Genetic impact of blood C-reactive protein levels on chronic spinal & widespread pain.

PURPOSE: Causal mechanisms underlying systemic inflammation in spinal & widespread pain remain an intractable experimental challenge. Here we examined whether: (i) associations between blood C-reactive protein (CRP) and chronic back, neck/shoulder & widespread pain can be explained by shared underlying genetic variants; and (ii) higher CRP levels causally contribute to these conditions. METHODS: Using genome-wide association studies (GWAS) of chronic back, neck/shoulder & widespread pain (N = 6063-79,089 cases; N = 239,125 controls) and GWAS summary statistics for blood CRP (Pan-UK Biobank N = 400,094 & PAGE consortium N = 28,520), we employed cross-trait bivariate linkage disequilibrium score regression to determine genetic correlations (rG) between these chronic pain phenotypes and CRP levels (FDR < 5%). Latent causal variable (LCV) and generalised summary data-based Mendelian randomisation (GSMR) analyses examined putative causal associations between chronic pain & CRP (FDR < 5%). RESULTS: Higher CRP levels were genetically correlated with chronic back, neck/shoulder & widespread pain (rG range 0.26-0.36; P ≤ 8.07E-9; 3/6 trait pairs). Although genetic causal proportions (GCP) did not explain this finding (GCP range - 0.32-0.08; P ≥ 0.02), GSMR demonstrated putative causal effects of higher CRP levels contributing to each pain type (beta range 0.027-0.166; P ≤ 9.82E-03; 3 trait pairs) as well as neck/shoulder pain effects on CRP levels (beta [S.E.] 0.030 [0.021]; P = 6.97E-04). CONCLUSION: This genetic evidence for higher CRP levels in chronic spinal (back, neck/shoulder) & widespread pain warrants further large-scale multimodal & prospective longitudinal studies to accelerate the identification of novel translational targets and more effective therapeutic strategies.

A Shared Genetic Signature for Common Chronic Pain Conditions and its Impact on Biopsychosocial Traits.

The multiple comorbidities & dimensions of chronic pain present a formidable challenge in disentangling its aetiology. Here, we performed genome-wide association studies of 8 chronic pain types using UK Biobank data (N =4,037-79,089 cases; N = 239,125 controls), followed by bivariate linkage disequilibrium-score regression and latent causal variable analyses to determine (respectively) their genetic correlations and genetic causal proportion (GCP) parameters with 1,492 other complex traits. We report evidence of a shared genetic signature across chronic pain types as their genetic correlations and GCP directions were broadly consistent across an array of biopsychosocial traits. Across 5,942 significant genetic correlations, 570 trait pairs could be explained by a causal association (|GCP| >0.6; 5% false discovery rate), including 82 traits affected by pain while 410 contributed to an increased risk of chronic pain (cf. 78 with a decreased risk) such as certain somatic pathologies (eg, musculoskeletal), psychiatric traits (eg, depression), socioeconomic factors (eg, occupation) and medical comorbidities (eg, cardiovascular disease). This data-driven phenome-wide association analysis has demonstrated a novel and efficient strategy for identifying genetically supported risk & protective traits to enhance the design of interventional trials targeting underlying causal factors and accelerate the development of more effective treatments with broader clinical utility. PERSPECTIVE: Through large-scale phenome-wide association analyses of >1,400 biopsychosocial traits, this article provides evidence for a shared genetic signature across 8 common chronic pain types. It lays the foundation for further translational studies focused on identifying causal genetic variants and pathophysiological pathways to develop novel diagnostic & therapeutic technologies and strategies.

Genetic risk for chronic pain is associated with lower antidepressant effectiveness: Converging evidence for a depression subtype.

INTRODUCTION: Chronic pain and depression are highly comorbid and difficult-to-treat disorders. We previously showed this comorbidity is associated with higher depression severity, lower antidepressant treatment effectiveness and poorer prognosis in the Australian Genetics of Depression Study. OBJECTIVE: The current study aimed to assess whether a genetic liability to chronic pain is associated with antidepressant effectiveness over and above the effect of genetic factors for depression in a sample of 12,863 Australian Genetics of Depression Study participants. METHODS: Polygenic risk scores were calculated using summary statistics from genome-wide association studies of multisite chronic pain and major depression. Cumulative linked regressions were employed to assess the association between polygenic risk scores and antidepressant treatment effectiveness across 10 different medications. RESULTS: Mixed-effects logistic regressions showed that individual genetic propensity for chronic pain, but not major depression, was significantly associated with patient-reported chronic pain (PainPRS OR = 1.17 [1.12, 1.22]; MDPRS OR = 1.01 [0.98, 1.06]). Significant associations were also found between lower antidepressant effectiveness and genetic risk for chronic pain or for major depression. However, a fully adjusted model showed the effect of PainPRS (adjOR = 0.93 [0.90, 0.96]) was independent of MDPRS (adjOR = 0.96 [0.93, 0.99]). Sensitivity analyses were performed to assess the robustness of these results. After adjusting for depression severity measures (i.e. age of onset; number of depressive episodes; interval between age at study participation and at depression onset), the associations between PainPRS and patient-reported chronic pain with lower antidepressant effectiveness remained significant (0.95 [0.92, 0.98] and 0.84 [0.78, 0.90], respectively). CONCLUSION: These results suggest genetic risk for chronic pain accounted for poorer antidepressant effectiveness, independent of the genetic risk for major depression. Our results, along with independent converging evidence from other studies, point towards a difficult-to-treat depression subtype characterised by comorbid chronic pain. This finding warrants further investigation into the implications for biologically based nosology frameworks in pain medicine and psychiatry.

Surface Normals and Light Directions From Shading and Polarization.

We introduce a method of recovering the shape of a smooth dielectric object using diffuse polarization images taken with different directional light sources. We present two constraints on shading and polarization and use both in a single optimization scheme. This integration is motivated by photometric stereo and polarization-based methods having complementary abilities. Polarization gives strong cues for the surface orientation and refractive index, which are independent of the light direction. However, employing polarization leads to ambiguities in selecting between two ambiguous choices of the surface orientation, in the relationship between the refractive index and zenith angle (observing angle). Moreover, polarization-based methods for surface points with small zenith angles perform poorly owing to the weak polarization. In contrast, the photometric stereo method with multiple light sources disambiguates the surface normals and gives a strong relationship between surface normals and light directions. However, the method has limited performance for large zenith angles and refractive index estimation and faces strong ambiguity when light directions are unknown. Taking the advantages of these methods, our proposed method recovers surface normals for small and large zenith angles, light directions, and refractive indexes of the object. The proposed method is positively evaluated in simulations and real-world experiments.

Genetic basis to structural grey matter associations with chronic pain.

Structural neuroimaging studies of individuals with chronic pain conditions have often observed decreased regional grey matter at a phenotypic level. However, it is not known if this association can be attributed to genetic factors. Here we employed a novel integrative data-driven and hypothesis-testing approach to determine whether there is a genetic basis to grey matter morphology differences in chronic pain. Using publicly available genome-wide association study summary statistics for regional chronic pain conditions (n = 196 963) and structural neuroimaging measures (n = 19 629-34 000), we applied bivariate linkage disequilibrium-score regression and latent causal variable analyses to determine the genetic correlations (rG) and genetic causal proportion (GCP) between these complex traits, respectively. Five a priori brain regions (i.e. prefrontal cortex, cingulate cortex, insula, thalamus and superior temporal gyrus) were selected based on systematic reviews of grey matter morphology studies in chronic pain. Across this evidence-based selection of five brain regions, 10 significant negative genetic correlations (out of 369) were found (false discovery rate < 5%), suggesting a shared genetic basis to both reduced regional grey matter morphology and the presence of chronic pain. Specifically, negative genetic correlations were observed between reduced insula grey matter morphology and chronic pain in the abdomen (mean insula cortical thickness), hips (left insula volume) and neck/shoulders (left and right insula volume). Similarly, a shared genetic basis was found for reduced posterior cingulate cortex volume in chronic pain of the hip (left and right posterior cingulate), neck/shoulder (left posterior cingulate) and chronic pain at any site (left posterior cingulate); and for reduced pars triangularis volume in chronic neck/shoulder (left pars triangularis) and widespread pain (right pars triangularis). Across these negative genetic correlations, a significant genetic causal proportion was only found between mean insula thickness and chronic abdominal pain [rG (standard error, SE) = -0.25 (0.08), P = 1.06 × 10-3; GCP (SE) = -0.69 (0.20), P = 4.96 × 10-4]. This finding suggests that the genes underlying reduced cortical thickness of the insula causally contribute to an increased risk of chronic abdominal pain. Altogether, these results provide independent corroborating evidence for observational reports of decreased grey matter of particular brain regions in chronic pain. Further, we show for the first time that this association is mediated (in part) by genetic factors. These novel findings warrant further investigation into the neurogenetic pathways that underlie the development and prolongation of chronic pain conditions.

Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness.

The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for their comorbidity in the Australian Genetics of Depression cohort study (N = 13,839). Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health. Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for 10 different antidepressants. Chronic pain was associated with an increased risk of depression (OR = 1.86 [1.37-2.54]), recent suicide attempt (OR = 1.88 [1.14-3.09]), higher use of tobacco (OR = 1.05 [1.02-1.09]) and misuse of painkillers (e.g., opioids; OR = 1.31 [1.06-1.62]). Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR = 0.75 [0.68-0.83]), escitalopram (OR = 0.75 [0.67-0.85]) and venlafaxine (OR = 0.78 [0.68-0.88]) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR = 0.45 [0.30-0.67]), escitalopram (OR = 0.45 [0.27-0.74]) and citalopram (OR = 0.32 [0.15-0.67]) specifically for chronic pain (among other indications) reported lower benefits compared to other participants taking these same medications but not for chronic pain. These findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further examination is warranted in targeted interventional clinical trials, which also include neuroimaging genetics and pharmacogenomics protocols. This work will advance the delineation of disease risk indicators and novel aetiological pathways for therapeutic intervention in comorbid pain and depression as well as other psychiatric comorbidities.

Attentional switching in humans and flies: rivalry in large and miniature brains.

Human perception, and consequently behavior, is driven by attention dynamics. In the special case of rivalry, where attention alternates between competing percepts, such dynamics can be measured and their determinants investigated. A recent study in the fruit fly, Drosophila melanogaster, now shows that the origins of attentional rivalry may be quite ancient. Furthermore, individual variation exists in the rate of attentional rivalry in both humans and flies, and in humans this is under substantial genetic influence. In the pathophysiological realm, slowing of rivalry rate is associated with the heritable psychiatric condition, bipolar disorder. Fly rivalry may therefore prove a powerful model to examine genetic and molecular influences on rivalry rate, and may even shed light on human cognitive and behavioral dysfunction.