It is found that genetic liability to headache, migraine, joint pain, and sciatica was causally associated with alterations in 15 structural IDPs, and changes in the surface area of three brain regions were linked to a lower risk of sciatica, low back pain, and overall pain.
Abstract
Abstract Background Observational studies have suggested that brain imaging-derived phenotypes (IDPs) may serve as specific markers of pain-related phenotypes and severity. However, the shared genetic architecture between pain and brain IDPs and their potential causal relationships remains unclear. Methods We applied linkage disequilibrium score regression and Mendelian randomization (MR) analyses to uncover genetic correlations and potential causal links of brain structural (33,224 UK Biobank participants) and functional (47,276 UK Biobank participants) changes with site-specific pain phenotypes (approximately 500,000 Finngen participants). The scoping literature review was conducted to compare current findings with previous observational studies. Results In this study, we identified 559 significant genetic correlations between 587 structural IDPs and 13 pain-related phenotypes. Using MR analyses, we found that genetic liability to headache, migraine, joint pain, and sciatica was causally associated with alterations in 15 structural IDPs. Additionally, changes in the surface area of three brain regions were linked to a lower risk of sciatica, low back pain, and overall pain. Among the six pain-related phenotypes associated with structural IDPs, further analyses demonstrated putative causal relationships between functional IDPs and these conditions. Notably, headache exhibited both significant structural and functional changes across three key brain regions: the superior frontal gyrus, lingual gyrus, and paracentral lobule. Conclusions These findings provide novel insights into the genetic correlations and genetically inferred associations between pain and neurobiological abnormalities from neuroimaging perspectives, with structural alterations as the primary findings and functional changes as complementary exploratory evidence, advancing the understanding of pain-related mechanisms.
An atlas of brain IDPs associated with bipolar disorder is established, by integrating epidemiological and genetic evidence, and candidate IDPs that were consistently associated with BD are highlighted across complementary analyses.
Wenzhuo Yang, Lin Pan, Haoqun Xie et al.· BMC Medicine· 0 citations
Background Neuropathic pain (NP) frequently co-occurs with sleep disorders, yet the causal relationship between the two remain unclear, necessitating further investigation to elucidate their intrinsic connection. Methods We conducted linkage disequilibrium score regression (LDSC), Mendelian randomization (MR), multivariable mendelian randomization (MVMR) and causal analysis using summary effect estimates (CAUSE) analyses based on genome-wide association study summary statistics of six NP subtypes (FinnGen R12) and six sleep traits (UK Biobank) to verify causal associations. Multi-method combined gene prioritization screening genes, with comprehensive sensitivity analyses and bias correction performed. Results Our analyses revealed that among all NP subtypes, only insomnia exerted a stable potential causal effect on sciatica. LDSC analysis revealed a significant positive genetic correlation between insomnia and sciatica (rg = 0.395, P < 0.0017). MR analyses demonstrated that insomnia significantly increased the risk of sciatica (OR = 3.15, 95% CI: 2.20–4.51, PIVW = 3.48E-10), with robust results confirmed by multiple sensitivity analyses. CAUSE further validated a positive causal association between insomnia and sciatica (OR = 3.899, 95% CI: 1.823–8.339, P = 0.003). MVMR proved the causal association remained significant after adjustment for psychiatric disorders (PIVW < 0.05). Heritability enrichment analysis indicated that the heritability of insomnia was mainly enriched in the central nervous system. And six potential pathogenic genes were screened via multiple integrated analytical methods. Among these candidates, EIF3KP1 and PPIP5K2 showed the strongest genetic evidence and were validated in the FinnGen database. Conclusion We identified a potential causal effect of insomnia on sciatica. The comorbidity of the two conditions may be regulated by genetic mechanisms associated with the central nervous system. EIF3KP1 and PPIP5K2 were prioritized as candidate genes, and further cellular and animal experiments are required to validate their potential as molecular targets for intervening in this comorbidity.
Shuyan Li, Xianmei Chen, Haiwen Cen et al.· Journal of Pain Research· 0 citations
BACKGROUND
Previous studies have indicated associations between imaging markers of cerebral small vessel disease (CSVD), but their genetic correlations remain largely unknown.
METHODS
We analyzed large-scale GWAS summary data for lacunar stroke (6,030 cases; 248,929 controls), cerebral microbleeds (N=25,862), white matter hyperintensities (WMH; 18,381 population-based subjects and 2,850 stroke patients), perivascular spaces (PVS; N=40,095), and brain volume (N=33,224). Linkage disequilibrium score regression (LDSR) was used to estimate heritability and genetic correlations. Bidirectional Mendelian randomization (MR) and mediation MR were performed to assess causal relationships.
RESULTS
Except for cerebral microbleeds, all other CSVD imaging markers showed significant heritability, with decreased brain volume being the most prominent. MR analyses provided evidence supporting potential unidirectional causal relationships where lacunar stroke increased the risk of WMH, PVS and decreased brain volume. MR identified a potential bidirectional causal relationship between WMH and decreased brain volume. Mediation analysis revealed that lacunar stroke mediated the effects of hypertension on various imaging markers.
CONCLUSION
Cerebral microbleeds appear genetically distinct from other CSVD markers. Lacunar stroke acts as a key upstream factor linking multiple imaging features, while WMH and brain atrophy exhibit a potential bidirectional causal relationship. These findings provide insight into the heterogeneous mechanisms underlying CSVD imaging markers.
Yuze Cao, Dingding Zhang, Jun Ni· Journal of Cerebral Blood Fl...· 0 citations
Background: Chronic pain affects hundreds of millions worldwide and remains a major clinical challenge, despite numerous available treatments. Advances in brain imaging offer a promising path toward identifying neural signatures of chronic pain, potentially enhancing diagnosis and guiding treatment. However, while a core set of brain regions, including the insula, cingulate, and somatosensory cortices, has been repeatedly implicated, findings regarding other regions and connectivity patterns involved remain inconsistent, with limited robust replication. Objective: To address these gaps, the present work characterizes resting-state functional connectivity and gray matter volume differences between chronic pain patients and pain-free controls. Methods: In this secondary analysis of publicly available data, anatomical and resting-state functional MRI were analyzed from 56 patients with chronic knee pain due to osteoarthritis and 20 pain-free controls. Group comparisons used Network-Based Statistic (NBS) and Bayesian multivariate regression models, controlling for demographic covariates. Results: In the pain group, about 75% of parcellated brain regions exhibited increased functional connectivity compared to controls. The 30 highest degree centrality regions in the NBS network were concentrated in regions consistent with prior pain neuroimaging findings. Additionally, chronic pain patients exhibited reduced gray matter volume (-3.98%; SD 1.2%) across 33% of parcellated brain regions, including key regions implicated in pain processing. Conclusions: These findings demonstrate widespread functional and anatomical neural alterations in chronic pain, revealing a global pattern of reorganization extending beyond previously reported network-pair effects. Characterizing such alterations may contribute to ongoing efforts to identify neuroimaging markers of chronic pain, with potential translational relevance.
L. Cohen-Blum, S. Eizman, P. Tétreault et al.· medRxiv· 0 citations
BACKGROUND
Chronic musculoskeletal pain (CMP) represents a significant global health burden, yet the neurobiological mechanisms underlying its development remain poorly understood. This study investigates the complex interplay between neuroticism, genetic risk, and amygdala morphology in CMP onset, recovery, and pain characteristics using UK Biobank data.
METHODS
We conducted longitudinal analyses on (1) 9382 pain-free individuals followed for CMP development and (2) 3460 CMP patients tracked for recovery outcomes. Neuroticism was quantified via a validated 12-item questionnaire assessing psychological distress. To assess chronic pain trajectories, we examined polygenic risk scores (PRS) for CMP and neuroticism, along with amygdala grey matter volumes, as predictors. Multivariate logistic and linear regression models were employed, followed by mediation analyses to elucidate underlying relationships between variables. Analyses were restricted to individuals of European ancestry.
RESULTS
We found that higher neuroticism scores, neuroticism PRS, and CMP PRS were significantly associated with increased risk of CMP onset and reduced likelihood of recovery across cohorts (all Pcorrected < 0.05). Both neuroticism scores and PRS were positively correlated with pain intensity, whereas CMP PRS were not. Additionally, amygdala grey matter volumes were significantly associated with neuroticism in the CMP onset cohort but not in the recovery group. Neuroticism mediated the relationship between CMP PRS and subsequent CMP onset with a small effect size, while no mediation was observed for CMP recovery.
CONCLUSIONS
This study demonstrated significant associations between neuroticism, genetic factors, and amygdala morphology in CMP trajectories, highlighting a potential neurobiological mechanism linking psychological vulnerability to chronic pain. These results underscore the importance of integrating psychological assessment and targeted interventions into comprehensive pain management strategies.
M. Cannistra, Yu Liu, V. Sacca et al.· Communications Medicine· 0 citations
Local brain age (LBA) is a spatially resolved biomarker of brain aging that captures regional deviations from chronological age, yet its genetic architecture in the subcortex remains unexplored. Here, we present the first genome-wide association study (GWAS) of subcortical LBA, estimated using a deep neural network applied to T1-weighted MRI scans from 41,957 cognitively normal participants in the UK Biobank. We computed LBA across 14 subcortical structures and identified 14 significant single-nucleotide polymorphisms (SNPs) across nine independent loci. These variants map to genes involved in cellular homeostasis, gene regulation, and synaptic and developmental signaling. A prominent signal emerged at the 17q21.31 haplotype, encompassing MAPT-related regulatory architecture, with significant associations across all subcortical regions. Across loci, we observed a recurring spatial pattern in which effect sizes are relatively larger in metabolically central structures such as the pallidum and thalamus compared to limbic regions. Together, these findings support a spatially structured pattern of genetic associations in subcortical brain aging. This work supports subcortical LBA as a genetically informed phenotype and provides a framework for linking common genetic variation to region-specific vulnerability and resilience in neurodegenerative disease.
Nicholas J. Kim, Ayati Mishra, Jeremy S Yu et al.· GeroScience· 0 citations
