Stress Related Disorder

Introduction

Stress-related disorders represent a diverse group of conditions arising from the interplay between an individual’s psychological and biological responses to stressful experiences. These disorders encompass a spectrum of mental health challenges, including depression, post-traumatic stress disorder (PTSD), and anxiety disorders, and can also influence the onset of chronic physical diseases.^[1] Understanding the mechanisms underlying these conditions is crucial due to their significant impact on individual well-being and public health.

Background

Stressful life events (SLEs) are a primary environmental factor contributing to the development of stress-related disorders. These events can range from major life changes such as the death of a spouse, divorce, or job loss, to more chronic, minor stressors like the fear of unemployment.^[2] Tools like the Social Readjustment Rating Scale (SRRS) are used to quantify the cumulative impact of such events, with higher scores indicating a greater risk for stress-related problems.^[2] The susceptibility to these disorders is not solely determined by exposure to stress but also by an individual’s genetic makeup, highlighting the importance of gene-environment interactions (GxE).^[3]

Biological Basis

The biological underpinnings of stress-related disorders involve complex genetic, epigenetic, and neurological mechanisms. Genome-wide association studies (GWAS) have been instrumental in identifying genetic variations associated with vulnerability to these conditions. For instance, the serotonin transporter gene, 5-HTT, and its polymorphic region 5-HTTLPR, have been extensively studied for their role in moderating the impact of life stress on depression []. Other genes, such as COMT (catechol-O-methyltransferase) and MAOA (monoamine oxidase A), are also implicated in the genetic modulation of the endocrine stress response []. COMT genotype, for example, can influence D1 receptor availability in cortical-limbic regions.^[4] Emerging candidates like RGS10 are also being explored for their potential role in stress-related disorders.^[2]Neurologically, stress can lead to impaired prefrontal cortical cognitive function.^[5]Furthermore, epigenetic changes, such as DNA methylation, caused by environmental stress are increasingly recognized as contributing factors to disease risk.^[2] For example, SNPs associated with emotion dysregulation, like rs6602398 in the IL2RA gene, have been linked to differential methylation regulation.^[6]

Clinical Relevance

Stress-related disorders manifest through a variety of symptoms, often assessed using standardized questionnaires such as the Center for Epidemiological Studies Depression (CES-D) scale or the K6 scale for psychological distress.^[7] Conditions like depression and PTSD are directly linked to stress exposure, with specific genetic variants potentially modulating their severity and onset.^[6] The genetic landscape of these disorders is complex, involving multiple genes and interactions. For instance, statistical epistasis between COMT and other genes like RGS4, G72 (DAOA), GRM3, and DISC1has been observed to influence the risk of schizophrenia, a disorder often exacerbated by stress.^[8] Understanding these genetic influences offers pathways for personalized diagnostic and therapeutic strategies.

The widespread prevalence and significant morbidity associated with stress-related disorders underscore their profound social importance. These conditions affect diverse populations globally, as evidenced by studies conducted in Japanese and African American cohorts.^[2] The identification of genetic loci, such as those found in a pilot genome-wide gene-environment study for depression (e.g., rs10510057 , rs13151036 , rs17193334 , rs10834377 , rs12701976 ), contributes to a deeper understanding of population-specific genetic risks and gene-environment interactions.^[2] By elucidating the genetic and environmental factors that contribute to stress susceptibility, researchers aim to develop more effective prevention programs, targeted interventions, and improved treatments that can mitigate the individual suffering and societal burden of these disorders.

Methodological and Statistical Constraints

Many genetic studies on stress related disorder face challenges related to sample size, which can limit the power to detect variants with the expected small effect sizes, a common characteristic in complex traits like major depressive disorder (MDD).^[9] Insufficient sample sizes can lead to imprecise assessment of risk variants and potentially inflated effect sizes for detected loci when compared to larger consortium studies.^[9] This limitation underscores the need for replication in independent and larger cohorts to confirm initial findings and ensure their robustness.^[6] Despite efforts to identify significant associations, even in more heritable subsets like recurrent early-onset MDD, genome-wide significant findings have often remained elusive.^[10]Cohort-specific biases can also influence findings, such as studies focusing on presumably healthy employee populations where depressive symptoms may not be normally distributed, potentially biasing p-values for some genetic markers.^[2]Furthermore, samples predominantly drawn from specific demographic groups, such as low-income African American populations, while valuable for addressing health disparities, may limit the generalizability of findings to other ancestries.^[6] While meta-analyses often employ rigorous quality control measures like checking allele frequencies against reference panels and assessing inflation through Q-Q plots and genomic control.^[7] concerns about population stratification in case-control designs persist.^[11] Family-based studies, which intrinsically account for shared ancestry, offer a robust approach to mitigate such stratification biases.^[11]

Phenotypic Complexity and Challenges

A significant limitation in the study of stress related disorder stems from the reliance on self-administered assessment questionnaires for measuring symptoms.^[2] This approach can introduce response bias, leading to either an over- or underestimation of the true associations between genetic variants and phenotypes.^[2] The subjective nature of psychiatric symptoms means that individuals may not always accurately identify or report their experiences, highlighting the potential benefit of incorporating more objective and thorough measures in future research.^[6] The inherent heterogeneity of complex phenotypes like MDD further complicates genetic investigations.^[10] Different individuals may harbor varying combinations of risk variants, leading to a spectrum of phenotypic symptoms, even within closely related individuals.^[10] Accurately delineating specific symptom profiles, such as typical versus atypical MDD, often proves challenging due to a lack of available or prohibitively expensive phenotypic data, such as advanced imaging.^[10]Therefore, balancing sample size with precise phenotype definition, potentially through the use of quantitative scores of severity and reliability, remains a critical strategy.^[10]

Unexamined Environmental and Epigenetic Influences

Many genetic studies on stress related disorder have not comprehensively assessed the impact of environmental factors, despite the widely recognized role of gene-environment interactions in the susceptibility and pathogenesis of conditions like depression.^[9]The omission of these crucial environmental variables can diminish the power of studies to detect relevant genetic associations and provide a complete picture of disease etiology.^[9] Understanding the interplay between genetic predispositions and environmental stressors is essential for a holistic understanding of these complex disorders.

Furthermore, the potential influence of epigenetic changes, such as DNA methylation, which can be modulated by environmental stress, often remains unexamined.^[2]While some research may explore associations between single nucleotide polymorphisms and differential methylation.^[6] comprehensive assessment of these dynamic modifications is often not integrated, representing a significant knowledge gap.^[2] Future research would benefit from prospective, longitudinal study designs to thoroughly investigate the temporal onset of symptoms and to capture the dynamic interplay of genetic, epigenetic, and environmental factors over time.^[6]

Variants

Genetic variations play a crucial role in influencing an individual’s susceptibility and response to stress-related disorders, often by modulating key biological pathways involved in brain function, inflammation, and cellular signaling. The PDE4B(Phosphodiesterase 4B) gene is central to this, encoding an enzyme that breaks down cyclic adenosine monophosphate (cAMP), a vital secondary messenger in various physiological processes, including neuronal activity and immune responses. Variants such asrs7528604 , rs2310752 , rs3009872 , and rs6694912 within or near PDE4B may alter the enzyme’s activity or expression, thereby influencing intracellular cAMP levels.^[12]Dysregulation of cAMP signaling is strongly implicated in the pathophysiology of stress-related conditions like anxiety and depression, affecting neuroplasticity, neurotransmitter balance, and the body’s inflammatory response, thus modulating vulnerability to psychological stress.^[12] Other genes involved in gene regulation and cellular processes also contribute to stress response. PGBD1 (PiggyBac Transposase Derived 1) is thought to be involved in genome plasticity and potentially gene regulation, with variants like rs6905391 , rs6901575 , and rs34878803 possibly impacting its function. Such changes could influence how cells adapt to stress at a genomic level, affecting the stability or expression of genes critical for stress resilience.^[12] Similarly, ZSCAN31 (Zinc Finger And SCAN Domain Containing 31) is a transcription factor, meaning it helps regulate the expression of other genes. Variants rs853676 , rs853681 , and rs853679 in ZSCAN31, along with intergenic variants rs853685 , rs56075693 , and rs34218844 located between SMIM15P2 and ZSCAN31, could modify this gene’s regulatory activity. Altered ZSCAN31 function could lead to inappropriate gene expression in response to stress, affecting neural circuits and inflammatory pathways associated with stress-related disorders.^[12] Non-coding RNAs, which do not produce proteins but play vital regulatory roles, also represent a significant area of genetic influence on stress. NIHCOLE(Non-coding RNA in human brain with altered expression in depressive disorder) is a long non-coding RNA strongly implicated in brain function and mood disorders, with variants such asrs13166408 , rs1372500 , and rs35949602 directly impacting its regulation or function. Intergenic variants rs12658032 , rs1363105 , and rs13166522 found between NIHCOLE and RNU6-334P may also affect NIHCOLE’s expression, potentially altering its role in neural plasticity and stress adaptation.^[12] Another long intergenic non-coding RNA, LINC03003, harbors the variant rs144447022 . LincRNAs like LINC03003 are known to regulate gene expression through various mechanisms, and variations can disrupt these regulatory networks, thereby influencing an individual’s neurobiological response to stress and contributing to the risk of stress-related disorders.^[12] Further genetic contributions come from regions involving pseudogenes and genes with broader cellular functions. The intergenic variant rs113209956 , located between the RN7SKP120 pseudogene and TUSC1 (Tumor Suppressor Candidate 1), could influence the expression of TUSC1. While TUSC1 is primarily known for its role in cell growth and apoptosis, these processes are intricately linked to cellular stress responses, where genetic variations can affect cellular resilience and programmed cell death under duress.^[12] Lastly, the variant rs1458103 found in the intergenic region between pseudogenes COX6A1P4 and MTND4LP18 might indirectly impact mitochondrial function. Mitochondria are central to cellular energy production and are highly sensitive to stress; their dysfunction is a recognized factor in the development of various psychiatric and stress-related conditions, suggesting that variations in these regions could play a subtle yet significant role in modulating stress resilience.^[12]

Key Variants

RS ID	Gene	Related Traits
rs7528604 rs2310752 rs3009872	PDE4B	social inhibition quality, attention deficit hyperactivity disorder, substance abuse anxiety, stress-related disorder anxiety, stress-related disorder, major depressive disorder anxiety disorder, stress-related disorder stress-related disorder
rs6905391 rs6901575 rs34878803	PGBD1	major depressive disorder anxiety, stress-related disorder, major depressive disorder
rs853676 rs853681 rs853679	ZSCAN31	anxiety, stress-related disorder, major depressive disorder staphylococcus seropositivity anxiety, major depressive disorder major depressive disorder, COVID-19
rs853685 rs56075693 rs34218844	SMIM15P2 - ZSCAN31	anxiety, stress-related disorder, major depressive disorder gout
rs6694912	PDE4B	anxiety, stress-related disorder, major depressive disorder anxiety, stress-related disorder
rs12658032 rs1363105 rs13166522	NIHCOLE - RNU6-334P	anxiety, stress-related disorder, major depressive disorder major depressive disorder depressive symptom bipolar disorder, major depressive disorder stroke, major depressive disorder
rs113209956	RN7SKP120 - TUSC1	anxiety disorder, stress-related disorder
rs13166408 rs1372500 rs35949602	NIHCOLE	anxiety, stress-related disorder, major depressive disorder
rs1458103	COX6A1P4 - MTND4LP18	anxiety disorder, stress-related disorder
rs144447022	LINC03003	intelligence anxiety, stress-related disorder, major depressive disorder Inguinal hernia schizophrenia glomerular filtration rate, major depressive disorder

Stress related disorder encompasses a range of conditions characterized by significant distress and functional impairment following exposure to a stressor. While a precise overarching trait definition for ‘stress related disorder’ can vary, related concepts such as “anxiety” and “neuroticism score” are frequently studied as integral components or predisposing factors.^[13] Neuroticism, for instance, is a personality trait reflecting a predisposition to experience negative emotions, which can influence an individual’s vulnerability to stress-related conditions.^[14]Historically, more colloquial terms like “suffer from nerves” or “nervous feelings” were used to describe states now understood within the broader framework of anxiety and stress responses.^[14] The integration of these terms highlights an evolving understanding from descriptive symptomology to more defined psychological constructs.

Operational Definitions and Assessment of Stressors and Symptoms

Operational definitions are crucial for research and clinical practice, delineating how stress and its manifestations are identified and measured. For example, a specific stressor can be operationally defined as “Illness/injury/bereavement stress in last 2 years,” providing a clear, time-bound criterion for exposure.^[15]The assessment of associated symptoms often involves measuring constructs such as “depression score” or the “frequency of tiredness/lethargy in last 2 weeks”.^[16]Pain is another significant and frequently measured symptom, with specific assessments including “Neck or shoulder pain experienced in last month,” “Pain all over body,” “Stomach or abdominal pain,” and “Facial pain,” which can be exacerbated by or contribute to stress.^[15]approaches extend to cognitive functions, where tasks like the “3-back task” are used to assess working memory (WM), a function known to be impacted by anxiety and stress.^[13]

Classification and Frameworks

Classification systems for stress related disorder often involve both categorical and dimensional approaches, reflecting the complexity of these conditions. Categorical definitions might identify the presence or absence of a significant stressor, such as “Illness/injury/bereavement stress”.^[15] or the diagnosis of “long-standing illness/disability/infirmity”.^[15] or “Disability diagnosed by doctor”.^[14] which can be direct or indirect stress-related outcomes. Conversely, dimensional approaches utilize “scores,” such as “depression score” or “neuroticism score,” to quantify the severity or intensity of symptoms and traits, allowing for a more nuanced understanding of individual differences and symptom gradations.^[16]While specific biomarkers for stress related disorder are not detailed, the of various physical and psychological parameters, from subjective well-being (SWB) to specific pain reports, contributes to a comprehensive diagnostic and research picture.^[15]

Emotional and Cognitive Disturbances

Clinical presentation of stress-related disorders often manifests as significant emotional and cognitive disturbances. Individuals may report feeling overwhelmed by emotions, perceiving everyday situations as disasters or crises, and experiencing difficulty in making sound decisions when under emotional duress, indicative of emotion dysregulation.^[6] Specific to post-traumatic stress disorder (PTSD), symptoms include re-experiencing the traumatic event, active avoidance of reminders, and a state of hyperarousal.^[6]Depressive symptoms, such as a pervasive lack of positive affect or heightened negative affect, are also common clinical phenotypes.^[7] These subjective experiences are typically assessed using self-report measures like the 12-item Emotion Dysregulation Scale (EDS), scored on a 7-point Likert scale, which has demonstrated high internal consistency (α=0.94).^[6] The Modified PTSD Symptom Scale (mPSS), a 17-item self-report, further quantifies the frequency of PTSD symptoms over a two-week period.^[6]For depressive symptoms, the Japanese version of the Center for Epidemiologic Studies Depression Scale (CES-D) and the 21-item Beck Depression Inventory-II (BDI-II) are widely utilized screening and assessment tools.^[2]While symptom presentation can vary, some individuals who have experienced trauma may not exhibit significant distress or anxiety, resulting in a zero symptom count on scales like the mPSS.^[17] Despite similar average emotion dysregulation scores across sexes, research suggests that the underlying biological pathways for emotion regulation may differ between males and females, influencing symptom expression and diagnostic patterns.^[6] The diagnostic significance of these measures is high; for instance, the CES-D serves as a screening tool for major depression, and scores from the mPSS and BDI-II can inform DSM-IV-TR diagnoses for PTSD and depression, respectively.^[2] Furthermore, emotion dysregulation shows strong correlations with current depression (rpb = 0.54) and PTSD (r = 0.43), highlighting its diagnostic and prognostic value.^[6]

Behavioral and Somatic Presentations

Stress-related disorders often encompass a range of behavioral and somatic presentations that impact an individual’s daily functioning and overall health. Behavioral manifestations can include making poor decisions during periods of intense emotion, reflecting the cognitive and behavioral aspects of emotion dysregulation.^[6] Somatic complaints, such as those assessed by specific domains of the CES-D scale, are also a recognized phenotype.^[7] Functional impairment, a critical aspect of severity, can be objectively measured using instruments like the MOS 36-Item Short-Form Health Survey (SF-36) or its shorter version, the SF-12, which yield Mental Component Summary (MCS) and Physical Component Summary (PCS) scores.^[18] These measures assess an individual’s deviation from an expected functional impairment score given their psychiatric symptom severity, providing an index of functional risk or resilience.^[18]Inter-individual variability in presentation is notable; for example, within ostensibly healthy employee populations, depressive symptoms assessed by the CES-D may not follow a normal distribution, often peaking at the lower end of the score range.^[2]Such atypical distributions can influence the interpretation of symptom severity and diagnostic thresholds. Sex differences are also observed, with women being more predisposed to certain autoimmune disorders associated with inflammation, where disease severity can fluctuate with sex hormone status, suggesting a complex interplay between biological factors and stress-related somatic symptoms.^[6] A high score of 300 or more on a stressful life events scale is a significant red flag, indicating major stress and an 80% chance of developing illness or experiencing health changes, underscoring the prognostic significance of these presentations.^[2]

Physiological and Genetic Indicators of Stress Response

Beyond observable symptoms, stress-related disorders involve complex physiological responses and are increasingly understood through genetic and biochemical indicators. The body’s endocrine stress response is a key component, with genetic variations in genes such as COMT (catechol-O-methyltransferase) influencing its modulation.^[19] For instance, COMT genotype can predict cortical-limbic D1 receptor availability, as measured by positron emission tomography (PET) using [11C]NNC112, offering a more objective, biomarker-based assessment of stress-related neurobiology.^[19] Another promising candidate for stress-related disorders is RGS10, highlighted for its potential role in these conditions.^[2] Exposure to stressful life events is a fundamental aspect of diagnosis for many stress-related disorders, assessed through scales like the stressful life events and response to stressful-life-events scale.^[17] The severity of stress exposure can be quantified, with a score of 300 or higher on such scales being a critical diagnostic indicator of major stress, predicting an elevated risk of illness or health changes.^[2] Variability in stress response is influenced by factors such as age and sex, with analyses often adjusting for these demographics.^[7]The impact of sex hormone status on the severity of inflammation-related autoimmune conditions in women further exemplifies the biological heterogeneity in stress response.^[6] The identification of specific genetic variations, such as the SNP rs6602398 , which is associated with emotion dysregulation and significantly correlated with current depression and PTSD in traumatized populations, provides crucial diagnostic and prognostic insights into the genetic underpinnings of stress vulnerability.^[6]

The etiology of stress-related disorders is complex and multifactorial, involving an intricate interplay of genetic predispositions, environmental exposures, developmental experiences, and various modulating factors. These disorders do not typically arise from a single cause but rather from a convergence of vulnerabilities and triggers that cumulatively impact an individual’s capacity to cope with stress.

Genetic Predisposition and Neurobiological Pathways

Genetic predisposition plays a significant role in an individual’s vulnerability to stress-related disorders. Genome-wide association studies (GWAS) have identified various single nucleotide polymorphisms (SNPs) linked to major depression and its symptoms.^[2] though consistent susceptibility genes have been challenging to pinpoint across studies.^[2] For instance, the RGS10 gene has emerged as a promising candidate worthy of further investigation in the context of stress-related disorders.^[2] Beyond individual variants, the interplay between multiple genes, known as epistasis, contributes to susceptibility; for example, statistical epistasis between the COMT gene and polymorphisms in RGS4, G72, GRM3, and DISC1has been observed to influence the risk of schizophrenia.^[8] These genetic factors often impact neurobiological pathways that mediate stress responses. Polymorphic variations in genes like 5-HTT, COMT, and MAOA are involved in the genetic modulation of the endocrine stress response.^[20] with COMT genotype specifically predicting cortical-limbic D1 receptor availability.^[4] Such genetic variations can influence the brain’s resilience to stress, as molecular mechanisms underlie stress-induced impairment of the prefrontal cortex.^[5]External stressors, like noise, can directly impair prefrontal cortical cognitive function, highlighting the vulnerability of these neural circuits.^[21]

Environmental Stressors and Developmental Influences

Environmental stressors are pivotal in the development of stress-related disorders, with stressful life events (SLEs) being a well-established risk factor for conditions like depression.^[2] The severity and number of SLEs, such as the death of a spouse, divorce, or personal injury, exhibit a dose-response relationship with the onset of depressive episodes.^[2] While both recent and distal stressors contribute, events occurring within the past 12 months tend to have the most direct etiological relevance to depression onset, although effects from earlier events can accumulate.^[2] Chronic, seemingly minor stressors, such as the fear of unemployment, can also significantly contribute to an individual’s overall stress burden and subsequent health risks.^[2]Beyond acute events, broader environmental contexts and developmental experiences profoundly shape vulnerability to stress-related disorders. Socioeconomic factors, such as low income, are prevalent among populations studied for genetic risk in stress-related disorders.^[6] suggesting a link between social disadvantage and increased vulnerability. Furthermore, early life influences, including childhood adversity and other adverse events, are strongly associated with adult psychiatric disorders.^[22] These distal stressors can exert long-lasting effects on psychopathology throughout an individual’s life course, often acting additively with more recent stressful experiences to increase the overall risk.^[2]

Gene-Environment Interactions and Epigenetic Mechanisms

The development of stress-related disorders is often not solely attributable to genetic factors or environmental stressors in isolation, but rather emerges from complex gene-environment (G × E) interactions. Individual genetic vulnerabilities modulate an individual’s sensitivity and response to stressful events, meaning specific alleles or genotypes can make a person more or less susceptible to the effects of environmental triggers.^[2] A well-studied example is the polymorphism in the serotonin transporter gene (5-HTTLPR), which has been shown to moderate the influence of life stress on the risk of depression.^[23] Meta-analyses have further substantiated this interaction, confirming that the 5-HTTLPR gene, when combined with stressful life events, significantly impacts depression risk.^[24]These intricate G × E interactions can manifest through epigenetic mechanisms, which involve changes in gene expression without altering the underlying DNA sequence. Environmental stress, particularly chronic or severe exposure, can induce epigenetic modifications such as DNA methylation.^[2] These methylation changes, which can be differentially regulated, are increasingly recognized as a pathway through which life experiences, especially early life adversity, can lead to long-term alterations in stress response systems and increase the risk for disorders like depression.^[2] Understanding these mechanisms is crucial for elucidating how environmental factors leave a lasting biological imprint on an individual’s vulnerability to stress.

Other Modulating Factors

Beyond genetic and environmental influences, several other factors contribute to the manifestation and course of stress-related disorders. Comorbidity with other psychiatric conditions is a significant aspect, as emotion dysregulation, a common feature in stress responses, shows strong associations with current depression and post-traumatic stress disorder (PTSD) in populations with a history of trauma.^[6] These co-occurring conditions can exacerbate the burden of stress-related disorders and complicate treatment pathways.

Age also plays a role, with studies indicating a relationship between age and the prevalence of depressive symptoms and the impact of stressful events.^[2]Furthermore, sex-specific differences in biological pathways are evident, particularly in emotion regulation, which can influence vulnerability. For instance, women exhibit a higher propensity for certain autoimmune disorders linked to inflammation, where disease severity can fluctuate with sex hormone status, such as during pregnancy or menopause.^[6] These physiological distinctions highlight how biological sex can modulate an individual’s response to stress and the development of related disorders.^[6]

Stress-related disorders involve complex biological mechanisms spanning molecular, cellular, and systemic levels, often influenced by genetic predispositions and environmental interactions. These disorders are characterized by disruptions in neuroendocrine regulation, neurotransmitter balance, immune function, and brain circuitry, all contributing to altered physiological and psychological responses to stress.

Neuroendocrine and Immunological Pathways in Stress Response

The body’s primary response to stress is orchestrated by the hypothalamic-pituitary-adrenal (HPA) axis, a complex neuroendocrine system that regulates the release of glucocorticoid hormones like cortisol. Under chronic stress, the negative feedback mechanisms that normally regulate the HPA axis can become disrupted, leading to persistently elevated glucocorticoid concentrations, which can have neurotoxic effects and contribute to the onset of depression.^[25] Impaired function of the glucocorticoid receptor (GR), a key biomolecule in this axis, is also implicated in HPA axis hyperactivity observed in major depressive disorder (MDD).^[26]The steroid hormone receptor signaling pathway, which largely overlaps with the intracellular receptor mediated signaling pathway, is closely associated with the efficacy of antidepressant treatments.^[26] Beyond the HPA axis, systemic inflammation plays a significant role in stress-related disorders. Inflammatory cytokines, such as interleukin-6 (IL-6), are linked to MDD and can be elevated during stress, influencing neurobiological processes.^[9] Genetic variants in the interleukin 2 receptor alpha gene (IL2RA), for instance, are associated with emotion dysregulation, depression, post-traumatic stress disorder (PTSD), and an increased risk of suicide attempts.^[6] The interplay between inflammation and mood disorders is well-documented, with the inflammasome pathway specifically linking psychological stress, depression, and systemic illnesses.^[27]Furthermore, the severity of inflammation-associated autoimmune disorders, which women are more prone to develop, can vary with sex hormone status, suggesting sex-specific biological pathways in emotion regulation.^[6]

Genetic and Epigenetic Modulators of Stress Vulnerability

Individual differences in genetic vulnerability significantly influence whether exposure to stressful life events (SLEs) leads to the development of stress-related disorders like depression.^[2] This concept is central to gene-environment (GxE) interaction, where specific genetic variations can modify an individual’s sensitivity to environmental stressors.^[2] For example, polymorphisms in the serotonin transporter gene (5-HTT or SLC6A4) have been shown to moderate the impact of life stress on depression risk.^[23] Similarly, polymorphic variations in genes encoding catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAOA), along with 5-HTT, are involved in the genetic modulation of the endocrine stress response.^[20] Epistasis, or the interaction between multiple genes, also contributes to risk; for instance, COMT shows statistical epistasis with genes like RGS4, G72 (DAOA), GRM3, and DISC1in influencing the risk of schizophrenia.^[8] Beyond these well-studied genes, other candidate genes have emerged in the context of stress-related disorders. BDNF(brain-derived neurotrophic factor) is a recognized candidate gene for depression.^[2] RGS10 (Regulator of G-protein Signaling 10) has been highlighted as a promising candidate for stress-related disorders based on recent research.^[2] Additionally, a locus upstream of WFDC11 (WAP Four-Disulfide Core Domain 11) at 20q13.12, specifically rs6073833 , has been associated with psychological distress.^[9] The genetic landscape also includes transcription factors like ZNF354C, where variants are associated with depression induced by interferon-based therapy.^[25]Crucially, environmental stress can induce epigenetic modifications, such as DNA methylation changes, which are increasingly recognized for their role in the risk for stress-related disorders.^[2]

Neurotransmitter Systems and Brain Circuitry Dysfunction

Stress significantly impacts neurotransmitter systems and specific brain regions, particularly the prefrontal cortex, which is critical for cognitive function and emotion regulation. Molecular mechanisms underlying stress-induced prefrontal cortical impairment are a key area of study in mental illness.^[5]with research showing that even noise stress can impair prefrontal cortical cognitive function.^[21] The COMT genotype, which affects catecholamine metabolism, influences cortical-limbic D1 receptor availability, highlighting its role in modulating dopamine signaling in brain regions relevant to stress response.^[4] Impairment of extraneuronal uptake or catechol-O-methyl transferase can lead to supersensitivity to catecholamines, further disrupting neurotransmitter balance.^[28] The serotonin transporter (5-HTT) plays a vital role in serotonin reuptake, and its polymorphisms can influence susceptibility to depression under stressful conditions.^[23] Beyond monoamines, the amygdala, a brain region central to emotional responses, shows altered excitability and synaptic plasticity in stress-related disorders, with proteins like PAM (Peptidylglycine Alpha-Amidating Monooxygenase) acting as regulators of this excitability.^[26]Furthermore, the calcium signaling pathway is a crucial molecular mechanism implicated in the pathophysiology of various psychiatric disorders, including MDD, bipolar disorder, and schizophrenia.^[6] Genes within this pathway are associated with structural and functional brain circuitry, particularly those involved in emotion processing and executive functioning.^[6]

Cellular Homeostasis and Regulatory Networks

At the cellular level, stress can disrupt homeostatic processes and activate various regulatory networks. Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, is implicated in depressive disorders.^[29] The transcription regulatory factor ZBTB3 (Zinc Finger and BTB Domain-Containing Protein 3) is involved in the transcriptional regulation of antioxidative enzymes and potentially influences the ROS pathway, thereby playing a role in the cellular response to oxidative stress.^[25] ZBTB3 also interacts with the glucocorticoid receptor (GR) in hippocampal neurons to regulate gene transcription in a GR-dependent manner, linking cellular stress responses to neuroendocrine signaling.^[25] Disruptions in cellular regulatory networks can impact fundamental biological processes such as neurogenesis, the formation of new neurons, which is known to mediate the effects of antidepressants.^[26] Genes like UPF1 (Regulator Of Nonsense Transcripts Homolog), HMGB1 (High Mobility Group Box 1), and FOXC1 (Forkhead Box C1) are involved in the differentiation of neural stem cells into neurons and overall neural development, suggesting their potential role in stress-related neuroplasticity.^[26] Additionally, other signaling pathways such as platelet-derived growth factor (PDGF) signaling and peroxisome proliferator-activated receptor (PPAR) signaling have been linked to psychological distress and MDD, indicating a broader network of cellular regulatory mechanisms affected by stress.^[9]

Neuroendocrine and Receptor-Mediated Signaling

Stress-related disorders involve significant dysregulation of neuroendocrine axes, notably the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-thyroid (HPT) axis, particularly during repeated stress exposure.^[30]The HPA axis’s hyperfunction can lead to excessive cortisol levels, which is implicated in the pathogenesis of depression.^[31] These neuroendocrine systems are crucial for maintaining homeostasis, and their dysregulation represents a core mechanism in the pathophysiology of stress-related conditions.

Beyond adrenal and thyroid regulation, other receptor systems play critical roles in neuronal signaling and mood. Metabotropic glutamate receptors are pivotal in the control of mood disorders, with their activation leading to intracellular signaling cascades that can evoke calpain-mediated degradation of prominentSp-family transcription factors, Sp3 and Sp4, in neurons.^[32] Intracellular signaling cascades also involve a range of kinases, such as PI3K, PDK1, PKA, PKC, PKG, RTK, and STK, alongside phosphatases like PP2A and PP2C, which mediate diverse cellular responses.^[33] The transcription factor CREB (cAMP response element-binding protein) is recognized as a multifaceted regulator essential for neuronal plasticity and protection, influencing long-term cellular adaptations to stress.^[34]

Inflammatory and Immune System Pathways

Inflammation is a significant contributor to mood disorders and major depression, with studies highlighting the interactions between inflammatory processes and mood.^[27] Cytokines, as key mediators of immune responses, are directly linked to the pathology of major depression.^[35] The inflammasome, an intracellular protein complex, acts as a critical pathway linking psychological stress, depression, and broader systemic illnesses.^[36] The immune response also involves proteins like C-reactive protein, whose role is studied in conditions such as schizophrenia, indicating a broader involvement of immune markers in psychiatric disorders.^[37] Genetic variations, such as the C401T polymorphism in the kynurenine aminotransferase IIgene, have been associated with altered immune responses, for instance, in patients with meningitis, suggesting a genetic predisposition influencing immune function in disease contexts.^[38] This intricate interplay between the immune system and neurological function underscores the systemic nature of stress-related pathology.

Metabolic Reprogramming and Oxidative Stress

Metabolic pathways are profoundly impacted by stress, with the kynurenine pathway being a significant example where its metabolites play a role in central nervous system disorders.^[30]Key enzymes like kynurenine aminotransferases, whose structure, expression, and function have been characterized in human and rodent brains, regulate the flux through this pathway.^[39] The human gene encoding alpha-aminoadipate aminotransferase (AADAT) is also involved in kynurenine metabolism, further illustrating the complexity of these biochemical routes.^[40]Oxidative stress is another critical mechanism contributing to depressive disorders, involving an imbalance between reactive oxygen species production and antioxidant defenses.^[29] For instance, the differential transcriptional control of the superoxide dismutase-2 kappaB element in neurons and astrocytes highlights specific cellular responses to oxidative challenges.^[41] While common inherited variations in mitochondrial genes have not been consistently enriched for associations with type 2 diabetes or related glycemic traits, the overall integrity of mitochondrial function and energy metabolism remains crucial for cellular resilience under stress.^[42]

Cellular Stress Responses and Regulatory Mechanisms

Cellular stress responses, such as endoplasmic reticulum (ER) stress, are fundamental mechanisms implicated in neurodegeneration and potentially stress-related disorders.^[43] The accumulation of misfolded proteins within the ER triggers the unfolded protein response, a highly regulated adaptive pathway that, if overwhelmed, can lead to cell death.^[44]Protein modification and degradation pathways are also vital, as exemplified by glutamate receptor activation causing calpain-mediated degradation of transcription factorsSp3 and Sp4.^[41] Gene regulation is tightly controlled by various mechanisms, including the identification of ZNF354C variants associated with depression stemming from interferon-based therapy.^[25] POK transcriptional repressors also play a role in functional regulation.^[45] Furthermore, microRNAs and their effectors represent selective and common long-term targets for the actions of mood-altering interventions, indicating their importance in gene expression modulation.^[46] Calcium signaling, mediated by proteins like STIM1 which heteromultimerizes TRPC channels to form store-operated channels, and its partner POST that targets STIM1 to multiple transporters, forms a crucial network for cellular communication and response to stress.^[47] These interconnected pathways demonstrate the complex systems-level integration underlying the physiological and pathological responses to stress.

Prevalence and Longitudinal Patterns in Large Cohorts

Population studies have extensively investigated the prevalence and incidence of stress-related disorders and their correlates across diverse populations. Large-scale cohort studies, often leveraging biobank data and longitudinal designs, provide critical insights into the temporal patterns of these conditions. For instance, meta-analyses of genome-wide association studies (GWAS) have identified specific genetic loci associated with broad depression phenotypes, a common stress-related disorder.^[48] Such studies aggregate data from numerous European and American cohorts, including participants from institutions like the Erasmus University Medical Center, Columbia University, and the University of Helsinki, thereby enhancing statistical power and the generalizability of findings.^[48] Beyond direct disorder diagnoses, large cohorts also measure related factors such as “neuroticism,” “subjective well-being,” and self-reported stress levels (e.g., “no illness/injury/bereavement stress in last 2 years”), providing a comprehensive view of mental health indicators within the population.^[15] Further epidemiological investigations delve into the demographic and socioeconomic factors influencing these disorders. Studies examining sleep duration, a factor often impacted by stress, have been conducted across vast populations, such as a multi-ancestry analysis involving 126,926 individuals.^[49] These extensive analyses, drawing from populations spanning from Shanghai to Reykjavik and Amsterdam to New Orleans, allow for the examination of how sleep patterns, and by extension potentially stress-related health outcomes, vary across different demographic groups and geographic regions.^[49] The use of such large and diverse samples is crucial for identifying robust epidemiological associations and understanding the population-level burden of stress-related conditions.

Cross-Population Comparisons and Ancestry-Specific Effects

Understanding the genetic and environmental factors contributing to stress-related disorders necessitates cross-population comparisons and the investigation of ancestry-specific effects. Multi-ancestry genetic studies are increasingly employed to identify loci and interactions that might be stratified by specific population groups. For example, a multi-ancestry sleep-by-SNP interaction analysis involving over 126,000 individuals from diverse geographic locations, including those in China, Iceland, and various European and American sites, has uncovered lipid loci whose effects are dependent on sleep duration.^[49]While this study primarily focused on lipid metabolism, its multi-ancestry design and large sample size demonstrate the methodology applicable to investigating stress-related phenotypes and their genetic underpinnings across varied ancestral backgrounds. Similarly, meta-analyses for broad depression phenotypes have involved collaborations across numerous international institutions in Europe and the United States, allowing for a broader assessment of genetic associations that may hold across different populations or highlight population-specific variations.^[48] These efforts are vital for ensuring that research findings are broadly applicable and for identifying health disparities that may exist due to unique genetic or environmental exposures in different ethnic groups.

Methodological Considerations in Population-Level Studies

The robust understanding of stress-related disorders at the population level relies on sophisticated methodological approaches, including large-scale study designs and meticulous data collection. Genome-wide association studies (GWAS) and meta-analyses, often involving hundreds of thousands of individuals, are central to identifying genetic associations with complex traits like depression or related risk factors. For instance, analyses for broad depression phenotypes have aggregated data from multiple large cohorts, providing increased statistical power to detect associations.^[48]Such studies often involve participants from well-characterized population cohorts, like those contributing to studies on lipid levels and coronary heart disease risk across 16 European cohorts, demonstrating the collaborative infrastructure for large-scale genetic epidemiology.^[50]These studies carefully consider representativeness and generalizability by drawing samples from diverse populations and employing methodologically similar designs across contributing cohorts. For example, research into schizophrenia has utilized cases from three methodologically consistent National Institute of Mental Health repository-based studies, complemented by screened controls from the general population, ensuring a robust and comparable dataset.^[51] While these extensive sample sizes and multi-center collaborations enhance the power to detect subtle effects and improve generalizability, researchers also acknowledge the importance of consistent phenotyping, often relying on self-reported measures for traits like stress, neuroticism, or sleep duration, which requires careful interpretation.^[15]

These questions address the most important and specific aspects of stress related disorder based on current genetic research.

1. My parents are always stressed; will I be too?

Not necessarily, but you might have a higher predisposition. Your genetic makeup, including variations in genes like 5-HTT and COMT, can influence how your body and mind respond to stress. However, your own life experiences and how you cope with them (gene-environment interactions) play a significant role in whether you develop a stress-related disorder.

2. Why does stress make me so anxious but my friend is fine?

It’s likely due to differences in your genetic makeup and how those genes interact with your environment. For example, variations in the 5-HTTLPR region of the 5-HTTgene can make some people more sensitive to the impact of life stress, leading to a stronger anxiety response compared to others with different genetic variants.

3. Can my constant work stress really make me sick physically?

Yes, it absolutely can. Chronic stress isn’t just mental; it can influence the onset of various chronic physical diseases. Your genetic predisposition, combined with ongoing stressful life events, can lead to biological changes, including epigenetic modifications, that increase your risk for physical health problems over time.

4. After a bad event, why do I struggle with my thoughts more than others?

Your individual genetic makeup can significantly influence how you process and recover from traumatic events. Specific genetic variants can modulate the severity and onset of conditions like PTSD or depression after stress exposure, making some people more vulnerable to persistent intrusive thoughts or emotional dysregulation than others.

5. Why do I struggle to focus when I’m feeling stressed?

Stress can actually impair your brain’s prefrontal cortical cognitive function, which is responsible for things like focus and decision-making. Certain genetic variations, such as those in genes likeCOMT, can influence how your brain responds to stress, potentially making you more susceptible to these cognitive difficulties.

6. Does my family’s background affect my risk for stress problems?

Yes, your genetic ancestry can play a role. Research in diverse populations, including Japanese and African American cohorts, has identified specific genetic loci associated with psychological distress and depression. These population-specific genetic risks mean that your background might influence your unique susceptibility and how you respond to stress.

7. Can my daily habits actually change how my stress genes work?

In a way, yes! Your environment and daily habits can cause epigenetic changes, like DNA methylation, which can alter how your genes are expressed without changing the DNA sequence itself. This means that while your genes don’t change, how they “turn on or off” in response to stress can be influenced by your lifestyle.

8. My sibling handles stress well, but I don’t. Why the difference?

Even within the same family, individual genetic variations and unique life experiences lead to different stress responses. You and your sibling inherit different combinations of genes, and these subtle differences, along with your distinct personal histories, contribute to how resilient or vulnerable each of you is to stress.

9. Can I do anything to prevent stress disorders if they run in my family?

Absolutely. While you can’t change your genes, understanding your genetic predispositions allows for more targeted prevention. Focusing on stress management techniques, seeking support, and maintaining a healthy lifestyle can positively influence gene-environment interactions, potentially mitigating your inherited risk.

10. Is it true that stress can make me feel emotionally out of control?

Yes, stress can definitely contribute to feeling emotionally dysregulated. Genetic variations, such as specific SNPs like rs6602398 in the IL2RA gene, have been linked to emotion dysregulation, especially when combined with stressful experiences. These genetic factors can influence how your brain processes and manages emotions under pressure.

This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

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