The Role of Mitochondrial DNA Copy Number in Neurodevelopmental Disorders: A Bidirectional Two-Sample Mendelian...

Recent studies have indicated a possible connection between impaired mitochondrial bioenergetics and neurodevelopmental disorders (NDDs) such autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Tourette's syndrome (TS). The precise causal relationship between them is yet uncertain. This study utilized bidirectional dual-sample Mendelian randomization (MR) analysis to investigate the causal relationship between Mitochondrial DNA (mtDNA) copy quantity, an indicator of mitochondrial malfunction, and NDDs.

The study utilized data from the Psychiatric Genomics Consortium (PGC) and IEU OpenGWAS Project database to investigate the relationship between mtDNA copy number and NDDs using MR method. The accuracy and confidence of our results were evaluated using the inverse-variance weighted (IVW) method along with sensitivity analyses such as weighted median, MR-Egger, and MR-PRESSO. Additionally, we conducted the same procedure in the reverse manner with instruments for NDDs.

A notable correlation was discovered between mtDNA copy number and ASD (OR=0.78, 95% CI: 0.65-0.94, P=0.0077). Furthermore, confirmatory GWAS data analysis yielded similar results, which were even more significant (OR=0.80, 95% CI: 0.68-0.93, P=0.0047). However, bidirectional two-sample MR analysis did not reveal significant correlations between mtDNA copy number and ADHD or TS.

This study has uncovered a significant genetic causal relationship between mtDNA copy number and ASD. No associations were discovered between ADHD and TS during the investigation. Due to the inherent constraints of MR investigations, additional study is needed to definitively clarify these genetic causal links.