Jiao Luo1,2, Zhongwei Xu3, Raymond Noordam2, Diana van Heemst2, Ruifang Li-Gao1,4,5. 1. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands. 2. Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. 3. Department of Medical Biochemistry and Biophysics, Section of Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden. 4. CoRPS Center of Research on Psychology in Somatic Diseases, Tilburg University, Tilburg, the Netherlands. 5. Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
Abstract
BACKGROUND AND AIMS: Observational studies have suggested a bidirectional association between depression and inflammatory bowel disease [IBD], including Crohn's disease [CD] and ulcerative colitis [UC]. However, it remains unclear whether the observed associations are causal due to the difficulties of determining sequential temporality. We investigated the association between depression and IBD by using bidirectional two-sample Mendelian randomization [MR]. METHODS: Independent genetic variants for depression and IBD were selected as instruments from published genome-wide association studies [GWAS] among individuals of predominantly European ancestry. Summary statistics for instrument-outcome associations were retrieved from three separate databases for both depression [Psychiatric Genomics Consortium, FinnGen and UK Biobank] and IBD [the largest GWAS meta-analysis, FinnGen and UK Biobank], respectively. MR analyses included the inverse-variance-weighted method, weighted-median estimator, MR-Egger regression, and sensitivity analyses of Steiger filtering and MR PRESSO. From either direction, analyses were performed per outcome database and were subsequently meta-analysed using a fixed-effect model. RESULTS: Genetically predicted depression [per log-odds ratio increase] was associated with a higher risk of IBD; odds ratios [95% confidence interval] for IBD, CD and UC were 1.20 [1.05, 1.36], 1.29 [1.07, 1.56] and 1.22 [1.01, 1.47] in a combined sample size of 693 183 [36 507 IBD cases], 212 172 [13 714 CD cases] and 219 686 [15 691 UC cases] individuals, respectively. In contrast, no association was observed between genetically influenced IBD and depression in 534 635 individuals [71 466 depression cases]. CONCLUSIONS: Our findings corroborated a causal association of depression on IBD, which may impact the clinical decision on the management of depression in patients with IBD. Though our results did not support a causal effect of IBD on depression, further investigations are needed to clarify the effect of IBD activity on depression [with different symptomology].
BACKGROUND AND AIMS: Observational studies have suggested a bidirectional association between depression and inflammatory bowel disease [IBD], including Crohn's disease [CD] and ulcerative colitis [UC]. However, it remains unclear whether the observed associations are causal due to the difficulties of determining sequential temporality. We investigated the association between depression and IBD by using bidirectional two-sample Mendelian randomization [MR]. METHODS: Independent genetic variants for depression and IBD were selected as instruments from published genome-wide association studies [GWAS] among individuals of predominantly European ancestry. Summary statistics for instrument-outcome associations were retrieved from three separate databases for both depression [Psychiatric Genomics Consortium, FinnGen and UK Biobank] and IBD [the largest GWAS meta-analysis, FinnGen and UK Biobank], respectively. MR analyses included the inverse-variance-weighted method, weighted-median estimator, MR-Egger regression, and sensitivity analyses of Steiger filtering and MR PRESSO. From either direction, analyses were performed per outcome database and were subsequently meta-analysed using a fixed-effect model. RESULTS: Genetically predicted depression [per log-odds ratio increase] was associated with a higher risk of IBD; odds ratios [95% confidence interval] for IBD, CD and UC were 1.20 [1.05, 1.36], 1.29 [1.07, 1.56] and 1.22 [1.01, 1.47] in a combined sample size of 693 183 [36 507 IBD cases], 212 172 [13 714 CD cases] and 219 686 [15 691 UC cases] individuals, respectively. In contrast, no association was observed between genetically influenced IBD and depression in 534 635 individuals [71 466 depression cases]. CONCLUSIONS: Our findings corroborated a causal association of depression on IBD, which may impact the clinical decision on the management of depression in patients with IBD. Though our results did not support a causal effect of IBD on depression, further investigations are needed to clarify the effect of IBD activity on depression [with different symptomology].