Circadian clock-related genome-wide Mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity

doi:10.21203/rs.3.rs-3292704/v1

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Circadian clock-related genome-wide Mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity

https://doi.org/10.21203/rs.3.rs-3292704/v1

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Background Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can lead to inflammatory diseases such as UC. This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences.

Methods Summary statistics were conducted on UC and its comorbidities, protein expression quantitative trait loci, DNA methylation and gene expression in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively). Genetic variants located within or near 120 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables, and the causal relationships with UC and its comorbidities were estimated through aggregated summary data-based MR (SMR) analysis.

Findings Through preliminary SMR analysis, we found a potential causal relationship between circadian clock-related genes and UC and its comorbidities. Our study identified strong evidence of positive correlation of four overlapping genes (CSNK1E, OPRL1, PIWIL2, and RORC) between MWAS and TWAS were identified in UC, three overlapping genes (OPRL1, CHRNB2, and FBXL17) in UC with PSC, and two overlapping genes (ARNTL and USP7) in UC with arthropathy.

Interpretations This SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. In addition, our research identified candidate genes which could serve as potential drug targets.

Mendelian randomization

Circadian rhythm disorder

UC and its comorbidities

Pharmaceutical targets

Ulcerative colitis (UC) is an immune-mediated chronic inflammatory bowel disease (IBD) characterized by persistent inflammation of the intestinal mucosa or lamina propria(1). According to a widely accepted framework, the complexity of the environment and the host increases the susceptibility to UC, and events like disruption of the mucosal barrier, imbalance of the intestinal microbial flora, and abnormal stimulation of the intestinal immune response are what actually cause the disease(2). Research reveals that circadian rhythm may be crucial in the pathogenesis of IBD because sleep and melatonin may alter the immune system and intestinal microbiota, which may contribute to the incidence and progression of IBD(3, 4). The circadian rhythm, also known as the circadian clock, is an endogenous "oscillator" in living things that controls nearly every aspect of biology and behavior, such as immune system function and metabolism, to ensure that internal physiology and the outside environment are in harmony(5, 6). Previous studies have shown that the immune system's dependence on circadian rhythm will influence the incidence and progression of IBD(7). Circadian rhythm can control immune system function by controlling circulating lymphocytes, natural killer (NK) cells, antibody formation, complement level, cytokine synthesis, host-pathogen interaction, and induction of innate and adaptive immunity(4, 8, 9). Additionally, chemokines and adhesion molecules on endothelial cells undergo diurnal variations that influence how leukocytes are transported to intestinal tissue(10). As a result, the immune system depends on circadian rhythm, and a disruption of this cycle may result in inflammatory illnesses like IBD. Further, some studies have suggested that circadian rhythm disruption may be a risk factor contributing to the progress of severe IBD(11). In order to better understand UC and its comorbidities, it is crucial to investigate the involvement of circadian rhythm disturbance.

Mendelian randomization (MR), which involves creating models using genetic variation as instrumental variables, is one technique used to investigate the causal link between risk factors and illness outcomes(12). Using random distribution of genetic variants that alter exposure, MR is considered as a "natural" randomized controlled experiment(13). It significantly removes the involvement of unobserved confounding variables and prevents reverse causality when compared to other study designs(14). Genome-wide association studies (GWAS), which examine DNA sequence variations brought on by single nucleotide mutations, weed out single nucleotide polymorphisms (SNPs) that differ significantly from one other. These SNPs consistently link to the investigated risk variables. Numerous risk factors have been linked to an increasing number of genetic variants. To explore the association between these genetic variants and the intended outcome in GWAS, researchers can employ these genetic variations as instrumental variables, which represent the risk factors that are near to lifetime exposure(12).

The MR investigation looking for a possible causal link between circadian rhythm disruption and ulcerative colitis and its comorbidities was not discovered. Hence, in our study, we aim to explore the causal association between circadian rhythm disorder and ulcerative colitis and its comorbidities characterized by genetic susceptibility of circadian clock-related genes through comprehensive MR analysis.

This study was carried out in accordance with the reporting guideline of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE, Supplementary Table 1)(15, 16).

Study design

The quantitative trait loci (QTL) and GWAS studies that provided the summary-level data for this SMR analysis are both publicly available (Fig. 1). Participants in each of these investigations gave their informed permission, and each study was authorized by the appropriate institutional review boards.

Data sources of circadian clock-related genes (CRGs)

CRGs were collected from the Gene Set Enrichment Analysis (GSEA) database (http://www.gsea-msigdb.org/gsea/msigdb) using “circadian clock” as the main search term, and one gene set related to circadian clock regulation were found and 120 genes were obtained.

Selection of genetic instruments

As shown in Table 1, we used available QTLs for CRGs. The expression QTL (eQTL) summary-level data were obtained from eQTLGen Consortium(17) (https://www.eqtlgen.org/) and GTEx Consortium V8(18) (https://gtexportal.org/), relevant information is detailed in the Table 1. MR methylation QTL (mQTL) instruments for genetic variants stably correlated with circadian rhythm-related gene methylation were selected using blood mQTL summary data from a meta-analysis of two cohorts (n = 1980)(19). We used the annotation file from Price et al.(20) to annotate the closest genes of DNA methylation probes. MR protein QTL (pQTL) instruments for genetic variants correlated with the expression of circadian rhythm-related protein were extracted using summary data from Pietzner et al.(21). For eQTL, mQTL and pQTL data, only probes having at least one common (minor allele frequency [MAF] > 1%) cis-QTL passing the genome-wide significant threshold (P_QTL<5×10^− 8), which associated with the expression of CRGs, were included in the SMR analyses. The cis region was defined as within 2 Mb of a probe in either direction.

Outcome sources

GWAS summary statistics for UC and its comorbidity were obtained from the FinnGen database, with a sample size of 341,859 for UC, 331,563 for UC with primary sclerosing cholangitis (PSC), and 339,549 for UC with arthropathy, respectively(22). The study population was restricted to individuals with European ancestry.

Table 1

Information of eQTL and GWAS summary data.
Characteristic	Resource	Sample size	Population ancestry
eQTL data
Whole blood	eQTLGen Consortium	31684	Predominantly European
Whole blood	GTExV8	755
Colon Sigmoid		373
Colon Transverse		406
mQTL data
Whole blood	McRae et al.	1980	European
pQTL data
Plasma	Pietzner et al.	10,708	European
GWAS summary data
UC	FinnGen	ncases: 4460 ncontrols: 337,399	European
UC with PSC		ncases: 189 ncontrols: 331,374
UC with arthropathy		ncases: 279 ncontrols: 339,270

eQTL expression quantitative trait loci, mQTL methylation quantitative trait loci, pQTL protein quantitative trait loci, UC ulcerative colitis, PSC primary sclerosing cholangitis, GTEx Genotype-TissueExpression.

Statistical analyses

MR analysis

Adopting cis-QTLs as a tool, the summary-data based MR (SMR) approach was used to produce effect estimates. SMR analyzes the relationship between a gene's level of expression and an outcome of interest using summary-level data from GWAS and cis-QTL investigations(23). Allele harmonization and analysis were performed using SMR software (version 1.03, https://yanglab.westlake.edu.cn/software/smr/#Overview). Odds ratio (OR) estimates of circadian rhythm dysregulation on the risk of UC and its comorbidity were calculated as follows: OR exp(β), where OR is the odds ratio estimate per 1-ln increase in circadian clock genome levels and exp is the base of the natural logarithm.

Sensitivity analysis

The SMR software was used to conduct the heterogeneity in the dependent instrument (HEIDI) test for the SMR technique to determine if the observed correlation between gene expression and the result was caused by a linkage scenario(23). Genomes of European ancestry acquired from the 1000 Genomes Project Consortium were used as a reference for the linkage disequilibrium (LD) calculation(24). The HEIDI test of P < 0.01 indicates that the association is probably due to linkage(25). There might be horizontal pleiotropy if an SNP is linked to the expression of many genes. We found other neighboring genes within a 1Mb window, whose expression was strongly correlated with the genetic instrumental mutation, and did SMR analysis to see if the expression of these genes was connected to the UC outcomes in order to evaluate the probability of horizontal pleiotropy.

The Bonferroni adjustment was used to modify the threshold of significance level to account for multiple testing, thus strong evidence was suggested for P < 0.05/the number of probes, and suggestive evidence of 0.05/the number of probes ≤ P ≤ 0.05.

Circadian clock genome-wide cis-QTLs

After SMR testing, 70 circadian clock-related transcripts from blood and 18 from the colon were obtained, respectively. To minimize the genome-wide type I error, P_{eSMR_BLOOD} <7.143×10^− 4 (Bonferroni correction, P < 0.05/70) and P_{eSMR_COLON} <2.778×10^− 3 (Bonferroni correction, P < 0.05/18) suggests strong evidence of an association, while 7.246×10^− 4 < P_{eSMR_BLOOD} <0.05 or 2.778×10^− 3 < P_{eSMR_COLON} < 0.05 indicating suggesting evidence.

For the causal effect between the DNA methylation of the circadian clock-related genome and outcomes, 452 unique genetic loci were identified, and P_mSMR<1.106×10^− 4 (Bonferroni correction, P < 0.05/452) suggests strong evidence of an association, while for the causal association between the circadian clock-related protein and outcomes, 19 circadian rhythm related protein expressions were selected, and P_pSMR<2.631×10^− 3 (Bonferroni correction, P < 0.05/19) suggests strong evidence of an association.

MR analysis of circadian clock genome-wide cis-eQTLs and UC

In SMR analysis of circadian clock genome-wide cis-eQTLs and UC (Fig. 2, Supplementary Table 2), results found strong evidence for the association of the increased expression of ID2 and RORC in the blood (equivalent to one standard deviation increase) with the lower risk of UC (OR 0.490, 95%CI 0.338–0.710; OR 0.317, 95%CI 0.171–0.586, respectively), while the increased expression of OPRL1 in colon correlated with a higher risk of UC (OR 1.263, 95%CI 1.121–1.424), indicating that upregulating the expression of ID2 and RORC in blood and downregulating the expression of OPRL1 in the colon might lower the risk of UC. Suggestive evidence was observed that the decreased expression of CSNK1D and OPRL1and increased expression of PRKAA1 in blood were associated with lower risk of UC (OR 0.833, 95%CI 0.720–0.964; OR 0.880, 95%CI 0.799–0.970; OR 0.594, 95%CI 0.354–0.996, respectively), while increased expression of CSNK1E and decreased expression of EZH2 and PIWIL2 were associated with a higher risk of UC (OR 1.414, 95%CI 1.022–1.956; OR 1.345, 95%CI 1.072–1.687; OR 1.807, 95%CI 1.001–3.261, respectively).

MR analysis of circadian clock genome-wide cis-eQTLs and UC with PSC

In SMR analysis of circadian clock genome-wide cis-eQTLs and UC with PSC (Fig. 2, Supplementary Table 2), results found suggestive evidence for the association of the increased expression of CHRNB2 and BTRC in blood with the lower risk of UC with PSC (OR 0.165, 95%CI 0.042–0.643; OR 0.162, 95%CI 0.029–0.912, respectively), while decreased expression of FBXL17 correlated with a higher risk of UC with PSC (OR 3.585, 95%CI 1.038–12.387). In the colon, it is suggestive that the increased expression of PML is correlated with a higher risk of UC with PSC (OR 2.634, 95%CI 1.176–5.898), while the increased expression of PPP1CB is correlated with a lower risk of UC with PSC (OR 0.394, 95%CI 0.158–0.984).

MR analysis of circadian clock genome-wide cis-eQTLs and UC with arthropathy

In SMR analysis of circadian clock genome-wide cis-eQTLs and UC with arthropathy (Fig. 2, Supplementary Table 2), results found suggestive evidence for the association of the increased expression of MTOR and ARNTL and decreased expression of USP7 in blood with the lower risk of UC with arthropathy (OR 0.343, 95%CI 0.155–0.759; OR 0.581, 95%CI 0.380–0.890; OR 0.036, 95%CI 0.002–0.843, respectively). And there is no significant genetic relationship between CRGs in the colon and UC with arthropathy.

MR analysis of circadian clock genome-wide cis-pQTLs and outcomes

Only 19 hypothesized circadian rhythm-related SNPs were retrieved from cis-pQTLs, and based on our recommended threshold following the SMR analysis, no causal connection was discovered. One explanation could be that the pQTL datasets are not fully established and only a small number of genetic variants that are strongly related with protein levels were found.

MR analysis of circadian clock genome-wide cis-mQTLs and outcomes

To determine if causal genes revealed by TWAS show a similar correlation at the methylome level, we performed methylome-wide association studies (MWAS) to provide insight into gene expression. In SMR analysis of circadian clock genome-wide cis-mQTLs and outcomes (Fig. 3, Supplementary Table 3), results found a total of 29 association signals across 25 unique genetic loci for UC, 23 association signals across 19 unique genetic loci for UC with PSC, and 22 association signals across 18 unique genetic loci for UC with arthropathy. Four overlapping genes (CSNK1E, OPRL1, PIWIL2, and RORC) between MWAS and TWAS were identified in UC, three overlapping genes (OPRL1, CHRNB2, and FBXL17) in UC with PSC, and two overlapping genes (ARNTL and USP7) in UC with arthropathy.

The circadian rhythm regulates daily cycles in physiology and behavior that allow organisms to keep track of the time of day. The circadian rhythm is also found in intestinal epithelial cells, where it plays a critical role in maintaining homeostasis, cell division, and permeability(26). In our study, we indicated that circadian rhythm dysregulation characterized by genetic predisposition has a causal association on UC and its comorbidities, and identified important putative causal CRGs as follows: 1) CSNK1E, OPRL1, PIWIL2, and RORC for UC; 2) OPRL1, CHRNB2, and FBXL17 for UC with PSC; 3) ARNTL and USP7 for UC with arthropathy. Our findings demonstrate that genetic factors influencing circadian rhythm dysregulation were related to the risk of UC and its comorbidities in a comorbidity type-specific way, providing strong support for the underlying mechanisms relating genetic loci, gene expression, and methylation to UC and its comorbidities.

Clock gene family member CSNK1E controls signaling pathways connected to the circadian molecular clock(27). It has been studied for decades how CSNK1E functions physiologically and it was found to be associated with cognitive deficits in schizophrenia(28), survival of several cancer(29, 30), heroin addiction, and opioid sensitivity(31). Studies have shown that CSNK1E was upregulated in UC patients(32). According to the DRUGBANK database (https://go.drugbank.com/), Seliciclib which targets CSNK1E has been investigating the mechanisms of chronic inflammation disorders. OPRL1 encodes a G protein-coupled receptor for nociceptin, an endogenous opioid-related neuropeptide, which is crucial in pain perception and nociception(33). A previous study has shown that the neuropeptide nociceptin/orphanin’ FQ (N/OFQ) has been identified as a promising immunomodulator for inflammatory bowel diseases(34). RORC is a critical transcription factor for Th17 polarization and function, and it plays a significant role in autoimmunity and inflammation(35). It is proved that RORC mRNA expression was increased in patients with UC(36). PIWIL2 is a member of the gene subfamily known as P-element-induced wimpy testis/Argonaute, whose members are distinguished by conversed PAZ and PIWI domains. These genes are the first class of genes recognized to be necessary for stem cell self-renewal in a variety of animals(37, 38). However, its causal effect with UC is not clear. In this study, we demonstrated that gene expression and methylation of CSNK1E, OPRL1, PIWIL2, and RORC have a causal relationship with UC.

CHRNB2 is a crucial component of the nicotinic acetylcholine receptor and is connected to nicotine dependence, epilepsy, and cancer patient metastasis(39, 40).The gene FBXL17 encodes a little-studied member of the F-box family of proteins, which are essential for the ubiquitin conjugation pathway and control important cellular functions like cell cycle progression, cell signaling, and receptor recycling. These processes all require quick alteration in protein levels(41). However, there is little evidence available concerning their role in UC or PSC. Our results showed a causal relationship between the gene expression and methylation of CHRNB2 and FBXL17 and UC with PSC.

It has been demonstrated that ARNTL controls hepatic drug metabolism, resulting in dosing time-dependent pharmacokinetics and pharmacological action. ARNTL participates in metabolic homeostasis including lipid, glucose, and cholesterol(42). ARNTL is essential for treating colitis, as demonstrated by a prior study that found the ARNTL-knockout mice model caused more severe colitis(43). Additionally, ARNTL is crucial for osteoarthritis chondrocyte growth and cartilage tissue integrity(44–46). Deubiquitinating enzyme USP7 has a role in the development of IBD by controlling Foxp3 expression and thereby impairing Treg cell functioning(47, 48). Moreover, in rheumatoid arthritis, USP7 is connected to the migration of synoviocytes that resemble fibroblasts(49). Our results were consistent in that there is a causal relationship between the gene expression and methylation of ARNTL and USP7 and UC with arthropathy, and can be the potential target of UC with arthropathy.

The primary strength of the current work is that we did multi-omics MR investigation between circadian rhythm dysregulation, which is defined by a genetic susceptibility in known CRGs with UC and associated comorbidities. Second, we limited the samples we studied to those of European ancestry, which reduced biases brought on by diverse genetic origins.

Several restrictions apply to this study as well. Although we drew from a variety of large GWAS data sources, neither the available eQTL dataset nor the mQTL dataset contained information on genetic variants related to gene expression or methylation levels in the X chromosome, Y chromosome, or circadian rhythm genome. Moreover, no genetic variants representing the expression of the circadian rhythm protein were found. Second, based on the software resources now available, we are unable to determine the direction of the association using bi-directional MR since the GWAS dataset that directly indicated circadian rhythm disruption is not accessible.

This study highlights the significance of circadian rhythm dysregulation in the pathogenesis of UC and its comorbidities by using MR to evaluate the potential causal association between circadian rhythm dysregulation, which is characterized by a genetic predisposition in CRGs, and UC and its comorbidities. In-depth study of the underlying biological pathways might be done using the discovered candidate genes as possible pharmaceutical targets for UC prevention and therapy.

Ethical Approval

This declaration is not applicable.

Competing interests

The authors affirm that this paper does not include any conflicts of interest.

Authors' contributions

JC, YW, and YL contributed to the conception and design of the study. YW, TY, ZL, SW and XC analyzed data and drafted the manuscript. YF, JL, YL, and JC provided valuable advice on the details of analyse and writing. All authors read and approved the final manuscript.

Funding

YF was supported by Basic and Applied Basic Research of Guangzhou City-University Joint Funding Project (2023A03J0738); YL and JC were supported by Research Fund for Zhaoyang Talents of Guangdong Provincial Hospital of Chinese Medicine (ZY2022KY10 and ZY2022YL04, respectively). Researchers were independent from funders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Availability of data and materials

The peer-reviewed articles indicated in table 1 and cited in this study provide the data that were used in this analysis. Summary statistics for GWAS are publicly assessable for download. Requests can be made for the statistical code required to duplicate the findings in the paper.

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No competing interests reported.

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Circadian clock-related genome-wide Mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity

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Abstract

Figures

Introduction

Materials and methods

Study design

Data sources of circadian clock-related genes (CRGs)

Selection of genetic instruments

Outcome sources

Statistical analyses

MR analysis

Sensitivity analysis

Results

Circadian clock genome-wide cis-QTLs

MR analysis of circadian clock genome-wide cis-eQTLs and UC

MR analysis of circadian clock genome-wide cis-eQTLs and UC with PSC

MR analysis of circadian clock genome-wide cis-eQTLs and UC with arthropathy

MR analysis of circadian clock genome-wide cis-pQTLs and outcomes

MR analysis of circadian clock genome-wide cis-mQTLs and outcomes

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1