Johnston Keira J A, Signer Rebecca, Huckins Laura M
Department of Psychiatry, Yale School of Medicine, Yale University, New Haven, CT 06511, USA.
Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA.
HGG Adv. 2025 Jan 9;6(1):100381. doi: 10.1016/j.xhgg.2024.100381. Epub 2024 Nov 4.
Chronic overlapping pain conditions (COPCs) are a subset of chronic pain conditions commonly comorbid with one another and more prevalent in women and individuals assigned female at birth (AFAB). Pain experience in these conditions may better fit with a new mechanistic pain descriptor, nociplastic pain, and nociplastic pain may represent a shared underlying factor among COPCs. We applied GenomicSEM common-factor genome-wide association study (GWAS) and multivariate transcriptome-wide association (TWAS) analyses to existing GWAS output for six COPCs in order to find genetic variation associated with nociplastic pain, followed by genetic correlation (linkage disequilibrium score regression), gene set, and tissue enrichment analyses. We found 24 independent single nucleotide polymorphisms (SNPs), and 127 unique genes significantly associated with nociplastic pain, and showed nociplastic pain to be a polygenic trait with significant SNP heritability. We found significant genetic overlap between multisite chronic pain and nociplastic pain, and to a smaller extent with rheumatoid arthritis and a neuropathic pain phenotype. Tissue enrichment analyses highlighted cardiac and thyroid tissue, and gene set enrichment analyses emphasized potential shared mechanisms in cognitive, personality, and metabolic traits and nociplastic pain along with distinct pathology in migraine and headache. We used a well-powered network approach to investigate nociplastic pain using existing COPC GWAS output, and show nociplastic pain to be a complex, heritable trait, in addition to contributing to understanding of potential mechanisms in development of nociplastic pain.
慢性重叠性疼痛病症（COPCs）是慢性疼痛病症的一个子集，通常相互共病，在女性和出生时被指定为女性的个体（AFAB）中更为普遍。这些病症中的疼痛体验可能更符合一种新的机械性疼痛描述符——神经可塑性疼痛，并且神经可塑性疼痛可能代表了COPCs之间共同的潜在因素。我们将基因组结构方程模型共同因素全基因组关联研究（GWAS）和多变量转录组全关联（TWAS）分析应用于六种COPCs的现有GWAS输出结果，以寻找与神经可塑性疼痛相关的基因变异，随后进行遗传相关性（连锁不平衡评分回归）、基因集和组织富集分析。我们发现了24个独立的单核苷酸多态性（SNP）以及127个与神经可塑性疼痛显著相关的独特基因，并表明神经可塑性疼痛是一种具有显著SNP遗传力的多基因性状。我们发现多部位慢性疼痛与神经可塑性疼痛之间存在显著的遗传重叠，在较小程度上与类风湿性关节炎和一种神经性疼痛表型也存在遗传重叠。组织富集分析突出了心脏和甲状腺组织，基因集富集分析强调了认知、人格和代谢性状与神经可塑性疼痛之间潜在的共同机制，以及偏头痛和头痛中独特的病理学机制。我们使用了一种强大的网络方法，利用现有的COPC GWAS输出结果来研究神经可塑性疼痛，并表明神经可塑性疼痛是一种复杂的、可遗传的性状，此外还有助于理解神经可塑性疼痛发生发展的潜在机制。
