揭示偏头痛亚型异质性和风险位点:整合全基因组关联研究和单细胞转录组学发现。

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Shuxu Wei, Yan Quan, Xinyi Li, Suiqin Zhong, Ling Xiao, Chao Yang, Ronghuai Shen, Xiaojia Lu, Lingbin He, Youti Zhang, Xianxi Huang
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引用次数: 0

摘要

背景:偏头痛是一种具有不同亚型(先兆偏头痛[MA]和无先兆偏头痛[MO])的衰弱性神经系统疾病,其遗传和空间异质性尚不清楚。虽然亚型之间的遗传相关性已经建立,但驱动其不同临床表型的空间分辨分子机制(特别是在组织微环境中)尚不清楚,这限制了靶向治疗的发展。方法:我们将FinnGen R11和国际队列的全基因组关联研究(GWAS)数据与转录组学、表观基因组学和空间分辨单细胞空间转录组学(sc-ST)图谱相结合。使用连锁不平衡评分回归(LDSC)、高清晰度似然(HDL)和分区遗传力分析评估遗传相关性和功能注释。多组学框架结合了表达和甲基化数量性状位点(eQTL/mQTL)的汇总孟德尔随机化(SMR)、基于功能汇总的归算(FUSION)、基因组注释的多标记分析(MAGMA)、关节组织归算增强PrediXcan分析(JTI-PrediXcan)和多基因优先评分(PoPS),基于方法学鲁棒性(≥2种分析方法)和跨亚型一致性对基因进行系统排序。通过复杂性状细胞的遗传信息空间图谱(gsMap)验证了组织富集特异性,gsMap是一种整合sc-ST和GWAS数据的新算法,可以在胚胎组织中以单细胞分辨率绘制亚型相关的细胞结构。结果:LDSC和HDL证实了MA和MO之间的强遗传相关性,但它们在功能基因组注释中显示出不同的功能结构,MA富集于保守的调控元件(如Backgrd_Selection_StatL2_0,富集= 1.38,P = 5.47 × 10-6),而MO富集于血管通路(如GERP)。NSL2_0,富集度= 2.12,P = 1.04 × 10-6)。Sc-ST显示空间分化的壁龛:MA在神经嵴来源组织(颌原基,p = 0.0039)和下丘脑小胶质邻接处显示产前富集,与神经免疫调节一致,而MO在血管平滑肌和肠-脑界面显示外周倾向,与LDSC-SEG/MAGMA血管通路证实。多组学整合鉴定出高置信度的交叉亚型基因(LRP1 [PoPS: Overall = 3.67, MO = 0.80]、PHACTR1 [PoPS: Overall = 2.65, MA = 0.33, MO = 1.28]、STAT6 [PoPS: Overall = 3.00, MO = 2.29]、RDH16、TTC24、ZBTB39、FHL5、MEF2D、NAB2、UFL1和REEP3),这些基因得到了≥2种方法的支持。亚型特异性基因包括ma相关的神经元调节因子(CACNA1A, KLHDC8B)和mo特异性血管/代谢基因(如ACO2, BCAR1, CCDC134)。结论:我们的研究描述了偏头痛异质性的空间约束机制:MA源于神经免疫-表观遗传失调,而MO由血管代谢紊乱驱动。关键基因和途径为亚型特异性治疗提供了可行的靶点。通过连接遗传结构与空间生物学,我们重新定义偏头痛的发病机制和精确的干预策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Unveiling migraine subtype heterogeneity and risk loci: integrated genome-wide association study and single-cell transcriptomics discovery.

Background: Migraine, a debilitating neurological disorder with distinct subtypes (migraine with aura [MA] and migraine without aura [MO]), exhibits genetic and spatial heterogeneity that remains poorly understood. While genetic correlations between subtypes are established, spatially resolved molecular mechanisms driving their divergent clinical phenotypes-particularly in tissue microenvironments-are unclear, limiting targeted therapeutic development.

Methods: We integrated genome-wide association study (GWAS) data from FinnGen R11 and international cohorts with transcriptomic, epigenomic, and spatially resolved single-cell spatial transcriptomics (sc-ST) profiles. Genetic correlations and functional annotations were assessed using Linkage Disequilibrium Score Regression (LDSC), High-Definition Likelihood (HDL), and partitioned heritability analyses. A multi-omics framework combined Summary Mendelian Randomization (SMR) for expression and methylation quantitative trait loci (eQTL/mQTL), Functional Summary-based Imputation (FUSION), Multi-marker Analysis of GenoMic Annotation (MAGMA), Joint-Tissue Imputation Enhanced PrediXcan Analysis (JTI-PrediXcan), and the Polygenic Priority Score (PoPS) to systematically prioritize genes based on methodological robustness (≥ 2 analytical approaches) and cross-subtype consistency. Tissue-enriched specificity was validated via genetically informed spatial mapping of cells for complex traits (gsMap), a novel algorithm integrating sc-ST and GWAS data to map subtype-associated cellular architectures at single-cell resolution across embryonic tissues.

Results: LDSC and HDL confirmed strong genetic correlations between MA and MO. But they showed divergent functional architectures in functional genomic annotations, with MA enriched in conserved regulatory elements (e.g., Backgrd_Selection_StatL2_0, enrichment = 1.38, P = 5.47 × 10-6) and MO in vascular pathways (e.g., GERP.NSL2_0, enrichment = 2.12, P = 1.04 × 10-6). Sc-ST revealed spatially divergent niches: MA showed prenatal enrichment in neural crest-derived tissues (jaw primordium, p = 0.0039) and hypothalamic microglial adjacencies, aligning with neuroimmune regulation, while MO exhibited peripheral tropism in vascular smooth muscle and gut-brain interfaces, corroborated by LDSC-SEG/MAGMA vascular pathways. Multi-omics integration identified high-confidence cross-subtype genes (LRP1 [PoPS: Overall = 3.67, MO = 0.80], PHACTR1 [PoPS: Overall = 2.65, MA = 0.33, MO = 1.28], STAT6 [PoPS: Overall = 3.00, MO = 2.29], RDH16, TTC24, ZBTB39, FHL5, MEF2D, NAB2, UFL1, and REEP3) supported by ≥ 2 methods. Subtype-specific genes included MA-associated neuronal regulators (CACNA1A, KLHDC8B) and MO-specific vascular/metabolic genes (e.g., ACO2, BCAR1, CCDC134).

Conclusion: Our study delineates spatially constrained mechanisms underlying migraine heterogeneity: MA arises from neuroimmune-epigenetic dysregulation, while MO is driven by vascular-metabolic perturbations. Key genes and pathways provide actionable targets for subtype-specific therapies. By bridging genetic architecture with spatial biology, we redefine migraine pathogenesis and precision intervention strategies.

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来源期刊
Journal of Headache and Pain
Journal of Headache and Pain 医学-临床神经学
CiteScore
11.80
自引率
13.50%
发文量
143
审稿时长
6-12 weeks
期刊介绍: The Journal of Headache and Pain, a peer-reviewed open-access journal published under the BMC brand, a part of Springer Nature, is dedicated to researchers engaged in all facets of headache and related pain syndromes. It encompasses epidemiology, public health, basic science, translational medicine, clinical trials, and real-world data. With a multidisciplinary approach, The Journal of Headache and Pain addresses headache medicine and related pain syndromes across all medical disciplines. It particularly encourages submissions in clinical, translational, and basic science fields, focusing on pain management, genetics, neurology, and internal medicine. The journal publishes research articles, reviews, letters to the Editor, as well as consensus articles and guidelines, aimed at promoting best practices in managing patients with headaches and related pain.
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