通过神经系统将慢性疼痛遗传学与迟发性哮喘联系起来的因果证据
2026/02/02
摘要
背景：慢性疼痛与哮喘存在关联，但其遗传和生物学关系的方向及基础仍不明确。
方法：我们对456958名英国生物银行参与者和25275名加拿大纵向衰老研究的欧洲裔参与者，针对九种慢性疼痛特征和三种哮喘发病年龄分层（儿童期哮喘发病年龄<18岁、成年期哮喘发病年龄18 - 40岁、迟发性哮喘发病年龄>40岁）开展了全基因组关联研究（GWAS）、GWAS多性状分析（MTAG）、多基因风险评分（PRS）预测、双变量因果模型分析和孟德尔随机化（MR）研究。我们运用基于基因、通路、组织和细胞类型的富集分析，对共享和独特的遗传结构进行了分析。
结果：多部位慢性疼痛（MCP）与哮喘表现出最强且最一致的遗传重叠，遗传相关性从儿童期哮喘（遗传相关系数rg = 0.01）到迟发性哮喘（rg = 0.40）逐渐增加。迟发性哮喘的估计因果变异约有1.8K个，儿童期哮喘的因果变异较少，约0.2K个，这些都嵌套在更广泛的MCP特征（约9.4K个）中。通过PRS、MR和纵向分析，我们发现MCP对迟发性哮喘具有因果作用。MR分析得出的顶级因果变异定位于GMPPB - RNF123、DCC和FOXP2基因。以MCP为条件，利用MTAG分析放大了迟发性哮喘变异效应大小，并揭示了在各通路、组织和细胞类型中富含免疫和中枢神经系统功能的基因。相比之下，儿童期哮喘仅表现出免疫特异性富集。
结论：这些发现揭示了将慢性疼痛与迟发性哮喘联系起来的神经功能，这与儿童期哮喘不同，并凸显了中枢神经系统对晚年出现的哮喘的影响。
Causal evidence linking chronic pain genetics to late-onset asthma via the nervous system
Goodarz Kolifarhood, Marc Parisien, Matt Fillingim, Charlise Chen, Yiran Chen, Nikolay Dimitrov, Maha Zidan, Lovéni Hanumunthadu, Peter H Her, Sahir Bhatnagar, Luda Diatchenko, Audrey V Grant
Abstract
Background: Chronic pain and asthma are associated, but the direction and basis of their genetic and biological relationship remain unclear.
Methods: We conducted genome-wide association studies (GWAS), multi-trait analysis of GWAS (MTAG), polygenic risk score (PRS) prediction, bivariate causal modelling, and Mendelian randomisation (MR) across nine chronic pain traits and three asthma age-of-onset strata (<18, 18-40, and >40 yr for childhood-, adult-, and late-onset asthma, respectively) in 456 958 UK Biobank and 25 275 Canadian Longitudinal Study on Aging participants of European descent. We analysed shared and distinct genetic architecture using gene-, pathway-, tissue-, and cell-type-based enrichment analyses.
Results: Multisite chronic pain (MCP) showed the strongest and most consistent genetic overlap with asthma, with genetic correlation increasing from childhood (rg=0.01) to late-onset asthma (rg=0.40). Estimated causal variants for late-onset asthma (∼1.8 K), and fewer for childhood asthma (∼0.2 K), were nested within a broader MCP profile (∼9.4 K). Using PRS, MR, and longitudinal analyses, we found that MCP contributes causally to late-onset asthma. Top causal variants from MR mapped to GMPPB-RNF123, DCC, and FOXP2. Conditioning by MCP amplified late-onset asthma variant effect sizes using MTAG, and uncovered genes enriched for immune and CNS function across pathways, tissues, and cell types. In contrast, childhood asthma showed immune-specific enrichment alone.
Conclusions: These findings reveal neurological function linking chronic pain to late-onset asthma, distinct from childhood asthma, and highlight a CNS contribution to asthma emerging later in life.
背景：慢性疼痛与哮喘存在关联，但其遗传和生物学关系的方向及基础仍不明确。
方法：我们对456958名英国生物银行参与者和25275名加拿大纵向衰老研究的欧洲裔参与者，针对九种慢性疼痛特征和三种哮喘发病年龄分层（儿童期哮喘发病年龄<18岁、成年期哮喘发病年龄18 - 40岁、迟发性哮喘发病年龄>40岁）开展了全基因组关联研究（GWAS）、GWAS多性状分析（MTAG）、多基因风险评分（PRS）预测、双变量因果模型分析和孟德尔随机化（MR）研究。我们运用基于基因、通路、组织和细胞类型的富集分析，对共享和独特的遗传结构进行了分析。
结果：多部位慢性疼痛（MCP）与哮喘表现出最强且最一致的遗传重叠，遗传相关性从儿童期哮喘（遗传相关系数rg = 0.01）到迟发性哮喘（rg = 0.40）逐渐增加。迟发性哮喘的估计因果变异约有1.8K个，儿童期哮喘的因果变异较少，约0.2K个，这些都嵌套在更广泛的MCP特征（约9.4K个）中。通过PRS、MR和纵向分析，我们发现MCP对迟发性哮喘具有因果作用。MR分析得出的顶级因果变异定位于GMPPB - RNF123、DCC和FOXP2基因。以MCP为条件，利用MTAG分析放大了迟发性哮喘变异效应大小，并揭示了在各通路、组织和细胞类型中富含免疫和中枢神经系统功能的基因。相比之下，儿童期哮喘仅表现出免疫特异性富集。
结论：这些发现揭示了将慢性疼痛与迟发性哮喘联系起来的神经功能，这与儿童期哮喘不同，并凸显了中枢神经系统对晚年出现的哮喘的影响。
（北京朝阳医院呼吸与危重症医学科 顾宪民 摘译 中日友好医院呼吸与危重症医学科 林江涛 审校）
（Br J Anaesth. 2026 Jan 17:S0007-0912(25)00823-2. doi: 10.1016/j.bja.2025.11.020.）
（Br J Anaesth. 2026 Jan 17:S0007-0912(25)00823-2. doi: 10.1016/j.bja.2025.11.020.）
Causal evidence linking chronic pain genetics to late-onset asthma via the nervous system
Goodarz Kolifarhood, Marc Parisien, Matt Fillingim, Charlise Chen, Yiran Chen, Nikolay Dimitrov, Maha Zidan, Lovéni Hanumunthadu, Peter H Her, Sahir Bhatnagar, Luda Diatchenko, Audrey V Grant
Abstract
Background: Chronic pain and asthma are associated, but the direction and basis of their genetic and biological relationship remain unclear.
Methods: We conducted genome-wide association studies (GWAS), multi-trait analysis of GWAS (MTAG), polygenic risk score (PRS) prediction, bivariate causal modelling, and Mendelian randomisation (MR) across nine chronic pain traits and three asthma age-of-onset strata (<18, 18-40, and >40 yr for childhood-, adult-, and late-onset asthma, respectively) in 456 958 UK Biobank and 25 275 Canadian Longitudinal Study on Aging participants of European descent. We analysed shared and distinct genetic architecture using gene-, pathway-, tissue-, and cell-type-based enrichment analyses.
Results: Multisite chronic pain (MCP) showed the strongest and most consistent genetic overlap with asthma, with genetic correlation increasing from childhood (rg=0.01) to late-onset asthma (rg=0.40). Estimated causal variants for late-onset asthma (∼1.8 K), and fewer for childhood asthma (∼0.2 K), were nested within a broader MCP profile (∼9.4 K). Using PRS, MR, and longitudinal analyses, we found that MCP contributes causally to late-onset asthma. Top causal variants from MR mapped to GMPPB-RNF123, DCC, and FOXP2. Conditioning by MCP amplified late-onset asthma variant effect sizes using MTAG, and uncovered genes enriched for immune and CNS function across pathways, tissues, and cell types. In contrast, childhood asthma showed immune-specific enrichment alone.
Conclusions: These findings reveal neurological function linking chronic pain to late-onset asthma, distinct from childhood asthma, and highlight a CNS contribution to asthma emerging later in life.
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