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已发表论文
线粒体 DNA 拷贝数在神经发育障碍中的作用：一项双向两样本孟德尔随机化研究
Authors Qiu X, Song H, Wu C , Chen C, Zhi H, Zhang C , Zhu X
Received 9 April 2025
Accepted for publication 20 September 2025
Published 24 November 2025 Volume 2025:18 Pages 2323—2332
DOI https://doi.org/10.2147/PRBM.S533506
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Einar Thorsteinsson
Xinhui Qiu,1,2 Huilu Song,1,2 Chenyang Wu,3,4 Chaojun Chen,1,2 Haimei Zhi,4 Chengyuan Zhang,1,2 Xiaobo Zhu1,2
1The Second Clinical Medical College, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People’s Republic of China; 2Children’s Medical Center, the second Qilu Hospital of Shandong University, Jinan, Shandong, 250033, People’s Republic of China; 3Department of Cardiology Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 4The First Clinical Medical College, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
Correspondence: Xiaobo Zhu, Children’s Medical Center, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan City, Shandong Province, 250033, People’s Republic of China, Email 201262015319@email.sdu.edu.cn
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
Keywords: neurodevelopmental disorders, mitochondrial DNA copy number, mendelian randomization, attention-deficit/hyperactivity disorder, autism spectrum disorder, Tourette syndrome
1The Second Clinical Medical College, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People’s Republic of China; 2Children’s Medical Center, the second Qilu Hospital of Shandong University, Jinan, Shandong, 250033, People’s Republic of China; 3Department of Cardiology Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 4The First Clinical Medical College, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
Correspondence: Xiaobo Zhu, Children’s Medical Center, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan City, Shandong Province, 250033, People’s Republic of China, Email 201262015319@email.sdu.edu.cn
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
Keywords: neurodevelopmental disorders, mitochondrial DNA copy number, mendelian randomization, attention-deficit/hyperactivity disorder, autism spectrum disorder, Tourette syndrome