Mendelian randomization infers the effect of 14 parental illnesses on 44 congenital anomalies

Background Congenital anomalies (CA), including congenital malformations (CM) and congenital deformities (CD), are significant health concerns influenced by genetic and environmental factors. Parental illnesses, especially those with genetic components, may affect the risk of congenital anomalies in offspring. Although clinical studies have suggested associations between certain parental illnesses and increased CM and CD risk, causal relationships remain unclear. This study employs a Mendelian randomization (MR) approach to investigate these potential causal links. Methods Fourteen parental illnesses were selected for this study: breast cancer, chronic bronchitis/emphysema, diabetes, heart disease, hypertension, and Alzheimer’s disease in mothers; and Alzheimer’s disease, bowel cancer, chronic bronchitis/emphysema, diabetes, heart disease, hypertension, lung cancer, and prostate cancer in fathers. Genetic variants associated with these illnesses were identified from genome-wide association studies (GWAS) in the UK Biobank. Genetic data for 44 congenital anomalies were sourced from the FinnGen database. Two-sample MR was conducted to estimate causal effects, with sensitivity analyses and multivariable MR (MVMR) to control for potential confounders. Results MR analysis revealed causal relationships between 13 parental illnesses and 13 specific congenital anomalies. Notably, mother’s hypertension significantly increased the risk of congenital hypothyroidism (IVW: OR = 7.969, 95% CI = 3.0826-20.6011, p = 4.20E-04), and father’s diabetes increased the risk of congenital heart defects in offspring (IVW: OR = 3.8E+09, 95% CI = 2.2E+04-6.6E+14, p = 3E-04). The associations’ strength varied with the type of parental illness and the specific congenital disease. Conclusion This study underscores the utility of MR in elucidating genetic influences of parental health conditions on congenital anomalies. The findings highlight the importance of managing parental health to reduce congenital anomalies risk in offspring. Further research is needed to explore underlying biological mechanisms and validate these findings in diverse populations.