAD, researchers genotyped a sample of individuals with diagnosed seasonal depression. The results of this were compared to a control group of non-SAD participants to determine the differential representation of alleles at the P10L and I394T loci. Here, the authors observed that all individuals carrying the homozygous T/T allele of the missense P10L variant were sufferers of SAD. It was also concluded that participants with the proposed defective T/T genotype were nearly 6 times more likely to be in the SAD group than the control. Interestingly, the homozygous C/C and heterozygous C/T alleles were observed with similar frequency across both groups for I394T and P10L. In contrast to its representation at P10L, the T/T genotype at I394T was identified in comparable frequency in each sample, seen in 46% of sufferers and 36% of control participants. Thus, it was determined that the allele associated with a higher propensity for SAD was T/T, specifically at the P10L locus on chromosome 10 (Roecklein et al., 2009).
Based on findings from Roecklein’s exploration into OPN4’s variants, identifying the P10L T/T allele’s linkage to SAD, a later study investigated the physical mechanism underlying this connection. This research, also by Roecklein, intended to determine whether the melanopsins expressed by different genotypes of P10L had differing effectiveness in their response to light signals. To achieve this, the authors focused on pupil contraction, also known as post-illumination pupil response (PIPR), a secondary function of the melanopsin-containing ipRGCs (Roecklein et al., 2013). Using PIPR as a proxy for ipRGC sensitivity, the authors observed the duration and magnitude of pupil diminution following exposure to blue light. Here, a sustained response was seen as indicative of more active ipRGCs. Procedurally, 500 nm wavelength blue light was used to simulate the visible light emitted by the sun (Roecklein et al., 2013). Based on the results of the previous genetic study, it was hypothesized that individuals carrying the T allele would demonstrate a diminished PIPR, indicative of dysfunction in their melanopsin. This would lead to abnormal signaling in the neuronal pathway that stimulates the production of melatonin, which is believed to cause the primary symptom of SAD: irregular sleep. When comparing the PIPR of SAD-afflicted individuals and a control group, the authors observed a noticeable contrast in total pupil response from baseline. Specifically, they noted a 0.22 mm difference in pupil size between the homozygous C/C genotype in the control and the T/T genotypes in the SAD group, indicative of a stunted response from the latter’s ipRGCs (Roecklein et al., 2013). This allowed them to conclude that the more frequent C allele conferred light-sensitive and functional melanopsins to ipRGCs while the T allele conversely coded for light-insensitivity. This affirms the conclusion of the initial paper by Roecklein, identifying the T/T genotype carriers as most at risk for seasonal depression. By extension, the PIPR results associated with the problem T allele on OPN4’s P10L supported my initial hypothesis that SAD was caused by defective melanopsins. Uncertainty in this determination could have further decreased had there been comparable studies by other authors that demonstrated similar results through the same or different techniques. However, given SAD is somewhat clinically overlooked, this has not yet been undertaken.
Usually, melatonin is produced cyclically over the day, with significant concentrations only occurring in the evening in response to low-light conditions (Tan et al., 2023). The unusual response to visual signals and the downstream irregularity in melatonin production caused by dysfunctional ipRGCs are likely exacerbated by the decrease in environmentally available light during winter. This is the result of intrinsically limited reception by insensitive melanopsins, compounded with an extrinsic lack of light as a signal input. For individuals expressing these proteins, a similar effect is likely not observed during the summer due to the overall elevated presence of light. This more prominent signal presence could therefore counteract the limited ability of the homozygous T/T variant of OPN4, thus explaining the seasonal nature of SAD. Throughout my research into SAD, I was most interested in the transience of its symptoms and how they improved over the course of the year. This relationship between seasons and symptoms could be explored further using the PIPR method employed by Roecklein. Here, participants from a SAD-suffering group and a control group could undergo pupil illumination in both the summer and the winter. The results of these different PIPRs could then be cross-referenced with the genetic composition of each individual to determine the OPN4 variant they express. This would allow researchers to determine whether SAD-experiencing individuals demonstrated a different pupil response depending on the season, as well as compare the magnitude of response to the baseline set by the control group. Given the results of Roecklein’s study, I hypothesize there would still be a difference in pupil response between the SAD and the non-SAD groups during the summer PIPR, although less so than in the winter.
Seasonal Affective Disorder appears to be at least partially caused by dysfunctional variants of the OPN4 gene, specifically the melanopsin coded by the homozygous T/T genotype at P10L. This insensitivity to light signals has significant implications for the endocrine regulation of human sleep cycles by disrupting the production of melatonin. The results of this interruption, such as increased fatigue or insomnia, are key factors in the clinical diagnosis of SAD. Thus, the combination of a genetic predisposition to underactive melanopsin and environmentally decreased light availability are likely significant contributors to the development of seasonal depression. Confidence in this could be supported through further research into other possible underlying mechanisms of SAD, including the role of decreased serotonin reuptake and the downregulation of Vitamin D production (Melrose, 2015). Therefore, while important, the effect of flawed melanopsins is presumably only one cornerstone in the foundation of SAD.
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