Approved Research

Understanding brain structure and function as an intermediary phenotype to chronic pain

Lay summary

Patients suffering from chronic pain commonly report emotional distress due to their pain. As a result, chronic pain patients are at risk for developing a variety of disorders including depression, anxiety, and addictive behaviours. They are also at risk of poor health behaviours, such as physical inactivity, malnutrition, substance use, and poor sleep that may contribute to the maintenance or worsening of their pain.

Investigating the role of these accompanying conditions, each with distinct genetic predispositions, is therefore crucial to understand brain structure and function as an intermediary phenotype to chronic pain. This will be done by incorporating these various disorders, mood-related measures, and health behaviours in one overarching burden score of pain and its chronicity. The proposed data request will include online follow-up questionnaires (mental health and pain-related measure), as well as common medical and health-related measures (general health, blood pressure, diagnosis, among others).

Scope extension:

It is known that 50-70% of chronic pain patients complain about poor sleep quality. A circular relationship is suggested between poor sleep and more pain. Given the important overlap between sleep disturbances and chronic pain, it is crucial to identify genetic etiology behind this interaction. Recently, we discovered genome-wide associations with sleep, pain and various related phenotypes, including anxiety. In this context we are seeking a replication study to analyse the interaction between sleep, pain, anxiety and genetic variants. We seek an opportunity to evaluate these associations in the UK biobank resources. Preliminary analyses have shown that the relationship between pain and sleep is mediated with tobacco use. While a number of demographic and psychosocial factors have been proposed to account for the association between smoking, sleep disturbances and these negative clinical pain outcomes, there is reason to believe that biological factors might also play a role. The requested data will permit examination of the genetic mechanisms that might underlie the link between smoking, sleep and chronic pain.

Previous studies have attempted to clarify the role of brain structure and function in chronic pain. Reviews of the pain-related brain imaging literature often reveal overlapping, but inconsistent findings as illustrated by one recent chronic low back pain brain imaging review by Kregel et al., 2015 (https://doi.org/10.1016/j.semarthrit.2015.05.002). We propose the inconsistencies are a function of studies being underpowered and not taking into account the phenotype and genotype of the subjects. With the addition of the requested data the association between pain, genotype and comorbidities will be investigated using brain structure and function as intermediate phenotypes. Positioned as intermediate phenotypes, we believe that brain structure and function will assist in clarifying the relationships between pain, genotype and comorbidities. These comorbidities include depression, anxiety, body mass index and sleep.

While associations of air pollution with diseases of the respiratory system are well known, air pollution damage has also been observed for outcomes across multiple organ systems, where these effects may be indirect such as through inflammatory processes, impacting on autoimmune diseases for example. Research over the last 15 years has pointed to air pollution as a risk factor for neurological diseases and neuropathy, including through neuro-inflammation and auto-antibody production. Specifically relating to pain outcomes, one study reported on an association between air pollution and abdominal pain.

Rural and urban environment may also serve to broadly classify subjects according to differences in environmental exposures, including air pollution. When considering chronic pain outcomes, however, the psychological effects of rural or urban environment may also play a role: a previous study found higher levels of chronic pain reporting among rural compared to urban participants, where the presence of greater distraction in an urban environment was thought to underlie these differences given the role of attention on symptom reporting.

Both genetic and epigenetic factors have been implicated in differential susceptibility to air pollution on health outcomes. Our previous work using a genomewide association study (GWAS) approach to identify the genetic basis for chronic pain development has revealed intriguing links among autoimmune diseases and chronic pain. Drawing on UKB data among white British subjects, both our own GWAS results, as well as published results from an independent research group focused on multisite chronic pain (MCP) have pointed to autoimmune conditions, specifically asthma, as displaying a high genetic correlation with development of chronic pain. We are therefore particularly interested in further characterizing the specific molecular underpinnings of these genomewide-level observations. Given that chronic pain is often managed through medications, which in turn impacts on pain experience, in the original application, we requested and were granted access to medication data, specifically items under Field 20003. We now also require related data-field "Number of treatments/medications taken". This variable will allow for the proper classification of study subjects as taking a particular medication or not taking any medication at all, or as missing. Further, a recent randomized clinical trial (that was not considered previously) showed higher analgesic efficacy for chronic back pain patients taking antibiotics compared with placebo, suggesting that antibiotics may be an effective treatment where the pain is secondary to a herniated disc condition, we also request variables describing antibiotic medications taken.  We request blood biochemistry and urine assays data for the exploration of these variables as potential mediators in fine causal investigation analyses following first pass GWAS study results of chronic pain. We are particularly interested in immune-related variables, e.g. C-reactive protein, an indicator of inflammation.

Patients suffering from chronic pain commonly report emotional distress due to their pain. As a result, chronic pain patients are at risk for developing a variety of disorders including depression, anxiety, and addictive behaviours. They are also at risk of poor health behaviours, such as physical inactivity, malnutrition, substance use, and poor sleep that may contribute to the maintenance or worsening of their pain. Investigating the role of these accompanying conditions, each with distinct genetic predispositions, is therefore crucial to understand brain structure and function as an intermediary phenotype to chronic pain. This will be done by incorporating these various disorders, mood-related measures, and health behaviours in one overarching burden score of pain and its chronicity. The proposed data request will include online follow-up questionnaires (mental health and pain-related measure), as well as common medical and health-related measures (general health, blood pressure, diagnosis, among others).

In Canada, it is estimated that approximately 20% of the population is currently suffering from a chronic pain condition. However, the level of disability is not only associated with pain, but with other symptoms such as fatigue, sleep disorders, and mood disturbances. In particular, cognitive impairment, which are difficulties in processes such as concentrating, making decisions or remembering events, is characteristic of individuals with chronic pain. Research conducted over the last couple of decades has provided evidence of cognitive impairment in people with chronic pain. However, despite patient complaints, until recently, there has been limited discussion and no systematic evaluation of the body of literature concerning cognitive impairment across chronic pain syndromes. Nor have modern meta-analytical methods been used to clarify and classify the extent to which and how cognition may be impaired among various chronic pain conditions. Seeing as though chronic pain is made of more than just physical pain, in order to aid in treatment efficacy as well as the development of novel therapeutics, factors contributing to the reduced functionality and persistence of disability and pain, such as dyscognition, must be understood and considered.

NEW SCOPE

It is known that the itch sensation travels through DRG; all conditions have itch in common. This is the broader context of deciphering the genetics of pain in various cell types in DRG. Based on the results from a recent study suggesting that the use of NSAIDs as being a risk factor for developing chronic pain [PMID 35544595] and that a low neutrophil count was also associated with higher incidence of chronic pain we aim to investigate how physical activity affects neutrophil count and the risk of developing chronic pain and NSAID-induced chronic pain, also looking at how exercise intensity might influence these findings.

Further scope extension:

It is known that 50-70% of chronic pain patients complain about poor sleep quality. A circular relationship is suggested between poor sleep and more pain. Given the important overlap between sleep disturbances and chronic pain, it is crucial to identify genetic etiology behind this interaction. Recently, we discovered genome-wide associations with sleep, pain and various related phenotypes, including anxiety. In this context we are seeking a replication study to analyse the interaction between sleep, pain, anxiety and genetic variants. We seek an opportunity to evaluate these associations in the UK biobank resources. Preliminary analyses have shown that the relationship between pain and sleep is mediated with tobacco use. While a number of demographic and psychosocial factors have been proposed to account for the association between smoking, sleep disturbances and these negative clinical pain outcomes, there is reason to believe that biological factors might also play a role. The requested data will permit examination of the genetic mechanisms that might underlie the link between smoking, sleep and chronic pain.

Previous studies have attempted to clarify the role of brain structure and function in chronic pain. Reviews of the pain-related brain imaging literature often reveal overlapping, but inconsistent findings as illustrated by one recent chronic low back pain brain imaging review by Kregel et al., 2015 (https://doi.org/10.1016/j.semarthrit.2015.05.002). We propose the inconsistencies are a function of studies being underpowered and not taking into account the phenotype and genotype of the subjects. With the addition of the requested data the association between pain, genotype and comorbidities will be investigated using brain structure and function as intermediate phenotypes. Positioned as intermediate phenotypes, we believe that brain structure and function will assist in clarifying the relationships between pain, genotype and comorbidities. These comorbidities include depression, anxiety, body mass index and sleep.

While associations of air pollution with diseases of the respiratory system are well known, air pollution damage has also been observed for outcomes across multiple organ systems, where these effects may be indirect such as through inflammatory processes, impacting on autoimmune diseases for example. Research over the last 15 years has pointed to air pollution as a risk factor for neurological diseases and neuropathy, including through neuro-inflammation and auto-antibody production. Specifically relating to pain outcomes, one study reported on an association between air pollution and abdominal pain.

Rural and urban environment may also serve to broadly classify subjects according to differences in environmental exposures, including air pollution. When considering chronic pain outcomes, however, the psychological effects of rural or urban environment may also play a role: a previous study found higher levels of chronic pain reporting among rural compared to urban participants, where the presence of greater distraction in an urban environment was thought to underlie these differences given the role of attention on symptom reporting.

Both genetic and epigenetic factors have been implicated in differential susceptibility to air pollution on health outcomes. Our previous work using a genomewide association study (GWAS) approach to identify the genetic basis for chronic pain development has revealed intriguing links among autoimmune diseases and chronic pain. Drawing on UKB data among white British subjects, both our own GWAS results, as well as published results from an independent research group focused on multisite chronic pain (MCP) have pointed to autoimmune conditions, specifically asthma, as displaying a high genetic correlation with development of chronic pain. We are therefore particularly interested in further characterizing the specific molecular underpinnings of these genomewide-level observations. Given that chronic pain is often managed through medications, which in turn impacts on pain experience, in the original application, we requested and were granted access to medication data, specifically items under Field 20003. We now also require related data-field "Number of treatments/medications taken". This variable will allow for the proper classification of study subjects as taking a particular medication or not taking any medication at all, or as missing. Further, a recent randomized clinical trial (that was not considered previously) showed higher analgesic efficacy for chronic back pain patients taking antibiotics compared with placebo, suggesting that antibiotics may be an effective treatment where the pain is secondary to a herniated disc condition, we also request variables describing antibiotic medications taken.  We request blood biochemistry and urine assays data for the exploration of these variables as potential mediators in fine causal investigation analyses following first pass GWAS study results of chronic pain. We are particularly interested in immune-related variables, e.g. C-reactive protein, an indicator of inflammation.

Patients suffering from chronic pain commonly report emotional distress due to their pain. As a result, chronic pain patients are at risk for developing a variety of disorders including depression, anxiety, and addictive behaviours. They are also at risk of poor health behaviours, such as physical inactivity, malnutrition, substance use, and poor sleep that may contribute to the maintenance or worsening of their pain. Investigating the role of these accompanying conditions, each with distinct genetic predispositions, is therefore crucial to understand brain structure and function as an intermediary phenotype to chronic pain. This will be done by incorporating these various disorders, mood-related measures, and health behaviours in one overarching burden score of pain and its chronicity. The proposed data request will include online follow-up questionnaires (mental health and pain-related measure), as well as common medical and health-related measures (general health, blood pressure, diagnosis, among others).

In Canada, it is estimated that approximately 20% of the population is currently suffering from a chronic pain condition. However, the level of disability is not only associated with pain, but with other symptoms such as fatigue, sleep disorders, and mood disturbances. In particular, cognitive impairment, which are difficulties in processes such as concentrating, making decisions or remembering events, is characteristic of individuals with chronic pain. Research conducted over the last couple of decades has provided evidence of cognitive impairment in people with chronic pain. However, despite patient complaints, until recently, there has been limited discussion and no systematic evaluation of the body of literature concerning cognitive impairment across chronic pain syndromes. Nor have modern meta-analytical methods been used to clarify and classify the extent to which and how cognition may be impaired among various chronic pain conditions. Seeing as though chronic pain is made of more than just physical pain, in order to aid in treatment efficacy as well as the development of novel therapeutics, factors contributing to the reduced functionality and persistence of disability and pain, such as dyscognition, must be understood and considered.

It is known that the itch sensation travels through DRG; all conditions have itch in common. This is the broader context of deciphering the genetics of pain in various cell types in DRG. Based on the results from a recent study suggesting that the use of NSAIDs as being a risk factor for developing chronic pain [PMID 35544595] and that a low neutrophil count was also associated with higher incidence of chronic pain we aim to investigate how physical activity affects neutrophil count and the risk of developing chronic pain and NSAID-induced chronic pain, also looking at how exercise intensity might influence these findings.

NEW SCOPE Apart from mental comorbidities, numerous physical comorbidities, including respiratory diseases, heart diseases, Thyroid conditions, diabetes, etc., have been proposed to explain the development of chronic pain in the general population. The available literature seems to strongly suggest an association between accumulated comorbid load and chronic pain (Dominick, Blyth et al. 2012).  Also, interestingly, large population-based studies have shown that chronic pain is associated with an increased prevalence of cardiovascular risk factors and metabolic syndrome (Goodson, Smith et al. 2013).  Overall, the characteristics of certain detectable metabolites can help identify biochemical molecules that distinguish the state of a disease, which could in turn, cause chronic pain.

We intend to look at the electronic health record to discover lifelong diseases and their onset, as well as the whole physical profile of an individual as contributing risk factors. We then intend to use participant's physical examination across various physiological systems to validate the etiology of their illnesses and relate them as contributors to the onset of chronic pain, and more specifically, chronic widespread pain.

Altogether we hope to better characterize factors that shape the expression of chronic non-musculoskeletal widespread pain conditions in the general population.

Scope extension:

It is known that 50-70% of chronic pain patients complain about poor sleep quality. A circular relationship is suggested between poor sleep and more pain. Given the important overlap between sleep disturbances and chronic pain, it is crucial to identify genetic etiology behind this interaction. Recently, we discovered genome-wide associations with sleep, pain and various related phenotypes, including anxiety. In this context we are seeking a replication study to analyse the interaction between sleep, pain, anxiety and genetic variants. We seek an opportunity to evaluate these associations in the UK biobank resources. Preliminary analyses have shown that the relationship between pain and sleep is mediated with tobacco use. While a number of demographic and psychosocial factors have been proposed to account for the association between smoking, sleep disturbances and these negative clinical pain outcomes, there is reason to believe that biological factors might also play a role. The requested data will permit examination of the genetic mechanisms that might underlie the link between smoking, sleep and chronic pain.

Previous studies have attempted to clarify the role of brain structure and function in chronic pain. Reviews of the pain-related brain imaging literature often reveal overlapping, but inconsistent findings as illustrated by one recent chronic low back pain brain imaging review by Kregel et al., 2015 (https://doi.org/10.1016/j.semarthrit.2015.05.002). We propose the inconsistencies are a function of studies being underpowered and not taking into account the phenotype and genotype of the subjects. With the addition of the requested data the association between pain, genotype and comorbidities will be investigated using brain structure and function as intermediate phenotypes. Positioned as intermediate phenotypes, we believe that brain structure and function will assist in clarifying the relationships between pain, genotype and comorbidities. These comorbidities include depression, anxiety, body mass index and sleep.

While associations of air pollution with diseases of the respiratory system are well known, air pollution damage has also been observed for outcomes across multiple organ systems, where these effects may be indirect such as through inflammatory processes, impacting on autoimmune diseases for example. Research over the last 15 years has pointed to air pollution as a risk factor for neurological diseases and neuropathy, including through neuro-inflammation and auto-antibody production. Specifically relating to pain outcomes, one study reported on an association between air pollution and abdominal pain.

Rural and urban environment may also serve to broadly classify subjects according to differences in environmental exposures, including air pollution. When considering chronic pain outcomes, however, the psychological effects of rural or urban environment may also play a role: a previous study found higher levels of chronic pain reporting among rural compared to urban participants, where the presence of greater distraction in an urban environment was thought to underlie these differences given the role of attention on symptom reporting.

Both genetic and epigenetic factors have been implicated in differential susceptibility to air pollution on health outcomes. Our previous work using a genomewide association study (GWAS) approach to identify the genetic basis for chronic pain development has revealed intriguing links among autoimmune diseases and chronic pain. Drawing on UKB data among white British subjects, both our own GWAS results, as well as published results from an independent research group focused on multisite chronic pain (MCP) have pointed to autoimmune conditions, specifically asthma, as displaying a high genetic correlation with development of chronic pain. We are therefore particularly interested in further characterizing the specific molecular underpinnings of these genomewide-level observations. Given that chronic pain is often managed through medications, which in turn impacts on pain experience, in the original application, we requested and were granted access to medication data, specifically items under Field 20003. We now also require related data-field "Number of treatments/medications taken". This variable will allow for the proper classification of study subjects as taking a particular medication or not taking any medication at all, or as missing. Further, a recent randomized clinical trial (that was not considered previously) showed higher analgesic efficacy for chronic back pain patients taking antibiotics compared with placebo, suggesting that antibiotics may be an effective treatment where the pain is secondary to a herniated disc condition, we also request variables describing antibiotic medications taken.  We request blood biochemistry and urine assays data for the exploration of these variables as potential mediators in fine causal investigation analyses following first pass GWAS study results of chronic pain. We are particularly interested in immune-related variables, e.g. C-reactive protein, an indicator of inflammation.

Patients suffering from chronic pain commonly report emotional distress due to their pain. As a result, chronic pain patients are at risk for developing a variety of disorders including depression, anxiety, and addictive behaviours. They are also at risk of poor health behaviours, such as physical inactivity, malnutrition, substance use, and poor sleep that may contribute to the maintenance or worsening of their pain. Investigating the role of these accompanying conditions, each with distinct genetic predispositions, is therefore crucial to understand brain structure and function as an intermediary phenotype to chronic pain. This will be done by incorporating these various disorders, mood-related measures, and health behaviours in one overarching burden score of pain and its chronicity. The proposed data request will include online follow-up questionnaires (mental health and pain-related measure), as well as common medical and health-related measures (general health, blood pressure, diagnosis, among others).

In Canada, it is estimated that approximately 20% of the population is currently suffering from a chronic pain condition. However, the level of disability is not only associated with pain, but with other symptoms such as fatigue, sleep disorders, and mood disturbances. In particular, cognitive impairment, which are difficulties in processes such as concentrating, making decisions or remembering events, is characteristic of individuals with chronic pain. Research conducted over the last couple of decades has provided evidence of cognitive impairment in people with chronic pain. However, despite patient complaints, until recently, there has been limited discussion and no systematic evaluation of the body of literature concerning cognitive impairment across chronic pain syndromes. Nor have modern meta-analytical methods been used to clarify and classify the extent to which and how cognition may be impaired among various chronic pain conditions. Seeing as though chronic pain is made of more than just physical pain, in order to aid in treatment efficacy as well as the development of novel therapeutics, factors contributing to the reduced functionality and persistence of disability and pain, such as dyscognition, must be understood and considered.

It is known that the itch sensation travels through DRG; all conditions have itch in common. This is the broader context of deciphering the genetics of pain in various cell types in DRG. Based on the results from a recent study suggesting that the use of NSAIDs as being a risk factor for developing chronic pain [PMID 35544595] and that a low neutrophil count was also associated with higher incidence of chronic pain we aim to investigate how physical activity affects neutrophil count and the risk of developing chronic pain and NSAID-induced chronic pain, also looking at how exercise intensity might influence these findings.

Apart from mental comorbidities, numerous physical comorbidities, including respiratory diseases, heart diseases, Thyroid conditions, diabetes, etc., have been proposed to explain the development of chronic pain in the general population. The available literature seems to strongly suggest an association between accumulated comorbid load and chronic pain (Dominick, Blyth et al. 2012).  Also, interestingly, large population-based studies have shown that chronic pain is associated with an increased prevalence of cardiovascular risk factors and metabolic syndrome (Goodson, Smith et al. 2013).  Overall, the characteristics of certain detectable metabolites can help identify biochemical molecules that distinguish the state of a disease, which could in turn, cause chronic pain.

We intend to look at the electronic health record to discover lifelong diseases and their onset, as well as the whole physical profile of an individual as contributing risk factors. We then intend to use participant's physical examination across various physiological systems to validate the etiology of their illnesses and relate them as contributors to the onset of chronic pain, and more specifically, chronic widespread pain.

Altogether we hope to better characterize factors that shape the expression of chronic non-musculoskeletal widespread pain conditions in the general population.

NEW SCOPE

We wish to extend our genetic studies of chronic pain and related conditions by considering family history information. Specifically, incorporating first degree relative family history variables of primary cases into a genomewide association (GWA) study framework for polygenic risk score (PRS) development may increase the predictive power of chronic pain condition modeling. A recent UK Biobank-based PRS study of three well-powered common diseases, type II diabetes, hypertension and depression, showed that incorporating family history (via a method named PRS-FH) led to a doubling of prediction R^2 compared to disease-specific PRS alone. To follow the scheme as proposed by this previous study would require chronic pain family history per se, which is not available in the UK Biobank. Nonetheless, another approach might be to consider conditions for which family history data is available and for which there is a high genetic correlation with chronic pain conditions. A GWA study of the most highly powered multisite chronic pain (MCP) phenotype, also drawing on the UKB, has shown that among other traits studied, highest genetic correlation for MCP was estimated for the category psychiatric traits, with major depressive disorder (MDD) coming out on top (rg = 0.53; SE = 0.03)(2). We therefore wish to adapt PRS-FH to the prediction of chronic pain conditions, including body-site specific chronic pain and multisite chronic pain (MCP) by including MDD (and possibly other conditions) into the model.

Further scope extension:

It is known that 50-70% of chronic pain patients complain about poor sleep quality. A circular relationship is suggested between poor sleep and more pain. Given the important overlap between sleep disturbances and chronic pain, it is crucial to identify genetic etiology behind this interaction. Recently, we discovered genome-wide associations with sleep, pain and various related phenotypes, including anxiety. In this context we are seeking a replication study to analyse the interaction between sleep, pain, anxiety and genetic variants. We seek an opportunity to evaluate these associations in the UK biobank resources. Preliminary analyses have shown that the relationship between pain and sleep is mediated with tobacco use. While a number of demographic and psychosocial factors have been proposed to account for the association between smoking, sleep disturbances and these negative clinical pain outcomes, there is reason to believe that biological factors might also play a role. The requested data will permit examination of the genetic mechanisms that might underlie the link between smoking, sleep and chronic pain.

Previous studies have attempted to clarify the role of brain structure and function in chronic pain. Reviews of the pain-related brain imaging literature often reveal overlapping, but inconsistent findings as illustrated by one recent chronic low back pain brain imaging review by Kregel et al., 2015 (https://doi.org/10.1016/j.semarthrit.2015.05.002). We propose the inconsistencies are a function of studies being underpowered and not taking into account the phenotype and genotype of the subjects. With the addition of the requested data the association between pain, genotype and comorbidities will be investigated using brain structure and function as intermediate phenotypes. Positioned as intermediate phenotypes, we believe that brain structure and function will assist in clarifying the relationships between pain, genotype and comorbidities. These comorbidities include depression, anxiety, body mass index and sleep.

While associations of air pollution with diseases of the respiratory system are well known, air pollution damage has also been observed for outcomes across multiple organ systems, where these effects may be indirect such as through inflammatory processes, impacting on autoimmune diseases for example. Research over the last 15 years has pointed to air pollution as a risk factor for neurological diseases and neuropathy, including through neuro-inflammation and auto-antibody production. Specifically relating to pain outcomes, one study reported on an association between air pollution and abdominal pain.

Rural and urban environment may also serve to broadly classify subjects according to differences in environmental exposures, including air pollution. When considering chronic pain outcomes, however, the psychological effects of rural or urban environment may also play a role: a previous study found higher levels of chronic pain reporting among rural compared to urban participants, where the presence of greater distraction in an urban environment was thought to underlie these differences given the role of attention on symptom reporting.

Both genetic and epigenetic factors have been implicated in differential susceptibility to air pollution on health outcomes. Our previous work using a genomewide association study (GWAS) approach to identify the genetic basis for chronic pain development has revealed intriguing links among autoimmune diseases and chronic pain. Drawing on UKB data among white British subjects, both our own GWAS results, as well as published results from an independent research group focused on multisite chronic pain (MCP) have pointed to autoimmune conditions, specifically asthma, as displaying a high genetic correlation with development of chronic pain. We are therefore particularly interested in further characterizing the specific molecular underpinnings of these genomewide-level observations. Given that chronic pain is often managed through medications, which in turn impacts on pain experience, in the original application, we requested and were granted access to medication data, specifically items under Field 20003. We now also require related data-field "Number of treatments/medications taken". This variable will allow for the proper classification of study subjects as taking a particular medication or not taking any medication at all, or as missing. Further, a recent randomized clinical trial (that was not considered previously) showed higher analgesic efficacy for chronic back pain patients taking antibiotics compared with placebo, suggesting that antibiotics may be an effective treatment where the pain is secondary to a herniated disc condition, we also request variables describing antibiotic medications taken.  We request blood biochemistry and urine assays data for the exploration of these variables as potential mediators in fine causal investigation analyses following first pass GWAS study results of chronic pain. We are particularly interested in immune-related variables, e.g. C-reactive protein, an indicator of inflammation.

Patients suffering from chronic pain commonly report emotional distress due to their pain. As a result, chronic pain patients are at risk for developing a variety of disorders including depression, anxiety, and addictive behaviours. They are also at risk of poor health behaviours, such as physical inactivity, malnutrition, substance use, and poor sleep that may contribute to the maintenance or worsening of their pain. Investigating the role of these accompanying conditions, each with distinct genetic predispositions, is therefore crucial to understand brain structure and function as an intermediary phenotype to chronic pain. This will be done by incorporating these various disorders, mood-related measures, and health behaviours in one overarching burden score of pain and its chronicity. The proposed data request will include online follow-up questionnaires (mental health and pain-related measure), as well as common medical and health-related measures (general health, blood pressure, diagnosis, among others).

In Canada, it is estimated that approximately 20% of the population is currently suffering from a chronic pain condition. However, the level of disability is not only associated with pain, but with other symptoms such as fatigue, sleep disorders, and mood disturbances. In particular, cognitive impairment, which are difficulties in processes such as concentrating, making decisions or remembering events, is characteristic of individuals with chronic pain. Research conducted over the last couple of decades has provided evidence of cognitive impairment in people with chronic pain. However, despite patient complaints, until recently, there has been limited discussion and no systematic evaluation of the body of literature concerning cognitive impairment across chronic pain syndromes. Nor have modern meta-analytical methods been used to clarify and classify the extent to which and how cognition may be impaired among various chronic pain conditions. Seeing as though chronic pain is made of more than just physical pain, in order to aid in treatment efficacy as well as the development of novel therapeutics, factors contributing to the reduced functionality and persistence of disability and pain, such as dyscognition, must be understood and considered.

It is known that the itch sensation travels through DRG; all conditions have itch in common. This is the broader context of deciphering the genetics of pain in various cell types in DRG. Based on the results from a recent study suggesting that the use of NSAIDs as being a risk factor for developing chronic pain [PMID 35544595] and that a low neutrophil count was also associated with higher incidence of chronic pain we aim to investigate how physical activity affects neutrophil count and the risk of developing chronic pain and NSAID-induced chronic pain, also looking at how exercise intensity might influence these findings.

Apart from mental comorbidities, numerous physical comorbidities, including respiratory diseases, heart diseases, Thyroid conditions, diabetes, etc., have been proposed to explain the development of chronic pain in the general population. The available literature seems to strongly suggest an association between accumulated comorbid load and chronic pain (Dominick, Blyth et al. 2012).  Also, interestingly, large population-based studies have shown that chronic pain is associated with an increased prevalence of cardiovascular risk factors and metabolic syndrome (Goodson, Smith et al. 2013).  Overall, the characteristics of certain detectable metabolites can help identify biochemical molecules that distinguish the state of a disease, which could in turn, cause chronic pain.

We intend to look at the electronic health record to discover lifelong diseases and their onset, as well as the whole physical profile of an individual as contributing risk factors. We then intend to use participant's physical examination across various physiological systems to validate the etiology of their illnesses and relate them as contributors to the onset of chronic pain, and more specifically, chronic widespread pain.

Altogether we hope to better characterize factors that shape the expression of chronic non-musculoskeletal widespread pain conditions in the general population.

We wish to extend our genetic studies of chronic pain and related conditions by considering family history information. Specifically, incorporating first degree relative family history variables of primary cases into a genomewide association (GWA) study framework for polygenic risk score (PRS) development may increase the predictive power of chronic pain condition modeling. A recent UK Biobank-based PRS study of three well-powered common diseases, type II diabetes, hypertension and depression, showed that incorporating family history (via a method named PRS-FH) led to a doubling of prediction R^2 compared to disease-specific PRS alone. To follow the scheme as proposed by this previous study would require chronic pain family history per se, which is not available in the UK Biobank. Nonetheless, another approach might be to consider conditions for which family history data is available and for which there is a high genetic correlation with chronic pain conditions. A GWA study of the most highly powered multisite chronic pain (MCP) phenotype, also drawing on the UKB, has shown that among other traits studied, highest genetic correlation for MCP was estimated for the category psychiatric traits, with major depressive disorder (MDD) coming out on top (rg = 0.53; SE = 0.03)(2). We therefore wish to adapt PRS-FH to the prediction of chronic pain conditions, including body-site specific chronic pain and multisite chronic pain (MCP) by including MDD (and possibly other conditions) into the model.

NEW SCOPE

To deepen the understanding of the complex biological mechanisms involved in chronic pain conditions such as fibromyalgia, angina, arthritis, migraine, among others. Metabolic alterations could accompany these conditions and could be used as predictors for diagnosis and prognosis. We believe that studying the metabolic profile of patients suffering from these conditions could reveal novel biomarkers that may aid in the early detection, management, and treatment strategies, ultimately improving patient outcomes.

Widespread pain conditions are polysymptomatic reporting symptoms beyond their chronic pain status per se. This new health and well-being questionnaire studying long-covid symptoms and impacts provides a detailed report of multi-system examination regarding UK Biobank's participants. We seek to improve our understanding of the complex interplay between chronic pain and various symptoms, ultimately contributing to the advancement of knowledge in this field.

It is known that 50-70% of chronic pain patients complain about poor sleep quality. A circular relationship is suggested between poor sleep and more pain. Given the important overlap between sleep disturbances and chronic pain, it is crucial to identify genetic etiology behind this interaction. Recently, we discovered genome-wide associations with sleep, pain and various related phenotypes, including anxiety. In this context we are seeking a replication study to analyse the interaction between sleep, pain, anxiety and genetic variants. We seek an opportunity to evaluate these associations in the UK biobank resources. Preliminary analyses have shown that the relationship between pain and sleep is mediated with tobacco use. While a number of demographic and psychosocial factors have been proposed to account for the association between smoking, sleep disturbances and these negative clinical pain outcomes, there is reason to believe that biological factors might also play a role. The requested data will permit examination of the genetic mechanisms that might underlie the link between smoking, sleep and chronic pain.

Previous studies have attempted to clarify the role of brain structure and function in chronic pain. Reviews of the pain-related brain imaging literature often reveal overlapping, but inconsistent findings as illustrated by one recent chronic low back pain brain imaging review by Kregel et al., 2015 (https://doi.org/10.1016/j.semarthrit.2015.05.002). We propose the inconsistencies are a function of studies being underpowered and not taking into account the phenotype and genotype of the subjects. With the addition of the requested data the association between pain, genotype and comorbidities will be investigated using brain structure and function as intermediate phenotypes. Positioned as intermediate phenotypes, we believe that brain structure and function will assist in clarifying the relationships between pain, genotype and comorbidities. These comorbidities include depression, anxiety, body mass index and sleep.

While associations of air pollution with diseases of the respiratory system are well known, air pollution damage has also been observed for outcomes across multiple organ systems, where these effects may be indirect such as through inflammatory processes, impacting on autoimmune diseases for example. Research over the last 15 years has pointed to air pollution as a risk factor for neurological diseases and neuropathy, including through neuro-inflammation and auto-antibody production. Specifically relating to pain outcomes, one study reported on an association between air pollution and abdominal pain.

Rural and urban environment may also serve to broadly classify subjects according to differences in environmental exposures, including air pollution. When considering chronic pain outcomes, however, the psychological effects of rural or urban environment may also play a role: a previous study found higher levels of chronic pain reporting among rural compared to urban participants, where the presence of greater distraction in an urban environment was thought to underlie these differences given the role of attention on symptom reporting.

Both genetic and epigenetic factors have been implicated in differential susceptibility to air pollution on health outcomes. Our previous work using a genomewide association study (GWAS) approach to identify the genetic basis for chronic pain development has revealed intriguing links among autoimmune diseases and chronic pain. Drawing on UKB data among white British subjects, both our own GWAS results, as well as published results from an independent research group focused on multisite chronic pain (MCP) have pointed to autoimmune conditions, specifically asthma, as displaying a high genetic correlation with development of chronic pain. We are therefore particularly interested in further characterizing the specific molecular underpinnings of these genomewide-level observations. Given that chronic pain is often managed through medications, which in turn impacts on pain experience, in the original application, we requested and were granted access to medication data, specifically items under Field 20003. We now also require related data-field "Number of treatments/medications taken". This variable will allow for the proper classification of study subjects as taking a particular medication or not taking any medication at all, or as missing. Further, a recent randomized clinical trial (that was not considered previously) showed higher analgesic efficacy for chronic back pain patients taking antibiotics compared with placebo, suggesting that antibiotics may be an effective treatment where the pain is secondary to a herniated disc condition, we also request variables describing antibiotic medications taken.  We request blood biochemistry and urine assays data for the exploration of these variables as potential mediators in fine causal investigation analyses following first pass GWAS study results of chronic pain. We are particularly interested in immune-related variables, e.g. C-reactive protein, an indicator of inflammation.

Patients suffering from chronic pain commonly report emotional distress due to their pain. As a result, chronic pain patients are at risk for developing a variety of disorders including depression, anxiety, and addictive behaviours. They are also at risk of poor health behaviours, such as physical inactivity, malnutrition, substance use, and poor sleep that may contribute to the maintenance or worsening of their pain. Investigating the role of these accompanying conditions, each with distinct genetic predispositions, is therefore crucial to understand brain structure and function as an intermediary phenotype to chronic pain. This will be done by incorporating these various disorders, mood-related measures, and health behaviours in one overarching burden score of pain and its chronicity. The proposed data request will include online follow-up questionnaires (mental health and pain-related measure), as well as common medical and health-related measures (general health, blood pressure, diagnosis, among others).

In Canada, it is estimated that approximately 20% of the population is currently suffering from a chronic pain condition. However, the level of disability is not only associated with pain, but with other symptoms such as fatigue, sleep disorders, and mood disturbances. In particular, cognitive impairment, which are difficulties in processes such as concentrating, making decisions or remembering events, is characteristic of individuals with chronic pain. Research conducted over the last couple of decades has provided evidence of cognitive impairment in people with chronic pain. However, despite patient complaints, until recently, there has been limited discussion and no systematic evaluation of the body of literature concerning cognitive impairment across chronic pain syndromes. Nor have modern meta-analytical methods been used to clarify and classify the extent to which and how cognition may be impaired among various chronic pain conditions. Seeing as though chronic pain is made of more than just physical pain, in order to aid in treatment efficacy as well as the development of novel therapeutics, factors contributing to the reduced functionality and persistence of disability and pain, such as dyscognition, must be understood and considered.

It is known that the itch sensation travels through DRG; all conditions have itch in common. This is the broader context of deciphering the genetics of pain in various cell types in DRG. Based on the results from a recent study suggesting that the use of NSAIDs as being a risk factor for developing chronic pain [PMID 35544595] and that a low neutrophil count was also associated with higher incidence of chronic pain we aim to investigate how physical activity affects neutrophil count and the risk of developing chronic pain and NSAID-induced chronic pain, also looking at how exercise intensity might influence these findings.

Apart from mental comorbidities, numerous physical comorbidities, including respiratory diseases, heart diseases, Thyroid conditions, diabetes, etc., have been proposed to explain the development of chronic pain in the general population. The available literature seems to strongly suggest an association between accumulated comorbid load and chronic pain (Dominick, Blyth et al. 2012).  Also, interestingly, large population-based studies have shown that chronic pain is associated with an increased prevalence of cardiovascular risk factors and metabolic syndrome (Goodson, Smith et al. 2013).  Overall, the characteristics of certain detectable metabolites can help identify biochemical molecules that distinguish the state of a disease, which could in turn, cause chronic pain.

We intend to look at the electronic health record to discover lifelong diseases and their onset, as well as the whole physical profile of an individual as contributing risk factors. We then intend to use participant's physical examination across various physiological systems to validate the etiology of their illnesses and relate them as contributors to the onset of chronic pain, and more specifically, chronic widespread pain.

Altogether we hope to better characterize factors that shape the expression of chronic non-musculoskeletal widespread pain conditions in the general population.

We wish to extend our genetic studies of chronic pain and related conditions by considering family history information. Specifically, incorporating first degree relative family history variables of primary cases into a genomewide association (GWA) study framework for polygenic risk score (PRS) development may increase the predictive power of chronic pain condition modeling. A recent UK Biobank-based PRS study of three well-powered common diseases, type II diabetes, hypertension and depression, showed that incorporating family history (via a method named PRS-FH) led to a doubling of prediction R^2 compared to disease-specific PRS alone. To follow the scheme as proposed by this previous study would require chronic pain family history per se, which is not available in the UK Biobank. Nonetheless, another approach might be to consider conditions for which family history data is available and for which there is a high genetic correlation with chronic pain conditions. A GWA study of the most highly powered multisite chronic pain (MCP) phenotype, also drawing on the UKB, has shown that among other traits studied, highest genetic correlation for MCP was estimated for the category psychiatric traits, with major depressive disorder (MDD) coming out on top (rg = 0.53; SE = 0.03)(2). We therefore wish to adapt PRS-FH to the prediction of chronic pain conditions, including body-site specific chronic pain and multisite chronic pain (MCP) by including MDD (and possibly other conditions) into the model.

To deepen the understanding of the complex biological mechanisms involved in chronic pain conditions such as fibromyalgia, angina, arthritis, migraine, among others. Metabolic alterations could accompany these conditions and could be used as predictors for diagnosis and prognosis. We believe that studying the metabolic profile of patients suffering from these conditions could reveal novel biomarkers that may aid in the early detection, management, and treatment strategies, ultimately improving patient outcomes.

Widespread pain conditions are polysymptomatic reporting symptoms beyond their chronic pain status per se. This new health and well-being questionnaire studying long-covid symptoms and impacts provides a detailed report of multi-system examination regarding UK Biobank's participants. We seek to improve our understanding of the complex interplay between chronic pain and various symptoms, ultimately contributing to the advancement of knowledge in this field.

NEW SCOPE: Numerous physical comorbidities, including respiratory diseases, heart diseases, Thyroid conditions, diabetes, etc., have been proposed to explain the development of chronic pain in the general population. Also, the available literature seems to strongly suggest an association between accumulated comorbid load and chronic pain. We intend to look at the electronic health records to discover lifelong diseases and their onset, as well as the whole physical profile of an individual as contributing risk factors to chronic pain