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Article(id=1322169020795704118, tenantId=1146029695717560320, journalId=1220038315760373764, issueId=1322168583854080893, articleNumber=null, orderNo=null, doi=10.12102/j.issn.1009-6493.2026.08.002, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1753113600000, receivedDateStr=2025-07-22, revisedDate=1774713600000, revisedDateStr=2026-03-29, acceptedDate=null, acceptedDateStr=null, onlineDate=1793159259270, onlineDateStr=2026-10-28, pubDate=1777046400000, pubDateStr=2026-04-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793159259270, onlineIssueDateStr=2026-10-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793159259270, creator=13701087609, updateTime=1793159259270, updator=13701087609, issue=Issue{id=1322168583854080893, tenantId=1146029695717560320, journalId=1220038315760373764, year='2026', volume='40', issue='8', pageStart='1241', pageEnd='1424', issueExtLink='null', onlineDate='null', pubDate='1777046400000', pubDateStr='2026-04-25', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1793159155095, creator='13701087609', updateTime=1793159155095, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext=null, issueFiles=null, downloadFileDto=null}, startPage=1249, endPage=1256, ext={EN=ArticleExt(id=1322169021156414263, articleId=1322169020795704118, tenantId=1146029695717560320, journalId=1220038315760373764, language=EN, title=Genetic association analysis and mechanism exploration between sleep characteristics and the risk of constipation, columnId=1220689484526572183, journalTitle=Chinese Nursing Research, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=
Objective

To explore the genetic causal association between six sleep characteristics and constipation using Mendelian randomization analysis.

Methods

This study selected the genome-wide association study data of six sleep characteristics from the OpenGWAS database of the Medical Research Council Integrative Epidemiology Unit at University of Bristol and the genome-wide association study data of constipation from the catalog database of Genome Wide Association Study.The inverse variance weighted method(IVW) was adopted as the main analysis method to evaluate the causal relationship between the six sleep characteristics and constipation.MR-Egger and weighted median method(WM) were used as supplementary evidence for the IVW results.At the same time,heterogeneity and horizontal pleiotropy tests were conducted to ensure the stability of the results.The instrumental variables of the positive results were annotated,and enrichment analysis of related genes was performed to predict their potential mechanisms.

Results

The IVW method results showed that insomnia increased the risk of constipation(P=0.002),and sleep duration also affected constipation(P=0.026).Sensitivity analysis indicated that the results were stable.Gene enrichment analysis revealed that insomnia may affect the occurrence of constipation through the immune system pathway,while sleep duration may exert its effect through mechanisms such as regulating the intestinal-brain neural function and catecholamine secretion.

Conclusions

Insomnia is a risk factor for constipation.Ensuring adequate sleep has guiding significance for the prevention and treatment of constipation.

, authors=Xinyue WU1, Lingling MO2, Kongming YANG3, Chuang CHEN2, authorsList=Xinyue WU, Lingling MO, Kongming YANG, Chuang CHEN, authorCompany=null, correspAuthors=Chuang CHEN, authorNote=null, correspAuthorsNote=
CHEN Chuang， E-mail：
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目的

采用孟德尔随机化分析探索6种睡眠特征与便秘之间的遗传因果关联。

方法

选取布里斯托大学医学研究委员会整合流行病学中心OpenGWAS数据库中6种睡眠特征的全基因组关联研究数据和GWAS catalog数据库中便秘的全基因组关联研究数据，采用逆方差加权法（IVW）作为主分析法评估6种睡眠特征与便秘之间的因果关系，孟德尔随机化-Egger法（MR-Egger法）和加权中位数法（WM）作为IVW结果的补充证据，同时进行异质性和水平多效性的检验以保证结果的稳定性。将阳性结果的工具变量进行注释，并对相关基因进行富集分析以预测其潜在机制。

结果

IVW法结果显示，失眠会增加便秘的发病风险（P=0.002），睡眠时间也会影响便秘（P=0.026）。敏感性分析显示结果较稳定。基因富集分析显示，失眠可能通过免疫系统通路影响便秘发生，而睡眠时间则可能通过调节肠-脑神经功能及儿茶酚胺分泌等机制发挥作用。

结论

失眠是便秘的危险因素，保障充足睡眠对预防和治疗便秘有指导意义。

, authors=吴新悦1, 莫灵玲2, 杨孔铭3, 陈闯2, *, *, authorsList=吴新悦, 莫灵玲, 杨孔铭, 陈闯, authorCompany=null, correspAuthors=陈闯, authorNote=

吴新悦，硕士研究生在读

, correspAuthorsNote=
陈闯，E-mail：
CHEN Chuang， E-mail：
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Details of data acquisition

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性状样本量（例）SNP总数（个）研究人群机构GWAS ID
睡眠时型413 3439 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-4956
嗜睡症460 9139 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-5776
早起461 6589 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-2772
失眠462 3419 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-3957
睡眠时间460 0999 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-4424
日间小睡462 4009 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-4616
便秘411 62324 176 599欧洲无ebi-a-GCST90018829
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数据获取的详细信息

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性状样本量（例）SNP总数（个）研究人群机构GWAS ID
睡眠时型413 3439 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-4956
嗜睡症460 9139 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-5776
早起461 6589 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-2772
失眠462 3419 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-3957
睡眠时间460 0999 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-4424
日间小睡462 4009 851 867欧洲布里斯托大学医学研究委员会整合流行病学中心ukb-b-4616
便秘411 62324 176 599欧洲无ebi-a-GCST90018829
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Results of forward MR analysis and sensitivity analysis of six sleep traits and constipation

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暴露结局方法OR值[95%CI]因果效应（P）多效性检验（P）异质性检验（P）
睡眠时型便秘IVW1.032[0.898,1.186]0.6590.161
MR-Egger0.980[0.636,1.509]0.9270.8050.148
WM1.000[0.816,1.226]0.999
嗜睡症便秘IVW1.408[0.752,2.634]0.2850.346
MR-Egger2.733[0.159,46.847]0.4940.6420.309
WM1.359[0.603,3.062]0.459
早起便秘IVW0.829[0.628,1.094]0.1850.093
MR-Egger0.913[0.330,2.525]0.8610.8480.081
WM0.812[0.553,1.193]0.289
失眠便秘IVW2.003[1.293,3.104]0.0020.122
MR-Egger1.385[0.116,16.495]0.7980.7680.103
WM1.927[1.103,3.368]0.021
睡眠时间便秘IVW0.741[0.570,0.964]0.0260.486
MR-Egger0.792[0.284,2.209]0.6580.8950.452
WM0.812[0.542,1.218]0.314
日间小睡便秘IVW1.326[0.999,1.760]0.0510.528
MR-Egger1.042[0.395,2.744]0.9350.6110.505
WM1.149[0.744,1.773]0.531
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6种睡眠特征与便秘正向孟德尔随机化分析与敏感性分析结果

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暴露结局方法OR值[95%CI]因果效应（P）多效性检验（P）异质性检验（P）
睡眠时型便秘IVW1.032[0.898,1.186]0.6590.161
MR-Egger0.980[0.636,1.509]0.9270.8050.148
WM1.000[0.816,1.226]0.999
嗜睡症便秘IVW1.408[0.752,2.634]0.2850.346
MR-Egger2.733[0.159,46.847]0.4940.6420.309
WM1.359[0.603,3.062]0.459
早起便秘IVW0.829[0.628,1.094]0.1850.093
MR-Egger0.913[0.330,2.525]0.8610.8480.081
WM0.812[0.553,1.193]0.289
失眠便秘IVW2.003[1.293,3.104]0.0020.122
MR-Egger1.385[0.116,16.495]0.7980.7680.103
WM1.927[1.103,3.368]0.021
睡眠时间便秘IVW0.741[0.570,0.964]0.0260.486
MR-Egger0.792[0.284,2.209]0.6580.8950.452
WM0.812[0.542,1.218]0.314
日间小睡便秘IVW1.326[0.999,1.760]0.0510.528
MR-Egger1.042[0.395,2.744]0.9350.6110.505
WM1.149[0.744,1.773]0.531
), ArticleFig(id=1322530820603102009, tenantId=1146029695717560320, journalId=1220038315760373764, articleId=1322169020795704118, language=EN, label=Table 3, caption=

Results of reverse MR analysis and sensitivity analysis of six sleep traits and constipation

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暴露结局方法OR值[95%CI]因果效应（P）多效性检验（P）异质性检验（P）
便秘睡眠时型IVW1.003[0.987，1.020]0.7010.296
MR-Egger0.987[0.961，1.013]0.3470.1530.386
WM0.997[0.974，1.021]0.809
便秘嗜睡症IVW1.000[0.991，1.009]0.6080.224
MR-Egger1.000[0.985，1.016]0.5120.9090.173
WM0.999[0.987，1.012]0.945
便秘早起IVW-mre1.007[0.991，1.023]0.4110.036
MR-Egger1.011[0.984，1.039]0.4480.7100.026
WM1.010[0.991，1.029]0.295
便秘失眠IVW1.010[0.997，1.023]0.1340.140
MR-Egger1.001[0.979，1.023]0.9250.3450.144
WM1.009[0.991，1.027]0.329
便秘睡眠时间IVW-mre0.987[0.972，1.003]0.1210.022
MR-Egger0.989[0.962，1.017]0.4500.8940.015
WM0.994[0.976，1.013]0.561
便秘日间小睡IVW0.998[0.989，1.007]0.7070.438
MR-Egger1.003[0.987，1.019]0.7180.4780.404
WM1.000[0.986，1.013]0.969
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6种睡眠特征与便秘反向孟德尔随机化分析与敏感性分析结果

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暴露结局方法OR值[95%CI]因果效应（P）多效性检验（P）异质性检验（P）
便秘睡眠时型IVW1.003[0.987，1.020]0.7010.296
MR-Egger0.987[0.961，1.013]0.3470.1530.386
WM0.997[0.974，1.021]0.809
便秘嗜睡症IVW1.000[0.991，1.009]0.6080.224
MR-Egger1.000[0.985，1.016]0.5120.9090.173
WM0.999[0.987，1.012]0.945
便秘早起IVW-mre1.007[0.991，1.023]0.4110.036
MR-Egger1.011[0.984，1.039]0.4480.7100.026
WM1.010[0.991，1.029]0.295
便秘失眠IVW1.010[0.997，1.023]0.1340.140
MR-Egger1.001[0.979，1.023]0.9250.3450.144
WM1.009[0.991，1.027]0.329
便秘睡眠时间IVW-mre0.987[0.972，1.003]0.1210.022
MR-Egger0.989[0.962，1.017]0.4500.8940.015
WM0.994[0.976，1.013]0.561
便秘日间小睡IVW0.998[0.989，1.007]0.7070.438
MR-Egger1.003[0.987，1.019]0.7180.4780.404
WM1.000[0.986，1.013]0.969
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睡眠特征与便秘发生风险的遗传关联分析及机制探索
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吴新悦 1 , 莫灵玲 2 , 杨孔铭 3 , 陈闯 2, *, *
护理研究 | 科研论著 2026,40(8): 1249-1256
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护理研究 |科研论著 2026 , 40 (8) : 1249 -1256
睡眠特征与便秘发生风险的遗传关联分析及机制探索
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吴新悦1, 莫灵玲2, 杨孔铭3, 陈闯2, *, *
作者信息
  • 1广西医科大学第一附属医院，广西 530021
  • 2广西医科大学附属肿瘤医院
  • 3辽宁中医药大学
通讯作者:
陈闯，E-mail：
CHEN Chuang， E-mail：
作者简介:

吴新悦，硕士研究生在读

Genetic association analysis and mechanism exploration between sleep characteristics and the risk of constipation
Xinyue WU1, Lingling MO2, Kongming YANG3, Chuang CHEN2
Affiliations
  • 1The First Affiliated Hospital of Guangxi Medical University, Guangxi 530021 China
  • 2Affiliated Tumor Hospital of Guangxi Medical University
  • 3Liaoning University of Traditional Chinese Medicine
    • Corresponding Author:
    CHEN Chuang， E-mail：
出版时间: 2026-04-25 doi: 10.12102/j.issn.1009-6493.2026.08.002
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摘要
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目的

采用孟德尔随机化分析探索6种睡眠特征与便秘之间的遗传因果关联。

方法

选取布里斯托大学医学研究委员会整合流行病学中心OpenGWAS数据库中6种睡眠特征的全基因组关联研究数据和GWAS catalog数据库中便秘的全基因组关联研究数据，采用逆方差加权法（IVW）作为主分析法评估6种睡眠特征与便秘之间的因果关系，孟德尔随机化-Egger法（MR-Egger法）和加权中位数法（WM）作为IVW结果的补充证据，同时进行异质性和水平多效性的检验以保证结果的稳定性。将阳性结果的工具变量进行注释，并对相关基因进行富集分析以预测其潜在机制。

结果

IVW法结果显示，失眠会增加便秘的发病风险（P=0.002），睡眠时间也会影响便秘（P=0.026）。敏感性分析显示结果较稳定。基因富集分析显示，失眠可能通过免疫系统通路影响便秘发生，而睡眠时间则可能通过调节肠-脑神经功能及儿茶酚胺分泌等机制发挥作用。

结论

失眠是便秘的危险因素，保障充足睡眠对预防和治疗便秘有指导意义。

便秘  /  睡眠特征  /  孟德尔随机化  /  失眠  /  机制  /  护理
Objective

To explore the genetic causal association between six sleep characteristics and constipation using Mendelian randomization analysis.

Methods

This study selected the genome-wide association study data of six sleep characteristics from the OpenGWAS database of the Medical Research Council Integrative Epidemiology Unit at University of Bristol and the genome-wide association study data of constipation from the catalog database of Genome Wide Association Study.The inverse variance weighted method(IVW) was adopted as the main analysis method to evaluate the causal relationship between the six sleep characteristics and constipation.MR-Egger and weighted median method(WM) were used as supplementary evidence for the IVW results.At the same time,heterogeneity and horizontal pleiotropy tests were conducted to ensure the stability of the results.The instrumental variables of the positive results were annotated,and enrichment analysis of related genes was performed to predict their potential mechanisms.

Results

The IVW method results showed that insomnia increased the risk of constipation(P=0.002),and sleep duration also affected constipation(P=0.026).Sensitivity analysis indicated that the results were stable.Gene enrichment analysis revealed that insomnia may affect the occurrence of constipation through the immune system pathway,while sleep duration may exert its effect through mechanisms such as regulating the intestinal-brain neural function and catecholamine secretion.

Conclusions

Insomnia is a risk factor for constipation.Ensuring adequate sleep has guiding significance for the prevention and treatment of constipation.

constipation  /  sleep characteristics  /  Mendelian randomization  /  insomnia  /  mechanism  /  nursing
吴新悦, 莫灵玲, 杨孔铭, 陈闯. 睡眠特征与便秘发生风险的遗传关联分析及机制探索. 护理研究, 2026 , 40 (8) : 1249 -1256 . DOI: 10.12102/j.issn.1009-6493.2026.08.002
Xinyue WU, Lingling MO, Kongming YANG, Chuang CHEN. Genetic association analysis and mechanism exploration between sleep characteristics and the risk of constipation[J]. Chinese Nursing Research, 2026 , 40 (8) : 1249 -1256 . DOI: 10.12102/j.issn.1009-6493.2026.08.002
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便秘是最常见的胃肠道疾病之一，通常有大便疼痛、排便时间延长、排便困难、排便次数少或不完整、便质干燥或变硬等症状[1-2]。相关研究显示，欧美国家便秘发病率为14%~30%，而我国成年人发病率为7.0%~20.3%，且随年龄增长而增加，60岁以上老年人功能性便秘的发生率为13%~38%[3-4]。便秘不仅发病率高，还与一些疾病关联密切，如直肠占位性病变、肝性脑病、阿尔茨海默病等，同时还促进急性心肌梗死、急性脑血管意外等疾病的发生[5]。便秘严重影响人们的生命质量，其病因学研究极具临床价值。研究证实，便秘发病主要与饮食结构、久坐不动等生活方式及肠道动力异常等因素相关[2]。近年来，也有研究发现，睡眠问题可能在多种胃肠道疾病的病因和病理生理机制中发挥关键作用，睡眠可能会显著影响便秘的发病。作为占据人生三分之一时间的睡眠活动，对维持人体健康至关重要，其受昼夜周期及生物节律调控，这些生理过程可以通过多种机制密切调节胃肠道功能[6-8]。有研究尝试褪黑素给药改善肠易激综合征的便秘情况[9]。但此类临床研究不仅过少，也未调查其他睡眠特征对便秘发病的影响，以荟萃分析和横断面研究为主，存在固有的方法学局限性。横断面研究因无法确定时间顺序且受信息和选择偏倚影响，而难以明确睡眠习惯与便秘是否构成因果关系。作为临床研究金标准的随机对照试验也存在缺陷，其严格的纳入标准导致研究人群同质化而影响结果的外部效度，还面临高昂的时间和经济成本[10]。此外，目前国内外相关的孟德尔随机化研究较少，且主要集中在睡眠与其他胃肠疾病（如结直肠癌、胃食管反流病等）的因果关联上[10-11]。所以，本研究采用孟德尔随机化分析评估睡眠相关特征与便秘发病风险的遗传因果关联。孟德尔随机化分析是一种表观遗传学研究策略，采用单核苷酸多态性（single nucleotide polymorphism,SNP）作为工具变量确定暴露对结局的因果关系。孟德尔随机化分析利用配子发生过程中等位基因的随机分布模拟随机对照试验，最大限度地减少混杂因素和反向因果关联的影响[12]，从而克服了横断面研究中无法确定暴露与结局的时间顺序且易受混杂因素影响的局限。此外，相较于随机对照研究，孟德尔随机化分析可利用现有数据库进行分析，具有成本低、周期短、样本量大、研究对象同质性小等显著优势。而本研究选择睡眠时型（早/晚）、嗜睡症、早起、失眠、睡眠时间和日间小睡这6种睡眠特征进行分析，因其分别代表睡眠的昼夜节律（时型、早起）、质量（失眠、嗜睡症）和行为模式（睡眠时间、日间小睡），涵盖了睡眠的不同维度，且均具有明确的遗传基础。应用双向孟德尔随机化分析探讨这些性状与便秘的因果关联，并通过SNP注释和基因富集分析揭示其潜在生物学机制，为便秘的预防和临床护理提供新证据。
1　研究方法
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1.1　研究设计
在暴露性状的全基因组关联研究（GWAS）汇总数据与结局性状的GWAS汇总数据互相独立的前提下，本研究以6种睡眠特征作为暴露性状，以便秘作为结局性状，使用两样本双向孟德尔随机化分析进行因果关联分析，以此探究6种睡眠特征与便秘的遗传因果效应。孟德尔随机化分析遵循以下三大核心假设[13-14]：工具变量与暴露性状强相关；筛选出的工具变量不受混杂因素影响；工具变量仅通过暴露影响结果。最后，对孟德尔随机化分析阳性结果的工具变量进行基因注释和富集分析，预测暴露与结局关联的潜在通路和生物学功能。
1.2　资料来源
与睡眠相关的6种特征有睡眠时型（早/晚）、嗜睡症、早起、失眠、睡眠时间和日间小睡等，其数据均来源于布里斯托大学医学研究委员会整合流行病学中心OpenGWAS数据库（https://gwas.mrcieu.ac.uk/datasets/），而便秘源于GWAS catalog数据库（https://www.ebi.ac.uk/gwas/studies/GCST90018829），各汇总数据的详细信息见表1，原始研究已获得伦理审批。
1.3　工具变量的筛选
为满足孟德尔随机化分析的三大核心假设，本研究以显著阈值（P<5×10-8）筛选出与暴露性状强相关的工具变量SNP。若以P<5×10-8为标准找不到候选SNP，则以P<5×10-6为显著阈值获得相关工具变量[15]。为了确保所选的工具变量SNP之间的独立性并消除连锁不平衡（LD）可能引入的偏差，本研究筛选的SNP需满足2个条件：任意两个基因间的物理距离超过10 000 kb，且其之间LD的r²<0.001。为评价弱工具变量偏倚，使用F统计量计算工具变量的效力，具体计算公式为F=（N-k-1）/k×R²/（1-R²）[16]，其中，N代表暴露性状研究的样本数，k代表其SNP的总数，R²表示工具变量解释暴露的程度。F>10说明选定的SNP是强工具变量，以此为标准进一步筛选SNP[17]。
1.4　统计分析方法
本研究以逆方差加权法（IVW）为主要分析方法，该法通过方差倒数加权整合各SNP的Wald比率，在有效工具变量无异质性和多效性时进行最优因果分析[18]。若其存在异质性，则以随机效应模型IVW法（IVW-mre）为主要分析方法[19]。此外，孟德尔随机化-Egger法（MR-Egger）和加权中位数法（WM）为本研究的补充方法。MR-Egger法通过带截距的加权回归可检测多效性；WM法则按权重排序SNP效应值后取中位数，在至少50%工具有效时能提供可靠分析[18,20]。敏感性分析可评估孟德尔随机化分析结果的稳定性及可靠性。首先，使用Cochran's Q检验进行异质性检验，若满足检验水准则存在异质性[21]。MR-Egger回归中的截距是反映水平多效性的有效指标，若满足检验水准则存在水平多效性[20]。本研究通过孟德尔随机化-PRESSO分析（MR-PRESSO）去除离群值以校正水平多效性[22]。为明确单个SNP对结果的影响并验证孟德尔随机化分析结果的稳健性，本研究采用了留一法（Leave-one-out检验）。这种方法通过依次排除单个SNP，然后计算剩余SNP组合产生的效应进行分析[23]。
所有分析在R（版本4.3.3）以及TwoSampleMR（版本0.6.1）和MRPRESSO（版本1.0）等软件包中进行。将比值比（OR）与95%CI作为评估暴露因素存在时相对风险的指标。检验水准α=0.05，当P<0.05时认为差异有统计学意义。
1.5　SNP注释
将双向孟德尔随机化分析所得阳性结果的SNP进行注释。使用SNP转换器g:SNPense进行注释，该g:SNPense是一种在线工具，用于将人类SNP标识符映射到相应的基因，并提供其预测的变异效应以及Ensembl变异数据[24]。
1.6　通路和功能富集分析
将SNP注释后所得的相关基因进行基因本体（gene ontology，GO）功能富集分析和京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）通路富集分析，以此揭示暴露与结局性状的潜在作用机制和关键通路。本研究的富集分析通过数据分析和可视化在线平台完成（https://www.bioinformatics.com.cn），以直观展示相关基因的功能分布和通路富集情况[25]。
2　结果
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2.1　工具变量
经过严格的筛选标准，在以6种睡眠特征为暴露且便秘为结局的正向孟德尔随机化分析中，分别纳入了151个与时型、30个与嗜睡症、75个与早起、37个与失眠、68个与睡眠时间、89个与日间小睡相关的SNP作为工具变量。在反向孟德尔随机化分析中，因以P<5×10-8为标准找不到候选SNP，所以将P<5×10-6为显著阈值标准，最终纳入15个便秘相关的SNP作为工具变量。
2.2　睡眠特征与便秘因果关联的正向孟德尔随机化分析结果
正向孟德尔随机化分析结果见表2。其中主要分析法IVW法结果显示失眠会增加便秘的发病风险（P=0.002），睡眠时间也会影响便秘的发病（P=0.026），同时WM法分析结果（P=0.021）再次佐证了失眠与便秘的发病关系。但IVW法显示剩余睡眠特征（睡眠时型、嗜睡症、早起、日间小睡）均与便秘无因果关联（P>0.05）。留一法检验证实，以失眠和睡眠时间为暴露的正向孟德尔随机化分析结果稳健，未发现显著异常SNP，且总效应线不过0（见图1）。散点图显示，3种孟德尔随机化分析方法因果方向一致，表明失眠会增加便秘风险，而延长睡眠时间则降低风险（见图2）。此外，Cochran's Q检验和MR-Egger intercept检验均未检测到异质性和水平多效性，进一步验证了研究结果的可靠性（P>0.05）。
2.3　睡眠特征与便秘因果关联的反向孟德尔随机化分析结果
反向孟德尔随机化研究以便秘为暴露，6种睡眠特征为结局，见表3。Cochran's Q检验显示，以早起和睡眠时间为结局的孟德尔随机化分析存在异质性，故采用IVW-mre法作为主要结果（P<0.05）。IVW法和IVW-mre法显示6种睡眠性状与便秘无反向因果关系（P>0.05），MR-Egger intercept检验显示分析均无水平多效性（P>0.05）。
2.4　SNP注释与基因富集分析的结果
对孟德尔随机化分析中阳性结果的SNP进行注释，分别获得了31个失眠与便秘因果关联的基因集和61个睡眠时间与便秘因果关联的基因集。为了探讨失眠和睡眠时间影响便秘发病可能的机制，对获得的基因集进行了GO功能富集分析和KEGG通路富集分析。GO功能富集分析结果显示，从生物学过程来看，失眠基因集主要与抗原处理、外源性抗原肽和抗原的提呈等免疫反应程序有关，睡眠时间基因集主要与解剖结构退化、纹状体发育、花被片下发育等有关；从细胞组分来看，失眠基因主要在RNA聚合酶Ⅱ转录调节复合物、尾鞘、β-连环蛋白-TCF复合物等，睡眠时间基因主要在突触后膜的整体成分以及内在成分、突触膜等；从分子功能来看，失眠基因集主要与I-SMAD结合、镁离子跨膜转运蛋白活性、RNA聚合酶Ⅱ通用转录起始因子结合等有关，睡眠时间基因集主要与金属离子跨膜转运蛋白活性、儿茶酚胺结合、氧化还原酶活性等有关（见图3）。KEGG通路富集分析显示，失眠基因集主要富集在脊髓小脑性共济失调、运动蛋白、亨廷顿舞蹈症等方面；睡眠时间基因集主要富集在多巴胺能突触、不饱和脂肪酸的生物合成、脂肪酸代谢等方面（见图4）。
3　讨论
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本研究使用双向孟德尔随机化分析进行6种睡眠特征与便秘的遗传关联分析，为便秘的预防和护理提供更有效的指导。正向孟德尔随机化分析表明，失眠可能增加便秘风险，睡眠时间也与便秘发病相关；反向孟德尔随机化分析未发现便秘对失眠或睡眠时间的影响。多项观察性研究也表明，失眠和睡眠时间不足可能增加便秘风险[9,26-28]，与本研究结果一致。本研究弥补了既往研究的不足，还为睡眠与胃肠疾病的关联研究提供了新证据。
有研究表明，人脑与胃肠系统之间存在着密切的联系，该联系主要通过免疫激活、肠道通透性调节以及肠道内分泌信号等机制实现，这些机制促进了信息在肠道和中枢神经系统之间的双向传递，人脑与胃肠系统的联系网络主要由交感神经和副交感神经系统共同调控[29-30]。而肠道蠕动减弱是便秘的关键病因，其受肠神经系统直接调控[2]。所以，失眠和睡眠时间可能是通过影响交感神经和副交感神经系统之间的功能影响便秘的发病。另外，有研究显示，免疫系统在肠-脑轴动态平衡中起关键中介作用，同时与睡眠呈双向关联：免疫激活影响睡眠节律，而睡眠也调控免疫系统[31-32]。结合GO功能富集分析结果，以失眠为暴露的孟德尔随机化研究获得的基因集，主要富集在参与免疫反应的生物学过程。所以，失眠可能是通过免疫反应机制影响便秘的发病。而以睡眠时间为暴露的孟德尔随机化研究显示，其基因集在GO功能富集分析中主要参与纹状体发育、突触膜结构及儿茶酚胺结合；KEGG通路富集分析则表明，这些基因聚集在多巴胺能突触、不饱和脂肪酸生物合成及脂肪酸代谢等通路。纹状体作为基底神经节的重要组成部分，整合皮层和丘脑的谷氨酸能及多巴胺能输入，参与运动调控[33]。突触是神经元信号传递的关键结构。研究表明，Omega-3多不饱和脂肪酸对突触结构和功能的维持至关重要，并且某些短链脂肪酸可通过刺激肠神经系统产生神经递质，增强胃肠动力[34-35]。此外，神经内分泌功能下降可能导致肛门括约肌收缩和胃肠蠕动减弱并伴儿茶酚胺分泌增加，进而引发便秘[36]。综上所述，睡眠时间可能通过影响脂肪酸代谢调节肠神经与中枢神经功能，同时参与儿茶酚胺分泌，进而影响便秘的发病。
4　局限性
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本研究还存在一定的局限性，由于采用欧洲人群GWAS数据，结果可能受人群和环境影响，导致结果外推性受限。未来应开展跨人群孟德尔随机化分析，并结合多组学数据探索基因-环境交互作用，以提升结果的普遍性和适用性。其次，由于缺乏年龄分层数据支持，本研究无法验证睡眠与便秘的因果关系是否受年龄影响。期待未来有更详细的年龄分层大规模GWAS数据支持进一步研究。此外，以失眠为暴露因素的孟德尔随机化研究获得的基因数量较少，基因富集分析的结果可能有偏差。最后，通过GO及KEGG富集分析预测失眠和睡眠时间影响便秘发病可能的机制，缺少具体基础实验的验证。尽管如此，本研究仍为睡眠与便秘的关联提供了重要证据，提示临床中应关注失眠和睡眠不足对便秘的影响，具有预防指导价值。

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2026年第40卷第8期
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doi: 10.12102/j.issn.1009-6493.2026.08.002
  • 接收时间：2025-07-22
  • 首发时间：2026-10-28
  • 出版时间：2026-04-25
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  • 收稿日期：2025-07-22
  • 修回日期：2026-03-29
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    1广西医科大学第一附属医院，广西 530021
    2广西医科大学附属肿瘤医院
    3辽宁中医药大学

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CHEN Chuang， E-mail：
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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