Association between human herpesviruses infections and childhood neurodevelopmental disorders: insights from two-sample mendelian randomization analyses and systematic review with meta-analysis

Abstract

Abstract Background The potential roles of viral infections in neurodevelopmental disorders (NDDs) have been suggested based on previous studies. Given the high prevalence of human herpesviruses (HHVs), the associations between HHVs infection and the risk of NDDs warrant explored. Methods Our study employs a two-sample Mendelian randomization (MR) analysis and systematic review with meta-analysis to investigate whether genetically predicted HHVs infection are linked to three main childhood NDDs—autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and Tourette syndrome (TS). We utilized genetic variants associated with HHV infections in genome-wide association study (GWAS) summary datasets of European populations to establish instrumental variables and statistics for three NDDs obtained from Psychiatric Genomics Consortium. MR analysis was performed using inverse-variance weighted, MR Egger, weighted median, simple median, weighted mode, and MR-PRESSO. In addition, publications associating HHVs infection with three NDDs were systematically searched using PubMed, Web of Science, and three Chinese databases for meta-analyses. Results The MR results found no evidence to support a link between genetically predicted HHVs infection and the risk of NDDs based on existing datasets. Twenty-seven observational studies on children with HHVs infection and NDDs were considered eligible. Meta-analysis showed that cytomegalovirus and HHV-6 infection were related with ASD, while Epstein-Barr virus and cytomegalovirus infection were associated with TD in Chinese population. Conclusions: These results contribute to a comprehensive understanding of the possibilities underlying HHV infections in affecting childhood NDDs. Further research is necessary to include larger and more robust statistics of HHV infections and NDDs. Trial registration This systematic review was registered at PROSPERO as CRD42024554169. Retrospectively registered 26 July 2024.

Keywords

• Neurodevelopmental disorders
• Human herpesviruses
• Mendelian randomization
• Genome-wide association study
• Systematic review