A number of observational studies indicate that insomnia is linked to inflammatory digestive diseases (IDDs). However, the definite relationship between insomnia and IDDs remains unclear.
Methods
We obtained the publicly available data from genome-wide association studies (GWAS) to conduct two-sample Mendelian randomization (MR) for association assessment. Five MR analysis methods were used to calculate the odds ratio (OR) and effect estimate, and the heterogeneity and pleiotropy tests were performed to evaluate the robustness of the variable instruments (IVs).
Results
One exposure and twenty outcome datasets based on European populations were included in this study. Using the inverse variance weighted method, we found insomnia was closely correlated with esophageal ulcer (OR = 1.011, 95%CI = 1.004–1.017, p = 0.001) and abdominal pain (effect estimate = 1.016, 95%CI = 1.005–1.026, p = 0.003). Suggestive evidence of a positively association was observed between insomnia and duodenal ulcer (OR = 1.006, 95%CI = 1.002–1.011, p = 0.009), gastric ulcer (OR = 1.008, 95%CI = 1.001–1.014, p = 0.013), rectal polyp (OR = 1.005, 95%CI = 1.000-1.010, p = 0.034), haemorrhoidal disease (OR = 1.242, 95%CI = 1.004–1.535, p = 0.045) and monocyte percentage (effect estimate = 1.151, 95%CI = 1.028–1.288, p = 0.014). No correlations were observed among other IDDs, phenotypes and biomarkers.
Conclusions
Our MR study assessed the relationship between insomnia and IDDs/phenotypes/biomarkers in depth and revealed potential associations between insomnia and ulcers of the esophagus and abdominal pain.
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Introduction
Inflammatory bowel disease (IBD) is a chronic, non-specific intestinal inflammatory illness that mostly includes Crohn’s disease (CD) and ulcerative colitis (UC) [1]. The incidence of IBD has increased globally in recent years, particularly in Europe and developing countries, posing a significant clinical challenge [2‐5]. Although its probable causes are unknown, the immune impairment viewpoint gives a full picture of the disease’s multi-factor origin [6]. Intestinal bacterial disorders are one of the reasons for the development of IBD, as confirmed by the randomized, controlled PRASCO trial (using the metagenome method) [7]. In addition, therapeutic nutrition was considered to be associated with IBD alleviation [8, 9].
More and more studies show that interrupted sleep and irregular day and night rhythms can cause severe damage to the gastrointestinal tract [10]. A prospective cohort study demonstrated that sleep insufficiency and daytime napping significantly increased the risk of IBD [11]. This potentially indicates that the ability to fine-tune our intestinal barrier and the normal interaction between the mucous immune system and microorganisms is disrupted when the rhythm of the central nervous system is disturbed during the day and night. On the contrary, another retrospective cohort study including 48,799 IBD patients found that IBD patients were correlated with a higher incidence ratio of insomnia with a hazard ratio (HR) of 1.99 [12]. Moreover, several studies also found a relatively consistent conclusion that IBD might promote insomnia, which could be illustrated as symptoms like pain worsened sleep quality [13‐15]. A questionnaire study showed that 81% of 312 respondents said they believed there was an interaction between sleep and IBD [15]. However, the association between insomnia and IBD still remains undefined. Current research may contain a selection bias by its nature, requiring us to interpret the results with caution. A randomized controlled study on this issue is urgently needed to confirm the potential relationship.
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Additionally, peptic ulcer disease(PUD) [16, 17] and intestinal polyp [18] were also considered to be potentially correlated with sleep duration. All of these inflammatory digestive diseases (IDDs) cause physical and mental suffering and a high medical burden for patients. Hence, it is of great clinical value to explore the potential association between them and insomnia to benefit patients through a lifestyle shift.
Mendelian randomization (MR) analysis is an epidemiological statistical technique that uses observational data to estimate causality. It has been widely used in inferring the potential causal relationships between an exposure and an outcome, owing to its advantage of minimizing the influence of confounders by introducing genetic variants as instrumental variables (IVs) [19, 20]. Using the characteristics of random allocation of allelic genetic polymorphisms, MR has largely overcome the disadvantages of reverse causality bias and ethical issues [21].
Here we extend the concept of IBD to IDDs, which include 10 benign gastrointestinal inflammatory diseases. Two-sample MR was performed to assess the potential associations between insomnia and inflammatory diseases/phenotypes/biomarkers. In this study, we aim to answer two core questions: (1) whether there are potential relationships between insomnia and IDDs (positive/negative). (2) whether potential links exist between insomnia and IDD-related phenotypes and biomarkers.
Materials and methods
Study design
The overview of study design and three core hypotheses for genetic IVs are demonstrated in Fig. 1: (1) Relevance hypothesis: single nucleotide polymorphisms (SNPs) are strongly correlated with insomnia (Fig. 1A); (2) Independence hypothesis: SNPs are independent of known confounders (Fig. 1B); (3) Exclusivity hypothesis: insomnia is the only approach for SNPs affecting IDDs/phenotypes/biomarkers (Fig. 1C) [22].
Fig. 1
Three core assumptions of the MR study. A SNPs are closely associated with exposure (insomnia); B SNPs are independent of confounders; C SNPs only affect outcomes (inflammatory digestive diseases, phenotypes and biomarkers) through exposure of insomnia. MR, mendelian randomization; SNPs, single nucleotide polymorphisms
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Exposure and outcome data
The open genome-wide association study (GWAS) database, based on scalable and high-performance cloud data infrastructure, supports complete GWAS summary datasets and metadata for the public (https://gwas.mrcieu.ac.uk/) [23]. This research was conducted using published data from GWASs of related traits in European individuals (both males and females included). The GWAS dataset for sleeplessness/insomnia (n = 462,341) was obtained from the MRC-IEU Consortium of the UK Biobank, in which estimated the correlation between insomnia and SNPs [24]. Ulcer of esophagus (n = 463,010), Duodenal ulcer (n = 462,933), Gastric ulcer (n = 462,933), Ulcerative colitis (n = 462,933), Crohn’s disease (n = 462,933), Colitis (n = 462,933), Polyp of stomach and duodenum (n = 463,010), Polyp of colon (n = 463,010) and Rectal polyp (n = 463,010) were obtained from the MRC-IEU Consortium [23]. Haemorrhoidal disease was obtained from the results reported by Zheng et al. [25]. For inflammatory digestive phenotypes, Nausea and vomiting (n = 463,010), Abdominal pain (n = 463,010), and Change in bowel habit (n = 463,010) were obtained from MRC-IEU Consortium [23]. Gastrointestinal (GI)-bleeding (n = 215,956) was obtained from the FinnGen biobank. As for inflammatory digestive biomarkers, C-reactive protein (CRP) level (n = 204,402) was derived from the results revealed by Ligthart et al. [26]. Neutrophil cell count (n = 563,946) and Lymphocyte cell count (n = 563,946) were achieved from Blood cell consortium [27]. Eosinophil percentage (n = 349,861), Basophil percentage (n = 349,861) and Monocyte percentage (n = 349,861) from Neale Lab. All the datasets were collected by using the TwoSampleMR R package. Details of all the datasets were summarized in Table 1.
Table 1
Baseline characteristics of insomnia and inflammatory digestive diseases, phenotypes and biomarkers
Trait
GWAS ID
Year
Author
Population
Sample Size
Case (n)
Control (n)
SNP (n)
Sleeplessness/insomnia
ukb-b-3957
2018
Ben Elsworth
European
462,341
-
-
9,851,867
Ulcer of esophagus
ukb-b-13,731
2018
Ben Elsworth
European
463,010
3,251
459,759
9,851,867
Duodenal ulcer
ukb-b-4725
2018
Ben Elsworth
European
462,933
1,908
461,025
9,851,867
Gastric ulcer
ukb-b-20,078
2018
Ben Elsworth
European
462,933
3,329
459,604
9,851,867
Ulcerative colitis
ukb-b-7584
2018
Ben Elsworth
European
462,933
2,439
460,494
9,851,867
Crohn’s disease
ukb-b-8210
2018
Ben Elsworth
European
462,933
1,401
461,532
9,851,867
Colitis
ukb-b-3044
2018
Ben Elsworth
European
462,933
1,193
461,740
9,851,867
Polyp of stomach and duodenum
ukb-b-3027
2018
Ben Elsworth
European
463,010
1,233
461,777
9,851,867
Polyp of colon
ukb-b-17,845
2018
Ben Elsworth
European
463,010
2,437
460,573
9,851,867
Rectal polyp
ukb-b-8348
2018
Ben Elsworth
European
463,010
1,837
461,173
9,851,867
Haemorrhoidal disease
ebi-a-GCST90014033
2021
Zheng T
European
944,133
218,920
725,213
8,424,267
Nausea and vomiting
ukb-b-4554
2018
Ben Elsworth
European
463,010
6,773
456,237
9,851,867
GI-bleeding
finn-b-K11_GIBLEEDING
2021
NA
European
215,956
4,992
210,964
16,380,464
Abdominal pain
ukb-b-6223
2018
Ben Elsworth
European
463,010
11,925
451,085
9,851,867
Change in bowel habit
ukb-b-10,368
2018
Ben Elsworth
European
463,010
2,443
460,567
9,851,867
C-reactive protein level
ieu-b-35
2018
Ligthart, S
European
204,402
NA
NA
2,414,379
Neutrophil cell count
ieu-b-34
2020
Vuckovic, D
European
563,946
NA
NA
NA
Lymphocyte cell count
ieu-b-32
2020
Vuckovic, D
European
563,946
NA
NA
NA
Eosinophill percentage
ukb-d-30210_irnt
2018
Neale lab
European
349,861
NA
NA
13,586,283
Basophil percentage
ukb-d-30220_irnt
2018
Neale lab
European
349,861
NA
NA
13,586,283
Monocyte percentage
ukb-d-30190_irnt
2018
Neale lab
European
349,861
NA
NA
13,586,283
GWAS Genome-wide association study, SNP Single nucleotide polymorphism, NA Not available
Ethics statement
The GWAS summary-level data are publicly available and approved by their corresponding ethical review boards. Ethics approval was exempted for our study.
SNPs selection and validation
In the present research, SNPs linked with insomnia were chosen and confirmed as IVs if they fulfilled the three conditions listed below: (1) The genome-wide significance threshold level was defined as p < 5E-08; (2) The linkage disequilibrium of SNPs threshold was set at r2 < 0.001 and Kb = 10,000 to avoid the bias caused by them [28]; (3) The F statistic was calculated to assess the strength of each IV. To mitigate the bias caused by a weak instrumental variable, each SNP included must satisfy the condition of F-value > 10 [29, 30]. The formula is as follows [31]:
Annotation: MAF: minor allele frequency = eaf.exposure; SE = se.exposure; \(\beta\) = beta.exposure; N: no. of samples; K: no. of SNPs.
Secondly, PhenoScanner V2 (http://www.phenoscanner.medschl.cam.ac.uk/) was used to remove the SNPs of confounders related to the exposure and outcome [32, 33]. Thirdly, data harmonization was performed to align the effect alleles of IVs.
Statistical analysis
To estimate the potential association between insomnia and different IDDs/phenotypes/biomarkers comprehensively, random/fixed-effects inverse variance weighting (R/F-IVW), MR Egger, Weighted median, Simple mode and Weighted mode were performed for sensitivity analyses. The Mendelian estimates of different validity assumptions can be obtained from the above methods [34, 35]. We adopted IVW as the primary analysis method to report the odds ratio (OR) with 95% confidence intervals (CI), owing to its remarkable performance on accurate estimates and SNPs validation [36]. Additionally, MR-Egger regression and IVW were utilized to assess the heterogeneity of IVs. We utilized the MR-Egger interception method to test for pleiotropy and kicked out outliers via the MR-PRESSO method [37]. We conducted a leave-one-out analysis to evaluate whether and which individual SNPs could affect the overall estimates disproportionately. The Bonferroni correction method [38] was used to safeguard against the effect of multiple tests. Instead of using a p-value threshold of 0.05, p < 0.005 (α = 0.05/10 outcomes), p < 0.0125 (α = 0.05/4 phenotypes) and p < 0.008 (α = 0.05/6 biomarkers) were considered to be statistically significant for inflammatory digestive outcomes, phenotypes and biomarkers, respectively. If the Bonferroni-corrected value < p < 0.05, potential evidence of correlation was indicated, which needs further validation. We implemented all statistical analyses and visualizations employing the “Two-Sample MR” package [27] in R (version 4.0.3).
Results
Selection and validation of IVs
After screening, 42 SNPs that correlated strongly with insomnia in individuals of European descent were identified as IVs. All of them were verified to meet the criteria for IVs, with an F value > 10 (summarized in Table 2).
Table 2
Single nucleotide polymorphisms used as instrumental variables in the Mendelian randomization analyses of insomnia
SNP
Chr
A1
A2
SE
Beta
MAF
F-statistics
Nearby gene
P-value
rs2803296
1
C
G
0.001
-0.009
0.544
33
CALML6
7.30E-09
rs12049261
1
C
G
0.002
0.011
0.293
47
RP11-478L17.1
6.80E-12
rs6690017
1
G
T
0.002
-0.010
0.409
46
DAB1
1.10E-11
rs2644128
1
G
C
0.001
0.011
0.548
51
NAV1
1.00E-12
rs4572538
2
T
C
0.002
-0.010
0.364
38
PABPC1P2
7.70E-10
rs56365214
2
A
C
0.002
-0.015
0.156
52
LINC01122
5.60E-13
rs4577309
2
G
A
0.001
-0.009
0.534
33
MFSD6
1.00E-08
rs12470989
2
G
A
0.002
-0.010
0.204
31
MAIP1
2.80E-08
rs113851554
2
T
G
0.003
0.047
0.057
199
MEIS1
2.90E-45
rs56093896
2
A
C
0.002
-0.012
0.214
47
IGKV1OR2-108
7.70E-12
rs2014830
3
T
C
0.002
-0.012
0.304
51
SEMA3F-AS1
8.90E-13
rs705219
3
A
T
0.002
0.013
0.887
33
RP11-384F7.2
1.20E-08
rs9845387
3
A
C
0.004
-0.022
0.040
33
LSAMP
7.10E-09
rs1988337
4
G
A
0.001
0.008
0.552
31
CCSER1
2.10E-08
rs11097861
4
G
A
0.002
0.010
0.716
37
RP11-729M20.1
1.10E-09
rs2604551
4
G
T
0.002
-0.008
0.640
30
RP11-665G4.1
4.70E-08
rs1592757
5
C
G
0.002
0.010
0.356
43
RP11-6N13.1
4.30E-11
rs7711696
5
T
G
0.002
0.011
0.305
48
SMAD5
4.10E-12
rs1430205
5
T
C
0.001
0.009
0.462
40
TMEM161B-AS1
2.10E-10
rs314280
6
G
A
0.001
0.010
0.547
42
LIN28B
7.30E-11
rs6975972
7
G
A
0.002
-0.009
0.579
36
C7orf50
2.00E-09
rs8180817
7
C
G
0.002
-0.010
0.431
44
FOXP2
2.70E-11
rs17151854
8
T
G
0.002
0.013
0.152
39
MSRA
3.80E-10
rs11790060
9
C
T
0.002
-0.010
0.331
43
RP11-165J3.6
5.80E-11
rs224032
10
A
G
0.001
0.008
0.550
32
ALDH7A1P4
1.80E-08
rs17709610
10
G
A
0.002
-0.010
0.298
37
ACTR1A
9.50E-10
rs2297787
10
A
T
0.003
-0.018
0.080
42
CNNM2
9.60E-11
rs72924721
11
T
C
0.003
0.016
0.073
33
CFL1
1.10E-08
rs10838708
11
A
G
0.002
-0.009
0.459
40
PSMC3
2.90E-10
rs68094047
12
T
C
0.002
0.010
0.251
36
MYO1H
1.70E-09
rs931221
12
A
T
0.002
0.011
0.237
37
RP11-788H18.1
1.30E-09
rs324017
12
C
A
0.002
-0.010
0.705
37
NAB2
1.40E-09
rs9570080
13
C
T
0.002
-0.011
0.344
45
RPP40P2
1.60E-11
rs6561715
13
A
T
0.002
-0.012
0.631
57
RP11-384G23.1
4.80E-14
rs1547630
13
A
G
0.002
0.009
0.652
34
SNORD44
5.80E-09
rs4886860
15
C
G
0.002
-0.012
0.767
45
PML
1.80E-11
rs11635495
15
C
T
0.001
0.009
0.512
40
IQCH-AS1
2.80E-10
rs2062113
16
C
T
0.002
-0.010
0.568
41
AC040163.1
1.60E-10
rs9894577
17
A
G
0.002
0.013
0.318
68
HEXIM1
1.30E-16
rs9906181
17
G
A
0.002
-0.009
0.688
31
KCNJ12
2.40E-08
rs11152363
18
A
G
0.002
0.016
0.186
66
TCF4
4.50E-16
rs56330606
19
G
A
0.002
0.009
0.379
37
ZNF585B
1.20E-09
SNP Single-nucleotide polymorphisms, Chr Chromosome, A1 Effect allele, A2 Other allele, SE Standard error, MAF Minor allele frequency
MR sensitivity analysis
We assessed the potential associations between insomnia and inflammatory digestive diseases, phenotypes and biomarkers in people of European descent mainly using the IVW approach. The results showed that insomnia might be positively correlated with all IDDs at the genetic level, while no statistically significant association was found for ulcerative colitis, Crohn’s disease, colitis, polyp of colon and polyp of the stomach and duodenum (all p > 0.05). Based on the analysis, we speculated that there might be a potential relationship between insomnia and ulcer of the esophagus (OR = 1.011, 95%CI = 1.004–1.017, p = 0.001). However, only suggestive evidence of positive associations was observed in duodenal ulcer (OR = 1.006, 95%CI = 1.002–1.011, p = 0.009), gastric ulcer (OR = 1.008, 95%CI = 1.001–1.014, p = 0.013), rectal polyp (OR = 1.005, 95%CI = 1.000-1.010, p = 0.034) and haemorrhoidal disease (OR = 1.242, 95%CI = 1.004–1.535, p = 0.045) (Fig. 2A). For most IDDs, the results of MR-Egger and weighted-median analyses revealed approximate estimates of lower exactness (Table 3). No obvious evidence of horizontal pleiotropy was detected (all p > 0.05). Based on the heterogeneity test, the fixed-effects model was applied to most IDDs except haemorrhoidal disease (p = 1.04E-08) which adopted the random-effects model to alleviate the effect of heterogeneity (Table 3).
Fig. 2
Associations of genetically predicted insomnia with inflammatory digestive diseases, phenotypes, and biomarkers. A Effect of insomnia on inflammatory digestive diseases using IVW analysis; B Effect of insomnia on inflammatory digestive phenotypes and biomarkers using IVW analysis. IVW, inverse-variance weighted; CI, confidence interval; OR, odds ratio; SNPs, single nucleotide polymorphisms
Table 3
Associations between genetically predicted insomnia and inflammatory digestive diseases in sensitivity analyses using the weighted-median and MR-Egger methods
Outcome
Weighted Median
MR-Egger
Heterogeneity
Pleiotropy
OR (95%CI)
P
OR (95%CI)
P
Q
P
Intercept
P
Ulcer of esophagus
1.011 (1.002–1.020)
0.017
1.011 (0.967–1.058)
0.623
41.84
0.167
-6.95E-06
0.977
Duodenal ulcer
1.004 (0.998–1.011)
0.203
0.994 (0.959–1.030)
0.740
26.64
0.690
1.29E-04
0.490
Gastric ulcer
1.006 (0.997–1.014)
0.201
0.996 (0.955–1.039)
0.865
36.15
0.368
1.20E-04
0.594
Ulcerative colitis
1.000 (0.992–1.007)
0.954
0.997 (0.962–1.033)
0.877
30.97
0.519
4.85E-05
0.798
Crohn’s disease
0.999 (0.992–1.007)
0.888
1.014 (0.965–1.066)
0.584
28.55
0.237
1.30E-04
0.618
Colitis
1.004 (0.997–1.010)
0.266
1.026 (0.986–1.067)
0.220
22.42
0.495
2.16E-04
0.286
Polyp of stomach and duodenum
1.005 (0.999–1.011)
0.117
1.020 (0.981–1.060)
0.331
21.16
0.629
1.68E-04
0.403
Polyp of colon
1.000 (0.992–1.007)
0.952
0.983 (0.947–1.020)
0.366
36.63
0.304
2.11E-04
0.293
Rectal polyp
1.005 (0.998–1.012)
0.203
0.973 (0.932–1.015)
0.214
30.82
0.425
3.33E-04
0.139
Haemorrhoidal disease
1.317 (1.071–1.619)
0.009
1.141 (0.568–2.294)
0.713
108.53
1.04E-08
1.00E-03
0.805
CI Confidence interval, MR Mendelian randomization, OR Odds ratio
×
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For inflammatory digestive phenotypes, the IVW analysis demonstrated that insomnia potentially correlated with abdominal pain (effect estimate = 1.016, 95%CI = 1.005–1.026, p = 0.003). Additionally, genetically predicted liability to insomnia might be positively correlated with nausea and vomiting and GI-bleeding, although no statistically significant results were obtained. To our surprise, an inverse association between insomnia and change in bowel habit (effect estimate = 0.998, 95%CI = 0.993–1.003, p = 0.485) was observed, although the result was not statistically significant (Fig. 2B). As to inflammatory biomarkers, except for the suggestive evidence of a positive relationship between insomnia and monocyte percentage (effect estimate = 1.151, 95%CI = 1.028–1.288, p = 0.014), no statistically significant association between insomnia and other biomarkers was observed (all p > 0.05) (Fig. 2B). Consistent with above, MR-Egger and weighted-median analyses revealed approximate estimates but of lower exactness (Table 4). No obvious evidence of horizontal pleiotropy was detected (all p > 0.05). According to the heterogeneity test, the fixed-effects model was applied to inflammatory digestive phenotypes, while the random-effects model was applied to inflammatory digestive biomarkers (Table 4).
Table 4
Associations between genetically predicted insomnia and inflammatory digestive phenotypes and biomarkers in sensitivity analyses using the weighted-median and MR-Egger methods
Outcome
Weighted Median
MR-Egger
Heterogeneity
Pleiotropy
EE (95%CI)
P
EE (95%CI)
P
Q
P
Intercept
P
Nausea and vomiting
1.007 (0.995–1.019)
0.234
1.007 (0.979–1.035)
0.653
43.21
0.223
1.09E-05
0.947
GI-bleeding
1.639 (0.639–4.204)
0.304
1.561 (0.237–10.290)
0.646
27.99
0.857
-1.19E-03
0.915
Abdominal pain
1.009 (0.993–1.025)
0.274
1.006 (0.973–1.040)
0.717
37.49
0.493
1.15E-04
0.553
Change in bowel habit
1.000 (0.993–1.007)
0.998
1.006 (0.971–1.043)
0.731
28.20
0.705
-8.57E-05
0.651
C-reactive protein level
1.109 (0.789–1.559)
0.552
1.103 (0.109–11.179)
0.935
43.96
6.01E-05
-2.72E-03
0.826
Neutrophil cell count
0.962 (0.859–1.076)
0.496
1.165 (0.743–1.826)
0.512
169.74
2.56E-20
-3.09E-03
0.250
Lymphocyte cell count
0.892 (0.797–0.999)
0.047
0.853 (0.506–1.437)
0.554
215.17
1.32E-28
7.92E-04
0.797
Eosinophill percentage
1.112 (0.986–1.253)
0.084
0.910 (0.561–1.475)
0.704
152.87
1.03E-15
1.57E-03
0.577
Basophil percentage
0.895 (0.792–1.011)
0.075
0.722 (0.507–1.027)
0.078
84.24
2.36E-05
2.85E-03
0.170
Monocyte percentage
1.048 (0.936–1.173)
0.418
0.909 (0.640–1.293)
0.600
86.81
6.99E-06
2.82E-03
0.175
CI Confidence interval, MR Mendelian randomization, EE Effect estimate
Scatter plots of the association between insomnia and IDDs/phenotypes and biomarkers showed similar results (Figs. 3 and 4). Forest plot displayed each SNP’s influence on the associations between insomnia and IDDs/phenotypes and biomarkers (Figs. 5 and 6). For additional confirmation, the leave-one-out sensitivity analysis showed that no particular SNP altered the total estimates of IVs excessively, which was consistent with previous results (Figs. 7 and 8). The absence of horizontal pleiotropy was also confirmed by the funnel plot (Figs. 9 and 10).
Fig. 3
Scatter plot of the association of insomnia with inflammatory digestive diseases. A Ulcer of the esophagus; B Duodenal ulcer; C Gastric ulcer; D Ulcerative colitis; E Crohn’s disease; F Colitis; G Polyp of stomach and duodenum; H Polyp of the colon; I Rectal polyp; J Haemorrhoidal disease. Each dot represents an SNP, which is plotted with standard error bars by the estimate of SNP on individual sleep condition and the estimate of SNP on the risk of inflammatory digestive diseases. The slopes of the lines correspond to estimates calculated using each of the five approaches. SNP, single nucleotide polymorphism
Fig. 4
Scatter plot of the association of insomnia with inflammatory digestive phenotypes and biomarkers. A Nausea and vomiting; B GI-bleeding; C Abdominal pain; D Change in bowel habit; E C-reactive protein level; F Neutrophil cell count; G Lymphocyte cell count; H Eosinophill percentage; I Basophil percentage; J Monocyte percentage. Each dot represents an SNP, which is plotted with standard error bars by the estimate of SNP on individual sleep condition and the estimate of SNP on the risk of inflammatory digestive phenotypes and biomarkers. The slopes of the lines correspond to estimates calculated using each of the five approaches. GI, gastrointestinal; SNP, single nucleotide polymorphism
Fig. 5
Forest plot of the association of insomnia with inflammatory digestive diseases. A Ulcer of the esophagus; B Duodenal ulcer; C Gastric ulcer; D Ulcerative colitis; E Crohn’s disease; F Colitis; G Polyp of stomach and duodenum; H Polyp of the colon; I Rectal polyp; J Haemorrhoidal disease. The dot and bar estimate the effect of each SNP related to insomnia on the risk of inflammatory digestive disease. SNP, single nucleotide polymorphism
Fig. 6
Forest plot of the association of insomnia with inflammatory digestive phenotypes and biomarkers. A Nausea and vomiting; B GI-bleeding; C Abdominal pain; D Change in bowel habit; E C-reactive protein level; F Neutrophil cell count; G Lymphocyte cell count; H Eosinophill percentage; I Basophil percentage; J Monocyte percentage. The dot and bar estimate the effect of each SNP related to insomnia on the risk of inflammatory digestive disease. GI, gastrointestinal; SNP, single nucleotide polymorphism
Fig. 7
Leave-one-out sensitivity analysis of the association of insomnia with inflammatory digestive diseases. A Ulcer of the esophagus; B Duodenal ulcer; C Gastric ulcer; D Ulcerative colitis; E Crohn’s disease; F Colitis; G Polyp of stomach and duodenum; H Polyp of the colon; I Rectal polyp; J Haemorrhoidal disease. The dot and bar demonstrate the sensitivity of IV by removing SNPs one at a time. IV, instrument variable; SNPs, single nucleotide polymorphisms
Fig. 8
Leave-one-out sensitivity analysis of the association of insomnia with inflammatory digestive phenotypes and biomarkers. A Nausea and vomiting; B GI-bleeding; C Abdominal pain; D Change in bowel habit; E C-reactive protein level; F Neutrophil cell count; G Lymphocyte cell count; H Eosinophill percentage; I Basophil percentage; J Monocyte percentage. The dot and bar demonstrate the sensitivity of IV by removing SNPs one at a time. IV, instrument variable; SNPs, single nucleotide polymorphisms; GI, gastrointestinal
Fig. 9
Funnel plot of the association of insomnia with inflammatory digestive diseases. A Ulcer of the esophagus; B Duodenal ulcer; C Gastric ulcer; D Ulcerative colitis; E Crohn’s disease; F Colitis; G Polyp of stomach and duodenum; H Polyp of the colon; I Rectal polyp; J Haemorrhoidal disease. Each black dot indicates a single nucleotide polymorphism
Fig. 10
Funnel plot of the association of insomnia with inflammatory digestive phenotypes and biomarkers. A Nausea and vomiting; B GI-bleeding; C Abdominal pain; D Change in bowel habit; E C-reactive protein level; F Neutrophil cell count; G Lymphocyte cell count; H Eosinophill percentage; I Basophil percentage; J Monocyte percentage. Each black dot indicates a single nucleotide polymorphism. GI, gastrointestinal
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Discussion
For all we know, this MR study is the first one conducted to determine if insomnia is potentially associated with inflammatory digestive diseases, phenotypes and biomarkers. Our study originally extended the narrow-sense concept of IBD to the broad-sense concept of IDD, incorporating several approximate gastrointestinal disorders. Based on the Two-Sample MR analysis, we thoroughly evaluated the potential relationship between insomnia and inflammatory digestive diseases, phenotypes and biomarkers. The results disclosed that insomnia was positively associated with ulcers of the esophagus and abdominal pain. Furthermore, although only suggestive evidence was obtained, potential relationships were observed between insomnia and duodenal ulcer, gastric ulcer, rectal polyp, haemorrhoidal disease, and monocyte percentage.
PUD remains a common disease endangering public health worldwide [39], and there is no effective solution. Some research has claimed that an unhealthy lifestyle plays a critical role in PUD [40]. Sleeplessness, as one of the risk factors, was considered to be closely correlated with the development and recurrence of PUD [41‐43]. To be consistent with this observational evidence, an MR study indicated a certain association between insomnia and PUD [16]. However, given the limitations of the previous studies, we conducted an MR analysis to investigate whether insomnia was closely correlated with PUD. Different from the previous MR study, we split PUD into ulcers of the esophagus, gastric, and duodenal regions for association assessments, respectively. When the three types of PUDs were treated as independent diseases, a potential association was observed between insomnia and them, respectively (all p < 0.05) (Fig. 2A). This result not only corroborated previous research but also provided more detailed and precise evidence. However, as components of IDDs, a definite association was solely observed between insomnia and ulcers of the esophagus. Only suggestive evidence existed for the potential relationship between insomnia and the other two PUDs, which might be attributed to stricter statistical thresholds. Although some studies revealed that digestive tract mucosa injury caused by immune, oxidative stress and circadian rhythm disturbances was the underlying mechanism of PUD induced by insomnia [10, 16], more randomized controlled trials (RCTs) and fundamental experiments are needed for further exploration and validation.
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Many clinical studies revealed a correlation between sleeplessness and IBD, in which deficiencies in sleep duration and efficiency were strongly correlated with the progression of IBD [44‐47]. Previous animal experiments [48, 49] and recent meta-analyses [50] have also confirmed the relationship between sleeplessness and IBD. Nevertheless, limited to the selection bias and potential confounders of the early studies, it is difficult to elucidate a causal relationship between them. Although our study failed to disclose any remarkable correlation between insomnia and IBD, the result was supported by a previous MR study [51]. Immune impairment and intestinal flora disruption caused by disturbed sleep rhythms are still widely recognized as an important trigger of IBD [6, 7, 10, 52], therefore, large-scale RCT/basic studies are urgently needed to further elucidate the intrinsic relationship between them.
Digestive tract polyps and haemorrhoidal diseases are common inflammatory proliferative diseases from a physiological angle. There is no available evidence to elucidate the association between sleep and these diseases. Although our study revealed no significant association between insomnia and digestive tract polyps for the first time, the ORs of these correlations were larger than 1 (Fig. 2A), indicating that insomnia might be a risk factor for these kinds of diseases. Besides, suggestive evidence was obtained from the potentially association between insomnia and haemorrhoidal diseases (Fig. 2A). However, these findings should be further validated in the future.
For inflammatory digestive phenotypes and biomarkers, the IVW method revealed that the genetic predisposition to insomnia was significantly correlated with abdominal pain and suggested evidence for a potential association between insomnia and monocyte percentage (Fig. 2B). Surprisingly, our analysis discovered no significant association between insomnia and other phenotypes and biomarkers. Such results might be attributed to the lack of high-specificity of these phenotypes and biomarkers for IDDs. Although specific pro-inflammatory cytokines (TNF-α, interleukin-1β and interleukin-6) were recognized to correlate with sleep and IBD closely [1, 53], we failed to obtain reliable evidence that insomnia had a potential relationship with the three inflammatory biomarkers due to the deficiency of the related GWAS dataset. As for the monocyte, a critical inflammatory-related immune cell, it is known to be closely correlated with insomnia [54, 55]. According to the studies, monocyte percentage is regulated by the circadian gene Bmal1 [56] and clock gene Arntl [57] and insomniac individuals have an increase in circulating monocytes. The findings of these studies provided credence to our research, but the definite association between insomnia and monocyte percentage still needs further validation.
There are several highlights to this study. The use of five MR analysis methods enhanced the reliability and comprehensiveness of the association assessment between exposure and outcome. And in essence, the MR study eliminated the potential confounders, reverse causality and other issues common in traditional epidemiological studies. Instead of a single SNP, multiple SNPs closely correlated with insomnia were used as IVs to decrease horizontal pleiotropy. Moreover, a homogenous population (European population) was used to reduce heterogeneity, which was prevalent when individuals of different races were included in genetic research. We further performed statistical corrections to make the results more robust.
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However, our research still has some unavoidable limitations. First, several datasets with higher specificity were not included due to their small sample size. This might result in the absence of some potential associations, which need large-scale RCTs and basic studies for further elucidation. Second, although the population in our study was highly homogenous, whether the results could be generalized to individuals of various ancestry populations remains unknown. Moreover, some phenotypes/biomarkers may be expressed only during certain time periods of life, resulting in some potential associations being missed. Genetic pleiotropy cannot be completely ruled out, although we have done our best to minimize it.
Conclusions
To sum up, our MR analysis revealed a well-established potential relationship between insomnia and IDDs/phenotypes/biomarkers including ulcer of the esophagus and abdominal pain, as well as suggestive evidence of a potential association among IDDs/phenotypes/biomarkers including gastric ulcer, duodenal ulcer, rectal polyp, haemorrhoidal disease and monocyte percentage. Sleep management and insomnia therapy may provide new insights into the prevention and treatment of IDDs and bring more benefits to patients.
Acknowledgements
Not applicable.
Declarations
Ethics approval and consent to participate
All methods were carried out in accordance with relevant guidelines and regulations.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
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