Elucidating the relationship between coffee consumption and obsessive-compulsive disorder: A Mendelian randomization study

doi:10.21203/rs.3.rs-4724718/v1

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Elucidating the relationship between coffee consumption and obsessive-compulsive disorder: A Mendelian randomization study

https://doi.org/10.21203/rs.3.rs-4724718/v1

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Background

The relationship between coffee consumption and obsessive-compulsive disorder (OCD) is inconsistent in previous clinical studies and is still in dispute. This study employs a Mendelian randomization approach to examine the causal relationship between coffee consumption and the prevention of OCD in a European population.

Methods

The summary statistics of coffee consumption (coffee intake, instant coffee intake, and filtered coffee intake) were obtained from the MRC Integrative Epidemiology Unit consortium, UK Biobank (UKB) data and OCD information was obtained from the FinnGen Consortium (1059 patients and 198110 controls). Sensitivity analysis under various model assumptions was carried out using multiple MR approaches to assess the impact of pleiotropy effects and outliers.

Results

Genetically predicted coffee consumption was associated with a lower risk of OCD in the main analysis (OR 0.332, 95% CI 0.117,0.943, P = 0.038), especially with instant coffee intake (OR = 0.014, 95%CI: 0,0.426, P = 0.014), but not with filter coffee (OR = 1.037, 95%CI: 0.772,1.392, P = 0.810). There was no significant heterogeneity and pleiotropy between the cohorts. The findings were strong and convincing as the results aligned with the previous study.

Conclusions

Our MR results based on genetic data revealed the potential protective effect of coffee intake and instant coffee intake on OCD, except for filtered coffee intake. Our results demonstrate the usefulness of coffee consumption habits in the diet in preventing OCD. Additional research with OCD sufferers and more reliable SNPs is required. It is also advised that our findings be verified.

Coffee consumption

obsessive-compulsive disorder

Mendelian Randomization

mental health

Coffee is the most consumed beverage in the world; during the past 20 years, its per capita intake has increased by 37%[1–3]. In the United States, the average daily intake of coffee among adults is 3.1 cups, with 64% of adults reporting daily coffee consumption[3, 4]. Due to the enormous popularity of coffee, scientists are paying close attention to the potential advantages and risks associated with its intake, with a special focus on the association between coffee consumption and mental disorders[5–7].

Obsessive-compulsive disorder (OCD) is a widespread, usually long-lasting mental disorder characterized by intrusive, unwanted thoughts (obsessions) and repetitive behaviors (compulsions) that a person feels driven to perform to alleviate the anxiety caused by the obsessions[8, 9]. It is linked to a general rise in suicidality and can lead to serious financial difficulties, severe distress for individuals, and major suffering for families[10]. Recent research has revealed a significant correlation between OCD and certain dietary factors, including the consumption of alcohol, suggesting that nutritional habits may play a role in the development and management of OCD symptoms[6, 11, 12]. So far, there have been few studies on coffee consumption and OCD, and the conclusions are inconsistent. Researchers conducted a clinical study and found that caffeine can be taken as an adjuvant therapy for obsessive-compulsive disorder and help lessen the intensity of its symptoms[6]. However, Harriet et al. noted that caffeine intake can exacerbate anxiety symptoms[13], which is a common symptom in OCD. Thus far, it remains unclear whether coffee consumption was causally associated with OCD.

Mendelian randomization (MR) is a research design that predicts the causal influence of exposure on outcomes by using single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to avoid bias[14, 15]. Because genetic variants are randomly assigned at conception, residual confounding is reduced and MR is less affected by reverse causation[16]. This means that a characteristic is typically unrelated to other traits (possible confounding factors or environmental factors)[17]. The limitations of observational research and RCTs may be overcome by MR since SNPs are naturally randomly distributed to people at meiosis[14, 18]. Consequently, the MR may be used in place of randomized controlled trials[19]. The purpose of this article is to use an MR approach to investigate the associations between coffee consumption and OCD in the European population.

Study design

In this study, we conducted a systematic evaluation of the potential causal relationship between coffee consumption (coffee intake, instant coffee intake, and filtered coffee intake) and the prevention of obsessive-compulsive disorder by employing a Twosample MR study design. We completed the three key assumptions during the MR analysis process[20]: 1) variations in genetics need to be closely linked to the exposure; 2) Genetic variances must not be influenced by any additional potential confounding factors; 3) instruments variables only influence the result by means of exposure (Fig. 1).

GWAS data sources for coffee consumption and OCD

The open genome-wide association study website (https://gwas.mrcieu.ac.uk/) provided the genome-wide association study (GWAS) data used in this investigation. Summary statistics for genetic variants associated with coffee consumption were derived from the MRC Integrative Epidemiology Unit consortium and UK Biobank (UKB) data, which contains over 60 thousand samples and 25 million SNPs as shown in Table 1. We obtained OCD GWAS data as outcomes from the FinnGen consortium databases, which supplied GWAS information on OCD including 1059 patients, 198110 controls, and over 16 million SNPs. Each employed GWAS received ethical approval from the relevant institutions.

Table 1

Details of studies included in Mendelian randomization analyses
Trait	Dataset	First author	Number of SNPs	Sample size	Year
coffee intake	ukb-b-5237	Ben Elsworth	9,851,867	428,860	2018
Instant coffee intake	ebi-a-GCST90096914	Pirastu N	5,733,790	180,764	2022
Filtered coffee intake	ukb-e-100270_CSA	Pan-UKB team	9,797,409	1,469	2020

Statistical analysis

Data analysis in this study was performed using R (version 4.3.2) through TwoSampleMR (0.6.3) package. The two-sample MR analysis may be diverse due to variations in chosen populations, experimental settings, and SNPS, which might skew the results of the causal effect estimation. The genome-wide significance criterion of P < 5e^− 8 was set for screening SNPs associated with exposure interest, whereas the criteria for linkage disequilibrium (LD) across SNPs for exposure were r2 > 0.001 and clump distance < 10000 kb. The F statistics and the proportion of explained variance (R2) of IVs were computed in this study to test the first assumption, while IV was deemed strong if F > 10[14]. Harmonize and remove the SNPs for being palindromic with intermediate allele frequencies and for incompatible alleles. Using the Mendelian random pleiotropic residuals and outliers (MR-PRESSO) technique, the potentially aberrant SNPs and the horizontal pleiotropy were better validated[21] and there were no outliers identified in this study. The primary analysis was conducted using the inverse-variance weighted (IVW) method. The weighted median, weighted mode, simple mode, and MR-Egger regression were among the several complementary MR detection techniques used to precisely assess causal effects and account for the impact of horizontal pleiotropy.

There was no heterogeneity among these IVs because the P-value of the test result was higher than 0.05. Therefore, in this investigation, the MR-Egger regression and the principal IVW analysis approach were conducted using the heterogeneity test. Horizontal pleiotropy was used to test for causal links between exposure and outcomes, demonstrating that instrumental variables can only affect outcomes through exposure. In the causal analysis, pleiotropy was deemed less likely or nonexistent if the P-value was higher than 0.05, meaning its impact could be disregarded. Finally, we used a leave-one-out analysis to verify the consistency of the findings. This approach is considered reliable if subtle changes are observed in the overall error bars following the deletion of each SNP. It mainly computes the MR results of the remaining IVs after eliminating IVs one at a time.

Table 2 displays the SNPs that were retrieved from the main MR analysis, with coffee consumption (coffee intake, instant coffee intake, and filtered coffee intake) serving as the exposure and OCD serving as the outcome. As shown in Fig. 2 and Table 3, using the inverse variance weighted model, we discovered evidence of the latent causal relationship between coffee intake (OR = 0.332, 95%CI: 0.117,0.943, P = 0.038)and instant coffee intake (OR = 0.014, 95%CI: 0,0.426, P = 0.014) with the prevention of OCD but not with filter coffee (OR = 1.037, 95%CI: 0.772,1.392, P = 0.810), showing that the risk of OCD fell by over 70% with coffee intake especially for instant coffee. Scatter plots of SNP effect sizes for coffee consumption and OCD are shown in Fig. 3. The estimations were all consistent with IVW except for filtered coffee intake, although P values for MR-Egger regression, Weighted median, Simple mode, and Weighted mode were not considered compelling evidence for statistical significance. Heterogeneity (P_MR−Egger=0.458, P_IVW =0.491) and horizontal pleiotropy (P = 0.601) were not observed utilizing Cochran’s Q-test (Table 3). The Mendelian randomized funnel plot also displays no heterogeneity between coffee intake, instant coffee intake, and filtered coffee intake with OCD.

Table 2

Characteristics of SNPs significantly associated with coffee consumption.
SNP	EA	NEA	P-value	Se	Beta	R2	F
coffee intake
rs10119174	C	G	1.00E-08	0.0016	-0.009	4.33E-05	18.557
rs1057868	T	C	5.40E-29	0.0018	0.020	1.62E-04	69.579
rs117810762	A	G	6.20E-09	0.0062	0.036	4.53E-05	19.423
rs117968677	A	G	1.90E-08	0.0055	-0.031	4.55E-05	19.508
rs12514566	A	G	2.40E-11	0.0017	-0.011	5.81E-05	24.899
rs12989746	T	G	2.80E-08	0.0019	0.010	4.02E-05	17.225
rs13054099	C	T	4.30E-09	0.0018	-0.011	4.48E-05	19.218
rs13163336	A	C	1.30E-11	0.0022	0.015	5.93E-05	25.444
rs1338549	G	T	5.60E-09	0.0016	-0.009	4.45E-05	19.067
rs13387939	A	C	9.80E-15	0.0021	0.017	7.79E-05	33.428
rs1421085	C	T	1.70E-29	0.0016	0.019	1.66E-04	70.996
rs1527961	C	T	1.70E-08	0.0024	-0.013	4.16E-05	17.822
rs17842490	G	A	3.30E-11	0.0068	-0.045	5.73E-05	24.579
rs1942965	C	T	3.80E-08	0.0016	-0.009	3.96E-05	16.997
rs2189234	G	T	1.80E-09	0.0017	0.010	4.71E-05	20.201
rs2465037	A	C	4.80E-10	0.0017	-0.011	5.09E-05	21.849
rs2472297	T	C	1.10E-142	0.0018	0.046	8.37E-04	359.225
rs2597805	T	C	2.00E-08	0.0018	0.010	4.21E-05	18.053
rs34060476	G	A	7.50E-15	0.0024	0.018	7.88E-05	33.777
rs4410790	C	T	1.20E-120	0.0017	0.039	7.10E-04	304.704
rs442355	C	G	1.90E-09	0.0019	-0.011	4.71E-05	20.183
rs4615895	A	G	4.20E-11	0.0018	0.012	5.72E-05	24.517
rs476828	C	T	5.60E-20	0.0019	0.017	1.09E-04	46.729
rs516636	A	C	4.00E-09	0.0020	0.012	4.51E-05	19.328
rs56113850	C	T	8.90E-15	0.0016	0.013	7.83E-05	33.567
rs57918684	A	G	8.60E-09	0.0022	0.013	4.34E-05	18.631
rs6062682	T	C	2.50E-10	0.0016	0.010	5.35E-05	22.946
rs6063085	C	A	4.50E-10	0.0017	0.010	5.07E-05	21.753
rs61928609	C	A	1.30E-11	0.0022	-0.015	5.97E-05	25.602
rs62064918	T	C	4.10E-08	0.0019	-0.010	3.93E-05	16.836
rs630194	C	T	2.30E-11	0.0017	-0.011	5.81E-05	24.929
rs6469262	C	T	1.90E-08	0.0016	-0.009	4.12E-05	17.664
rs7224815	T	A	3.70E-11	0.0016	-0.011	5.70E-05	24.433
rs73075167	T	A	5.00E-11	0.0024	-0.016	5.81E-05	24.900
rs75347775	A	G	2.70E-08	0.0019	0.010	4.04E-05	17.305
rs780093	C	T	1.00E-15	0.0017	0.013	8.36E-05	35.862
rs7811609	T	C	4.00E-08	0.0017	0.009	3.91E-05	16.785
rs78267637	G	C	3.90E-09	0.0043	-0.025	4.74E-05	20.330
rs8056750	T	C	1.30E-09	0.0017	0.011	5.11E-05	21.904
rs9398171	T	C	1.10E-09	0.0018	0.011	4.85E-05	20.794
Instant coffee intake
rs12046747	A	G	3.28E-08	0.0011	-0.006	1.69E-04	30.536
rs12902945	T	G	6.43E-11	0.0009	0.006	2.36E-04	42.686
rs1481012	G	A	3.79E-11	0.0014	-0.009	2.42E-04	43.717
rs17685	A	G	3.16E-19	0.0010	0.009	4.44E-04	80.333
rs2106727	G	A	6.43E-71	0.0009	0.016	1.75E-03	317.026
rs2472297	T	C	1.08E-94	0.0010	0.020	2.35E-03	426.211
rs34060476	G	A	3.34E-12	0.0013	0.009	2.68E-04	48.479
rs35198275	G	A	6.17E-10	0.0013	-0.008	2.12E-04	38.266
rs56113850	C	T	1.74E-11	0.0009	0.006	2.50E-04	45.242
rs6062357	T	C	3.40E-10	0.0009	0.006	2.18E-04	39.428
rs953442	C	T	1.46E-08	0.0010	0.006	1.78E-04	32.105
Filtered coffee intake
rs10863359	C	T	3.49E-11	0.075	0.497	1.25E-02	18.534
rs140948748	A	G	1.41E-08	0.139	0.786	1.35E-02	20.058
rs143400648	A	C	2.73E-09	0.125	0.746	1.19E-02	17.616
rs150630551	G	A	1.64E-08	0.119	0.674	1.04E-02	15.451
rs78560564	C	T	3.30E-08	0.060	0.334	8.33E-03	12.317
rs79326525	C	T	5.03E-09	0.122	0.715	1.08E-02	15.955
Abbreviations: SNP Single-nucleotide polymorphism, EA Effect allele, NEA noneffect allele, SE, standard error, EAF Effect allele frequency.

Table 3

MR estimates for the associations of coffee consumption with OCD based on Inverse variance weighted, MR Egger, Weighted median, Simple mode, and Weighted mode.
Exposure	MR methods	OR (95%CI)	P-value	Q-value of heterogeneity	P-value of pleiotropy
coffee intake	MR Egger	0.204(0.025,1.663)	0.146	0.458	0.601
	Weighted median	0.333(0.073,1.519)	0.156
	Inverse variance weighted	0.332(0.117,0.943)	0.038	0.491
	Simple mode	0.19(0.006,5.979)	0.351
	Weighted mode	0.251(0.044,1.42)	0.126
Instant coffee intake	Weighted median	0.007(0,0.466)	0.021
	Inverse variance weighted	0.014(0,0.426)	0.014	0.238
	Simple mode	0.001(0,0.663)	0.065
	Weighted mode	0.02(0,1.598)	0.111
Filtered coffee intake	MR Egger	1.076(0.311,3.728)	0.914	0.173	0.955
	Weighted median	1.032(0.72,1.481)	0.862
	Inverse variance weighted	1.037(0.772,1.392)	0.810	0.271
	Simple mode	0.728(0.384,1.378)	0.374
	Weighted mode	1.302(0.738,2.298)	0.404

The Leave-One-Out plot is shown in Fig. 4. Based on the results of the earlier heterogeneity and pleiotropy tests, we saw that the right terminal of the confidence interval for a number of SNPs surpassed the invalid line in the Leave-One-Out test. The small number of SNPs was thought to be the cause. Therefore, it is likely that there is a causal link between coffee consumption and OCD.

Research has examined the connection between caffeine, the most important substance in coffee, on OCD symptoms[2, 6, 22, 23]. The results, however, are unclear and point to a complicated relationship that might differ greatly among people. In this study, we investigated the association between coffee consumption and obsessive-compulsive disorder using the data from public GWAS databases. Using Mendelian randomization analysis, we discovered that there was no significant link between filtered coffee and OCD, but there was a negative correlation between coffee intake and instant coffee intake and OCD. Using the IVW technique, we discovered a causal link between coffee intake and instant coffee intake and OCD. The five MR studies, however, could not find a causal link between filtered coffee and OCD. To the best of our knowledge, there has few any clarification on the causative association between coffee consumption and OCD thus far.

Previous research on the association between OCD and coffee has not yielded a consistent result. In mice, an acute high dose of caffeine initially decreased compulsive-like nest building behavior, but then increased it for several hours before decreasing again over 24 hours[24]. However, Chronic high-dose caffeine also increased compulsive-like nest building in mice[24]. As with the confusing results of preclinical studies, clinical trials have also produced inconsistent results. A previous study reported that coffee intake can be taken as an adjuvant therapy for obsessive-compulsive disorder and help lessen the intensity of its symptoms[6]. A possible mechanism is that caffeine affects adenosine receptors and serotonin reuptake, which may help alleviate OCD symptoms[6]. However, the same source also warns that coffee intake can exacerbate anxiety, a common component of OCD, suggesting that while it might help some individuals, it could worsen symptoms in others[6]. Moreover, another study indicates that while moderate caffeine intake has been associated with fewer depressive symptoms and cognitive failures, its effects on OCD specifically are less well-documented[22]. This underscores the variability in caffeine's impact, which could be influenced by individual differences in genetic makeup and the presence of specific psychiatric conditions. In summary, while there is some evidence suggesting that caffeine could potentially serve as a helpful tool in managing OCD symptoms, the research is far from conclusive. The effects of caffeine on OCD appear to be highly individualized, with potential benefits being moderated by factors such as the individual's anxiety levels, genetic makeup, and overall mental health condition.

This study avoided confounding risk variables and reverse causation by employing bidirectional Mendelian randomization and a clear definition of coffee consumption. Our results indicated that coffee intake was negatively correlated with OCD when the coffee subtype was not considered. After exploring the relationship by subtype, instant coffee intake showed a negative association with OCD, while filtered coffee intake did not. More than half of the UK biobank participants preferred drinking instant coffee[25]. We inferred that instant coffee played a key role in the association that coffee consumption had a negative effect on OCD. Previous studies did not take coffee types into account, and the inconsistent results might be attributed to small sample sizes or a lack of a classification of coffee type.

Limitations also exist for this MR investigation. First of all, this study did not include the amount of drinking, drinking time and other factors. Secondly, we did not categorize coffee varieties with milk further. Coffee with milk, such as latte, cappuccino, and expresso, may have an impact on OCD. Finally, the breadth of the study is restricted by the statistical MR of genetic aggregation, and individual differences exist. Nonetheless, the effect estimate is less than 1 due to multiple complementary approaches, and all were negatively associated, making it unlikely that there is a bias. When the effect is very tiny or nonexistent, MR analysis typically yields solid proof.[26].

In conclusion, this study's findings revealed the potential protective effect of coffee intake on OCD especially instant coffee, while filtered coffee did not. It suggests that an ordinary diet may be helpful in both preventing and treating mental health issues. Our results partially aligned with previous observational research. However, greater validation in larger prospective trials and more in-depth mechanistic research are needed to better explain the causal links between coffee consumption and OCD.

Ethics approval and consent to participate

Each employed GWAS received ethical approval from the relevant institutions.

Consent for publication

Not applicable.

Availability of data and material

The complete GWAS summary datasets, which contain the data supporting the study's conclusions, are publicly accessible in the IEU GWAS database (https://gwas.mrcieu.ac.uk), which can be queried using the R package of TwoSampleMR.

Competing interests

The authors declare no competing interests.

Funding

This work was supported in part by grants from the China Postdoctoral Science Foundation (2023M744055).

Authors' contributions

WJW conceived the idea of compiling this article. FMY and LZG prepared the figures and tables. All authors performed the literature search, wrote the manuscript, and approved the submission of the article.

Acknowledgements

Thanks to the public databases for providing us with data, and thanks to the developers of R software and R packages for their contributions and convenience.

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Elucidating the relationship between coffee consumption and obsessive-compulsive disorder: A Mendelian randomization study

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