Background: Mendelian randomization (MR) provides unconfounded estimates. MR is open to selection bias when the underlying sample is selected on surviving to recruitment on the genetically instrumented exposure and competing risk of the outcome. Few methods to address this bias exist.
Methods: We show that this selection bias can sometimes be addressed by adjusting for common causes of survival and outcome. We use multivariable MR to obtain a corrected MR estimate for statins on stroke. Statins affect survival, and stroke typically occurs later in life than ischemic heart disease (IHD), making estimates for stroke open to bias from competing risk.
Results: In univariable MR in the UK Biobank, genetically instrumented statins did not protect against stroke [odds ratio (OR) 1.33, 95% confidence interval (CI) 0.80–2.20] but did in multivariable MR (OR 0.81, 95% CI 0.68–0.98) adjusted for major causes of survival and stroke [blood pressure, body mass index (BMI), and smoking initiation] with a multivariable Q-statistic indicating absence of selection bias. However, the MR estimate for statins on stroke using MEGASTROKE remained positive and the Q statistic indicated pleiotropy.
Conclusion: MR studies of harmful exposures on late-onset diseases with shared etiology need to be conceptualized within a mechanistic understanding so as to identify any potential bias due to survival to recruitment on both genetically instrumented exposure and competing risk of the outcome, which may then be investigated using multivariable MR or estimated analytically and results interpreted accordingly.
Background: Associations between inflammatory bowel disease (IBD) [including ulcerative colitis (UC) and Crohn’s disease (CD)] and ankylosing spondylitis (AS) were discovered in observational studies, but no evidence supported the causal relationship between the two diseases.
Methods: We employed two-sample Mendelian randomization (MR) to estimate the unconfounded bidirectional causal associations between IBD (including UC and CD) and AS. We selected single-nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) after strictly assessing the quality of the studies in the IEU GWAS database. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results.
Results: We found positive causal effects of genetically increased UC, CD, and IBD risk on AS (e.g., UC and AS, IVW OR: 1.0256, 95% CI: 1.0130∼1.0385, p = 6.43E-05). However, we did not find significant causal associations of AS with UC, CD, or IBD (e.g., AS and UC, IVW OR: 1.1858, 95% CI: 0.8639∼1.6278, p = 0.2916). The sensitivity analysis also confirmed that horizontal pleiotropy was unlikely to bias the causality (e.g., UC and AS, MR-Egger: intercept p = 0.1326). The leave-one-out analysis also demonstrated that the observed links were not driven by SNP. No evidence of heterogeneity was found between the genetic variants (e.g., UC and AS, MR-Egger: Q statistic = 43.1297, I2<0.0001, p = 0.7434).
Conclusion: Our results provide new evidence indicating there are positive causal effects of IBD on AS in the European population. We suggest that the features of inflammatory bowel disease in particular should be assessed in the diagnosis of ankylosing spondylitis. We also provide some advice for preventing and treating the two diseases.
Background: Alcohol use has been linked to a number of physical conditions, but the relationship between alcohol drinking and depression, one of the most common mental disorders that is a significant contributor to the global burden of disease, is still under debate. We aim to help fill the literature gap on the causal effect of alcohol use on depression by using genetic instruments of ALDH2 rs671 and ADH1B rs1229984 in the Mendelian randomization (MR) framework.
Materials and Methods: We collected a sample of 476 middle-aged and older adults from mainland China. The 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) was used to measure the status of depression. The frequency and intensity of alcohol consumption were measured by (1) a binary indicator of drinking or not, (2) the total number of drinking occasions during the past 30 days, and (3) the weekly ethanol consumption in grams.
Results: MR estimates indicated that alcohol use was causally associated with a lower risk of depression. Parameter estimates of drinking or not (b = −0.127, p = 0.048), number of drinking occasions (b = −0.012, p = 0.040), and weekly ethanol consumption (b = −0.001, p = 0.039) were all negative and statistically significant. The results were robust after adjustments for potential confounders (e.g., income, smoking, and parental drinking behaviors), and the exclusion of heavy or former drinkers.
Conclusions: This is one of the first study to investigate the causal relationship between alcohol use and mental health using an MR design in East Asian populations. Further studies are needed to clarify the mechanisms of this causal link.