Abstract
Although functional gastrointestinal disorder (FGID) is a common clinical condition, its risk factors remain unclear. We performed a Mendelian randomization study to explore the association between plasma lipids and the risk of FGID. Instrumental variables closely related to six plasma lipids were obtained from the corresponding genome-wide association studies, and summary-level data on FGID, including irritable bowel syndrome (IBS) and functional dyspepsia (FD), were extracted from the FinnGen study. The primary inverse variance weighted method and other supplementary analyses were used to evaluate the causal relationship between diverse plasma lipids and FGID. For each increase in the standard deviation of triglyceride levels, there was a 12.0% increase in the risk of IBS rather than that of FD. Low- and high-density lipoprotein cholesterol, total cholesterol, apolipoprotein A, and apolipoprotein B levels were not associated with the risk of IBS or FD. Through this study, we identified the causal role of triglycerides in the pathogenesis of IBS, which could benefit further basic and clinical research.
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Introduction
Functional gastrointestinal disorders (FGIDs), now termed disorders of gut–brain interaction1, are prevalent as they affect more than one-third of the population2, and refer to symptoms such as abdominal discomfort, diarrhea, constipation, bloating, fullness, nausea, and vomiting without underlying structural defects3. Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are the two most common types of the 26-adult-classified FGIDs identified using the Rome criteria. However, the pathogenesis of these diseases remains unclear4. The possible pathological mechanisms of FGID, including gut–brain dysfunction, psychological factors, chronic infections, disorders of the intestinal microbiota, systemic immune activation, alterations in intestinal permeability, low-grade mucosal inflammation, abnormalities in the bile salt metabolism, abnormalities in the serotonin metabolism, and genetic factors, have been widely studied currently5. However, most of the present studies are cross-sectional or case–control observational studies, in which potential residual confounding factors and reverse causality issues could affect the results.
Several studies on hormones, blood lipids, and proteins in patients with FGIDs have been conducted because its diagnosis is based on symptom criteria that lack biochemical markers6,7,8,9. Some researchers have found that the concentration of plasma lipids, especially triglycerides, is significantly higher in patients with IBS than that in controls6,10, and that lipid intermediates or end products of cholesterol metabolism are more prominent in IBS than in FD8. Some researchers believe that the triglyceride levels increase due to the pathophysiological changes such as the low-grade mucosal inflammation which caused by IBS, increased intestinal mucosal permeability, and abnormal intestinal motility associated with IBS would reduce the absorption of fats in the gastrointestinal tract10. Further, evidence shows that one of the main characteristics of patients with IBS is poly-unsaturated fatty acid malabsorption11. In contrast, some studies have suggested that hypertriglyceridemia is a risk factor rather than the result of IBS, as the use of lipid-lowering drugs can reduce the clinical symptoms in patients with IBS12,13. These two contradictory views make it difficult to determine a causal relationship between elevated triglyceride levels and IBS in traditional observational studies. Simultaneously, it is not easy to study the results by conducting randomized controlled trials for the high costs, long experiment time and ethical concerns.
Mendelian randomization (MR) is an ideal epidemiological approach that uses genetic instrumental variables (IVs) in non-experimental data to assess the causal effect of exposure on outcomes to enhance a causal inference14. Genetic variants are relatively independent of self-selected behaviors and are established long before disease manifestation, as they are randomly assigned to offspring. This is equivalent to the random process in randomized controlled clinical trials. Therefore, the MR method can be used in cases in which the exposure factors are expensive or difficult to assess, to eliminate residual confounding factors, and prevent reverse causality. Considering the unclear causal relationship between increased plasma lipid levels and FGID, in this study, we conducted a MR study to investigate the association between plasma lipids and the risk of FGID.
Materials and methods
Data source and open genome-wide association studies (GWAS) statistics
Data related to elevated levels of plasma lipids were obtained from the UK Biobank (UKB), a repository of biomedical data and research resources collected the genetic and clinical information on half a million participants in the United Kingdom15. The consortium of FGID, which includes IBS and FD, belongs to the FinnGen study16, a new study that integrates genetic information with digital healthcare data from people in Finland.
Single nucleotide polymorphism (SNP) selection and assumption
The assumptions used for the genetic variation met the following three basic requirements: (1) this variation was strongly associated with exposure (related hypothesis); (2) the variance did not affect the outcome because of the confounding factors (independence hypothesis); and (3) this variant did not directly affect the through indirect exposure (excluding hypothesis) (Fig. 1). For SNP selection, we set the statistical significance level (p < 5 × 10–8) to rigorously confirm genome-wide significant correlations to satisfy our hypothesis (1). In order to attenuate the disequilibrium of the linkage in SNP, we established the threshold (R2 < 0.001) and a specific mutation frequency, the minor allele frequency (MAF > 1%). For hypotheses (2) and (3), we examined each SNP in PhenoScanner, a public database on the association between human genetics and phenotypes, and excluded genome-wide SNPs that were significantly associated with potential confounders. Palindromic variants were removed to verify the harmonization of the variants, as it was challenging to verify the alleles for which they were correctly directed.
Statistical analysis of primary MR
We chose the inverse-variance weighted (IVW) method, which is considered the most effective analysis method using reliable IVs, as the main analysis technique in our study17. When the pleiotropic effects of IVs were absent, and the sample size was large enough, the IVW estimate was reliable, accurate, and close to the true value18. When heterogeneity was statistically significant (p < 0.05), the multiplicative random effects IVW model was used. Otherwise, a fixed effects model was used. In addition to IVW, other reliable techniques were used to guarantee the accuracy and consistency of the results, including the MR-Egger method19, weighted median18, penalized weighted median estimator20,21, and maximum likelihood method22. Using scatter, funnel plots and forest to visualize the results and demonstrate the validity and stability of MR study.
The heterogeneity test was used to determine the conformance of each SNP using the MR-Egger and inverse-variance weighted techniques to calculate Cochran’s Q statistics. Heterogeneity was considered statistically significant at p < 0.05. A leave-one-out analysis was performed, and the results were compared with those of a global IVW analysis to confirm the reliability and stability of the causal relationship14. The MR-Egger intercept test was used to assess horizontal pleiotropy14. All analyses were performed by the R software (version 4.1.1) and the two-sample MR package.
Results
GWASs of plasma lipids levels
The GWAS of various plasma lipids levels were obtained from the UK Biobank, covering 187,365–403,943 participants, and 125–362 highly associated SNPs were recovered. The FinnGen study, which included 4605 and 4376 participants, produced the GWAS for IBS and FD, respectively (Table 1). Robust genetic IVs for six kinds of plasma lipidi levels were identified by the FinnGen database using open GWAS platforms (https://gwas.mrcieu.ac.uk) to determine the effect of plasma lipids levels-related genetic IVs on IBS and FD. The functions of “extract_outcome_data” and “harmonise_data” was used in conducting the identification process, and 81–315 SNPs were extracted for the subsequent causality analysis (Tables 2, 3).
Primary MR analysis
No causal relationship was found between the five plasma lipids (low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, total cholesterol, apolipoprotein A1, and apolipoprotein B) and FGID (including IBS and FD) (Tables 2, 3). Moreover, the IVW method did not reveal a causal relationship between triglycerides and FD. However, it revealed a positive causal relationship between triglycerides and IBS (IVW, OR/95% CI 1.120/[1.010, 1.243], p < 0.05) (Table 2). The risk of IBS was increased by 12.0% for each standard deviation increase in genetically determined plasma lipid levels. Moreover, we have not only used the primary IVW analysis method but also other statistical methods to verify the accuracy of the main results, such as weighted median estimator, the MR-Egger, maximum likelihood estimation, and penalized weighted median estimator methods. Visualizing the effect size of each MR method by using a scatter plot (Figs. 2, 3); visualizing the individual SNP estimates of the outcomes by using a forest plot (Supplementary Figs. 1, 2); and the distribution balance of the single SNP effects is showed by using a funnel plot (Supplementary Figs. 3, 4). These plots suggest that the effects of each SNP and its distribution were in equilibrium.
Sensitivity analysis
Using the Cochran’s Q test to measure heterogeneity. The effects of HDL-cholesterol on IBS were significantly and statistically heterogeneous among the genetic IVs (IVW, p = 0.01) (Table 4). The IVW multiplicative random-effects model was applied to the associations to calculate causal effects. Furthermore, no significant statistical heterogeneity was found among the genetic IVs for the effects of the remaining five plasma lipids on IBS and the effects of all six plasma lipids on FD (IVW, p ≥ 0.05). Accordingly, the fixed-effects IVW model was performed in the primary MR analysis.
Leave-one-out analysis was used to assess the effects of a single SNP on the final MR results. After the sequential omission of the single SNP, the other causal effects of various plasma lipids on FGID found in the leave-one-out analysis were consistent with those found in the primary MR studies, showed that no single SNP significantly affected the final result (Supplementary Figs. 5, 6). This suggests that these MR studies are credible and reliable.
A horizontal pleiotropic effect test was used to determine whether plasma lipid-related genetic IVs could lead to FD via other potential pathways. There is no significant horizontal pleiotropy in our MR analyses (all p values > 0.05). This indicates that our MR studies were probably not affected by potential confounding pathways, and the results were robust, credible, and reliable (Table 5).
Discussion
Till date, several metabolomic analyses have identified that plasma lipid levels, including triglyceride, fatty acid, cholesterol, and several other lipid metabolite levels, differ between patients with FGID and controls, and this variability also occurs in different types of FGID8,11,23,24, however, it is difficult to explain the exact causal relationship between the diseases and the change in plasma lipid levels because of the limitations of the traditional observational study methods. In contrast, MR is used to study the causal relationship between exposure and outcome using genetic variation that is randomly distributed and not influenced by confounding factors such as IVs25. This enables us to assess the relationship between increased plasma lipid levels and FGID. This two-sample MR study showed that increased triglyceride levels increase the risk of IBS rather than that of FD. However, there is not any causal relationship between other plasma lipids (LDL-cholesterol, HDL-cholesterol, total cholesterol, apolipoprotein A1, and apolipoprotein B) and FGID.
Plasma lipids include free fatty acids, triglycerides, and cholesteryl esters. Triglycerides are the major form of intracellular and plasma fatty acids storage and transport, which stores most of the energy for regulating physiological functions26. However, abnormal levels of triglyceride lead to several kinds of diseases, including coronary heart disease, acute pancreatitis, metabolic syndrome, and microvascular complications in patients with diabetes such as diabetic nephropathy and other diseases10,27,28,29.
After eliminating potential confounders such as sex, age, and the first 10 genetic principle components, we found that 312 genetic IVs acquired from the UK biobank were tightly associated with triglycerides. The maximum likelihood estimation, penalized weighted median estimator, weighted median estimator, and MR-Egger, also proofed that increased triglyceride levels resulting from genetic factors may increase the risk of IBS. The pleiotropic analysis did not show significant pleiotropic effect between triglycerides genetic variants and IBS (Table 2), and the leave-one-out analysis detected there is not a statistically significant single SNP associated with the results (Fig. 3). Based on the results, we found that plasma lipids, particularly triglycerides, affected the pathogenesis of IBS. Moreover, triglycerides showed an exact causal relationship with IBS, and no other causal relationships were detected in the remaining groups, including LDL-, HDL-cholesterol, total cholesterol, apolipoprotein A, and apolipoprotein B. The correctness and reliability of the relationship were proven by sensitivity analyses, such as the pleiotropic test. Supplementary MR methods also validated these results. Among the 12-MR analysis groups, the HDL-cholesterol groups showed significant statistical heterogeneity. We cannot determine the exact source of the heterogeneity because of the limited access to the original data; however, we speculate that it may be caused by factors such as depression, anxiety, and education. A multiplicative random-effects IVW model was performed to alleviate this effect. Further, this investigation was carried out to explore the causal effects of plasma lipids on FGID. However, traditional epidemiological studies have a difficult problem as the value of plasma lipid levels cannot be accurately detected and the intake value cannot be monitored. This could be solved by using MR. In a traditional epidemiological study, plasma lipid levels can be affected by diet, exercise, body conditions, and other factors that change the relationship with IBS. The influence of diet or other habits on plasma lipid levels could not be judged without an original article on plasma lipid GWAS statistics. But, our study explored variations in the FGID risk based on plasma lipid levels determined by genetic variants. We designed a MR analysis to avoid traditional confounders like diet and other habits by introducing IVs and monitoring their interference using sensitivity analysis. Therefore, the influence of confounding factors did not affect the results.
Based on the present study, the potential mechanisms suggesting that triglycerides are associated with an increased risk of IBS remain unknown. Therefore, we propose several potential possibilities based on the mechanisms contributing to IBS such as disturbances in the intestinal microbiota, immune activation, low-grade mucosal inflammation, and altered intestinal permeability5, in addition to notable influences from obesity and diet30. First, a previous study showed that high levels of triglyceride lead to triglyceride-rich lipoproteins enriched with apoC-III, which affects the signaling pathways that activate NFKβ and increase inflammatory molecules31, which suggesting that it could increase intestinal mucosal inflammation. Second, researchers suggest that the environment for microbial survival in the gut is altered by hyperlipidemia, leading to intestinal flora dysbiosis that aggravates a lipid metabolism disorder, which is an important risk factor for IBS32,33. Third, zonulin is considered a serum biomarker that reflects intestinal permeability, which is a manifestation of IBS34,35. However, the zonulin expression level in the IBS group was not different from that in the control group after adjusting for confounders. Zonulin levels are related to glucose levels, dyslipidemia, and insulin resistance36. Therefore, the increase in intestinal permeability could be caused by dyslipidemia, which increases zonulin levels and induces IBS. Fourth, diet has long been linked with IBS as a double-edged sword, it is a cause of diseases but also a treatment for symptom relief37. Some study suggested that gastrointestinal symptoms were frequently reported after intake of high-fat foods38,39,40, which can increase the level of plasma triglyceride41,42. According to these results, we hypothesized that there may be an increased triglyceride component to the exacerbation of IBS symptoms caused by high-fat foods. Last but not least, a systematic review suggested that obesity is also a relative risk factors of IBS43 and we all known that IBS patients weigh more than healthy controls, and some researches also proved that the obesity patients always have elevated plasma triglyceride levels44. Combined with our results it is easy to find that the mechanisms of obesity aggravating IBS may include the high-level of triglyride. In summary, the possible mechanisms of triglyceride-induced IBS are still unclear; here, we only present speculations and hypotheses based on existing studies and our results, which suggest that increased triglycerides increase the risk of IBS rather than that of FD. Our MR study had several strengths. First, we analyzed the causal relationship between plasma lipid concentrations and FGID, and this could provide a clear direction for pathological studies. Second, this study was established based on the three main assumptions of the IVs, which conform to the checklist for performing MR investigations and make our conclusions reasonable and reliable45. Third, this study benefited from large-scale GWAS of European ancestry, which helped in preventing bias in population stratification. Finally, we used five different MR analysis methods to ensure the consistency of the causal effects.
However, this study had some limitations. First, the outcomes cannot be generalized for all species, and the relationship may change in individuals of other ancestries. The results of the exposure (different plasma lipids) and outcome (IBS and FD) statistics for the genetic IVs were all obtained from the GWAS of European ancestry. Second, the diagnostic methods for IBS and FD could differ between hospitals and health-care systems as they follow a diagnosis of exclusion; similarly, different information acquisition and data processing methods may bias the results. Third, we did not include all dimensions of different plasma lipids in our study, as mentioned previously, because of the lack of an explored GWAS. Finally, although we removed the confounding effects of linkage disequilibrium and pleiotropy, biological mechanisms and genetic co-inheritance, such as gene expression, gene–gene interactions, and gene–environment interactions, could still affect the accuracy of our results.
In conclusion, our study provides genetic evidence that triglycerides are an important risk factor for IBS rather than FD, and this might help in the prevention of IBS if a larger, randomized, controlled cohort study is conducted. Moreover, LDL-cholesterol, HDL-cholesterol, total cholesterol, apolipoprotein A1, and apolipoprotein B levels were not associated with the risk of IBS or FD. However, our study was based on plasma lipid levels determined by genetic variants, which could only account for a part of the IBS risk variation. Therefore, a large-sample, randomized, controlled cohort study is required to clarify the association between plasma lipid levels and IBS. More types of plasma lipids should be explored to determine their causal effects on FGID through further mining and improvement of databases.
Conclusion
Our MR study showed that triglycerides had a positive causal effect on IBS rather than on FD. LDL-cholesterol, HDL-cholesterol, total cholesterol, apolipoprotein A1, and apolipoprotein B levels were not associated with the risk of IBS or FD.
Data availability
Publicly available datasets were analyzed in this study. The dataset(s) supporting the conclusions of this article are available in the UK Biobank [https://www.ukbiobank.ac.uk/] and FinnGen Study [https://www.finngen.fi/en/].
Abbreviations
- FGID:
-
Functional gastrointestinal disease
- IBS:
-
Irritable bowel syndrome
- FD:
-
Functional dyspepsia
- MR:
-
Mendelian randomization
- IVs:
-
Instrumental variables
- GWAS:
-
Genome-wide association studies
- UKB:
-
UK Biobank
- SNP:
-
Single nucleotide polymorphism
- IVW:
-
Inverse-variance weighted
References
Drossman, D. A. & Hasler, W. L. Rome IV-functional GI Disorders: Disorders of gut–brain interaction. Gastroenterology 150(6), 1257–1261 (2016).
Koloski, N. A., Talley, N. J. & Boyce, P. M. Epidemiology and health care seeking in the functional GI disorders: A population-based study. Am. J. Gastroenterol. 97(9), 2290–2299 (2002).
Black, C. J. et al. Functional gastrointestinal disorders: Advances in understanding and management. Lancet 396(10263), 1664–1674 (2020).
Aziz, I. et al. The prevalence and impact of overlapping Rome IV-diagnosed functional gastrointestinal disorders on somatization, quality of life, and healthcare utilization: A cross-sectional general population study in three countries. Am. J. Gastroenterol. 113(1), 86–96 (2018).
Holtmann, G., Shah, A. & Morrison, M. Pathophysiology of functional gastrointestinal disorders: A holistic overview. Dig. Dis. 35(Suppl 1), 5–13 (2017).
Eriksson, E. M. et al. Irritable bowel syndrome subtypes differ in body awareness, psychological symptoms and biochemical stress markers. World J. Gastroenterol. 14(31), 4889–4896 (2008).
Fraser, K. et al. Su1576—Metabolomic profiling of subjects with functional gastrointestinal disorders: A case/control study in New Zealand reveals significant perturbations in plasma lipid and metabolite levels. Gastroenterology 156(6), 569–570 (2019).
Karpe, A. V. et al. Utilising lipid and arginine and proline metabolism in blood plasma to differentiate the biochemical expression in functional dyspepsia (FD) and irritable bowel syndrome (IBS). Metabolomics 18(6), 38 (2022).
Schmulson, M. J. & Drossman, D. A. What is new in Rome IV. J. Neurogastroenterol. Motil. 23(2), 151–163 (2017).
Guo, Y. et al. Irritable bowel syndrome is positively related to metabolic syndrome: A population-based cross-sectional study. PLoS ONE 9(11), e112289 (2014).
Solakivi, T. et al. Serum fatty acid profile in subjects with irritable bowel syndrome. Scand. J. Gastroenterol. 46(3), 299–303 (2011).
Camilleri, M. Review article: New receptor targets for medical therapy in irritable bowel syndrome. Aliment Pharmacol. Ther. 31(1), 35–46 (2010).
Di Pierro, F., Putignano, P. & Villanova, N. Retrospective analysis of the effects of a highly standardized mixture of Berberis aristata, Silybum marianum, and monacolins K and KA in diabetic patients with dyslipidemia. Acta Biomed. 88(4), 462–469 (2018).
Little, M. Mendelian randomization: Methods for using genetic variants in causal estimation. J. R. Stat. Soc. 181(2), 549–550 (2018).
Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562(7726), 203–209 (2018).
Kurki, M. I. et al. Unique Genetic Insights from Combining Isolated Population and National Health Register Data (2022).
Wooldridge, J. M. Introductory Econometrics: A Modern Approach (Delhi Cengage Learning, 2009).
Bowden, J. et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 40(4), 304 (2016).
Burgess, S. & Thompson, S. G. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur. J. Epidemiol. 32(5), 32 (2017).
Hemani, G. et al. Automating Mendelian Randomization Through Machine Learning to Construct a Putative Causal Map of the Human Phenome (2017).
Burgess, S. et al. Robust Instrumental Variable Methods Using Multiple Candidate Instruments with Application to Mendelian Randomization (2016).
Milligan, B. G. Maximum-likelihood estimation of relatedness. Genetics 163(3), 1153–1167 (2003).
Han, L. et al. Altered metabolome and microbiome features provide clues in understanding irritable bowel syndrome and depression comorbidity. ISME J. 16(4), 983–996 (2022).
Kilkens, T. O. et al. Fatty acid profile and affective dysregulation in irritable bowel syndrome. Lipids 39(5), 425–431 (2004).
Zhang, Y. et al. Causal relationship between particulate matter 2.5 and hypothyroidism: A two-sample Mendelian randomization study. Front. Public Health 10, 1000103 (2022).
Alves-Bezerra, M. & Cohen, D. E. Triglyceride metabolism in the liver. Compr. Physiol. 8(1), 1–8 (2017).
Tesfaye, S. et al. Vascular risk factors and diabetic neuropathy. N. Engl. J. Med. 352(4), 341–350 (2005).
Tirosh, A. et al. Changes in triglyceride levels and risk for coronary heart disease in young men. Ann. Intern. Med. 147(6), 377–385 (2007).
Yang, A. L. & McNabb-Baltar, J. Hypertriglyceridemia and acute pancreatitis. Pancreatology 20(5), 795–800 (2020).
Sherwin, L. B. et al. Gender and weight influence quality of life in irritable bowel syndrome. J. Clin. Med. 6(11), 103 (2017).
Welty, F. K. How do elevated triglycerides and low HDL-cholesterol affect inflammation and atherothrombosis? Curr. Cardiol. Rep. 15(9), 400 (2013).
Ley, R. E. et al. Microbial ecology: Human gut microbes associated with obesity. Nature 444(7122), 1022–1023 (2006).
Hongfang, C. et al. Intake of a high-fat diet alters intestinal flora in male SD rats. Chin. J. Microecol. 24(02), 102–108 (2012).
Fasano, A. Intestinal permeability and its regulation by zonulin: Diagnostic and therapeutic implications. Clin. Gastroenterol. Hepatol. 10(10), 1096–1100 (2012).
Ohlsson, B. An Okinawan-based Nordic diet improves glucose and lipid metabolism in health and type 2 diabetes, in alignment with changes in the endocrine profile, whereas zonulin levels are elevated. Exp. Ther. Med. 17(4), 2883–2893 (2019).
Ohlsson, B., Orho-Melander, M. & Nilsson, P. M. Higher levels of serum zonulin may rather be associated with increased risk of obesity and hyperlipidemia, than with gastrointestinal symptoms or disease manifestations. Int. J. Mol. Sci. 18(3), 582 (2017).
Galica, A. N., Galica, R. & Dumitrașcu, D. L. Diet, fibers, and probiotics for irritable bowel syndrome. J. Med. Life 15(2), 174–179 (2022).
Böhn, L. et al. Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. Am. J. Gastroenterol. 108(5), 634–641 (2013).
Na, W. et al. High-fat foods and FODMAPs containing gluten foods primarily contribute to symptoms of irritable Bowel syndrome in Korean adults. Nutrients 13(4), 1308 (2021).
Tigchelaar, E. F. et al. Habitual diet and diet quality in irritable Bowel syndrome: A case–control study. Neurogastroenterol. Motil. 29(12), e13151 (2017).
Li, X. et al. High-fat diet promotes experimental colitis by inducing oxidative stress in the colon. Am. J. Physiol. Gastrointest. Liver Physiol. 317(4), G453–G462 (2019).
Wardani, H. A. et al. Development of nonalcoholic fatty liver disease model by high-fat diet in rats. J. Basic Clin. Physiol. Pharmacol. 30(6), 20190258 (2019).
Zia, J. K. et al. Risk factors for abdominal pain-related disorders of gut–brain interaction in adults and children: A systematic review. Gastroenterology 163(4), 995–1023 (2022).
Robertson, R. P. et al. Accelerated triglyceride secretion. A metabolic consequence of obesity. J. Clin. Investig. 52(7), 1620–1626 (1973).
Burgess, S. et al. Guidelines for performing Mendelian randomization investigations. Wellcome Open Res. 4, 186 (2020).
Acknowledgements
The authors thank all the investigators from the databases mentioned in our study for collecting and publishing the data.
Funding
This research was supported by the National Natural Science Foundation of China (No. 82070547).
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D.L., and Y.T.: designed the research. J.H.: contributed to data collection. B.Z.: analyzed data or performed the statistical analysis. M.X. prepared the manuscript. All authors wrote the manuscript. All authors read and approved the final manuscript.
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Xu, M., Liu, D., Tan, Y. et al. A Mendelian randomization study on the effects of plasma lipids on irritable bowel syndrome and functional dyspepsia. Sci Rep 14, 78 (2024). https://doi.org/10.1038/s41598-023-50459-9
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DOI: https://doi.org/10.1038/s41598-023-50459-9
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