Background & Aims
Chronic pain has a prevalence of >10% and confers a tremendous burden on affected individuals and society (1-4). Recent genome-wide association studies (GWAS) have unveiled high genetic correlations between multisite chronic pain (MCP) and inflammatory diseases (5,6), which are common chronic pain co-morbidities (7). We previously examined the overlapping genetics of MCP and asthma specifically, highlighting the importance of age-of-onset (AO) as a proxy for genetic heterogeneity in asthma (8). There, we found that the genetic correlation between MCP and asthma was AO-dependent. We hypothesized that these results were not unique to asthma, therefore we extended our investigation to include other inflammatory conditions such as hay fever, eczema, and chronic obstructive pulmonary disease (COPD).
Methods
Age-of-onset strata of cases for self-reported, doctor-diagnosed asthma, hay fever, eczema, and COPD were defined among 457,461 European-descent subjects from the UK Biobank (UKB) (9): <18 years (childhood), 18-40 years (younger-adult), > 40 years (older-adult), and contrasted to healthy controls (hereafter AO-strata). GWA scans were run across MCP and AO-strata on 9.2 million variants (10). Meta-analyses were conducted across MCP and AO-strata pairs (11). We then used causal mixture models to estimate counts of distinct and overlapping causal genetic variants (12). Next, we investigated mediation in multi-trait association signals using a causal pathway framework (13). We also explored causal pathways considering temporality across several time points of the UKB and the Canadian Longitudinal Study of Aging (CLSA) cohorts (14). Finally, we investigated the functional implications of signals through gene-based, gene-set, and cell-specific heritability enrichment analyses (15,16).
Results
The largest estimated number of overlapping causal variants was found between MCP and older adult asthma (1,800 variants). Estimates for MCP with younger adult and childhood asthma, and with hay fever, eczema & COPD AO-strata, were much lower (50-400 variants). A total of 1,416 older-adult asthma causal variants were found to be mediated by MCP, including eQTL variants in the locus of the chronic pain gene DCC Netrin 1 Receptor (DCC) (5,17). MCP among asthma-free subjects was associated with increased odds for future older adult asthma, in both the UKB and CLSA cohorts. The combined meta-analysis of MCP with older adult asthma pointed to excess differential gene expression in the cerebellum, with vocal learning behavior as a biological function which connects the larynx to the brain via the nervous system. Additional brain cell types were identified through heritability enrichment in the meta-analysis compared to single-trait GWA scans on MCP and older adult asthma.
Conclusions
Taken together, our results highlight the striking overlapping genetics of MCP and older adult asthma, supported by meta-analysis, temporality, specific causal variants, causal pathways, and functional data. No other inflammatory traits beyond asthma revealed substantial shared genetic overlap with MCP. Though, contrary to other findings in the literature that examined chronic pain versus asthma per se (without considering AO) (18,19), MCP was found to be causal for older adult-onset asthma, the reverse causal direction was unsupported. Differential gene expression mapping to central nervous system tissues was found for signals that showed synergistic effects across MCP and older adult asthma. These findings align with both human data and animal experiments, elucidating the role of the central nervous system in the pathogenesis of adult asthma (20,21), including interactions between the nervous and immune systems (22).
References
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Presenting Author
Goodarz Kolifarhood
Poster Authors
Topics
- Epidemiology