Abstract

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.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was funded by Jilin Province Science and Technology Development Grant (grant Nos. 20210101452JC and YDZJ202301ZYTS096)

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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Yes

Footnotes

E-mail addresses: YanHui Li: yan_huijlu.edu.cn, Wenjing Shao: shaoshaojlu.edu.cn, Tian Tian: tiantian0113jlu.edu.cn

Data Availability

All data produced in the present study are available upon reasonable request to the authors.

https://gwas.mrcieu.ac.uk/

AbbreviationsCACongenital anomaliesCMcongenital malformationsCDcongenital deformitiesIVWInverse variance weightedIVsInstrumental variablesSNPsSingle Nucleotide PolymorphismsMRMendelian randomizationUVMRUnivariable MRMVMRMultivariable MROROdds ratioCIconfidence intervalGWASGenome-Wide Association StudyUKBBUnited Kingdom Biobank