Objective

Accumulative evidence indicates a critical role of mitochondrial function in ASD implying ASD risk may be linked to mitochondrial dysfunction due to DNA (mtDNA) variations. Although a few studies have explored the association between mtDNA variations and ASD, the role of mtDNA in ASD is still unclear. Here, we aimed to investigate whether mitochondrial DNA haplogroups are associated with the risk of ASD.

Method

Two European cohorts and an Ashkenazi Jewish (AJ) cohort analyzed, included 2,062 ASD patients in comparison with 4,632 healthy controls. DNA samples were genotyped using Illumina HumanHap550/610 and Illumina 1M arrays, inclusive of mitochondrial markers. Mitochondrial DNA (mtDNA) haplogroups were identified from genotyping data using HaploGrep2. A mitochondrial genome imputation pipeline was established to detect mtDNA variants. We conducted a case-control study to investigate potential associations of mtDNA haplogroups and variants with the susceptibility of ASD.

Results

We observed that the ancient adaptive mtDNA haplogroup K was significantly associated with decreased risk of ASD by the investigation of two European cohorts including a total of 2,006 cases and 4,435 controls (odds ratio 0.64, P=1.79 × 10^-5), and we replicated this association in an Ashkenazi Jewish (AJ) cohort including 56 cases and 197 controls (odds ratio 0.35, P=9.46 × 10^-3). Moreover, we demonstrate that the mtDNA variants, rs28358571, rs28358584 and rs28358280 are significantly associated with ASD risk. Further expression quantitative trait loci (eQTLs) analysis indicated that the rs28358584 and rs28358280 genotypes are associated with expression levels of nearby genes in brain tissues suggesting those mtDNA variants may confer risk to ASD via regulation of expression levels of genes encoded by the mitochondrial genome.

Conclusion

This study helps shed light on the contribution of mitochondria in ASD and provides new insights into the genetic mechanism underlying ASD, suggesting the potential involvement of mtDNA encoded proteins in the development of ASD.

中文翻译：

---

线粒体 DNA 单倍群 K 可以保护欧洲血统人群的自闭症谱系障碍风险

客观的

积累的证据表明线粒体功能在 ASD 中发挥着关键作用，这意味着 ASD 风险可能与 DNA (mtDNA) 变异导致的线粒体功能障碍有关。尽管一些研究探讨了线粒体DNA变异与自闭症谱系障碍之间的关联，但线粒体DNA在自闭症谱系障碍中的作用仍不清楚。在这里，我们的目的是研究线粒体 DNA 单倍群是否与 ASD 风险相关。

方法

两个欧洲队列和一个德系犹太人 (AJ) 队列进行了分析，其中包括 2,062 名自闭症谱系障碍 (ASD) 患者，与 4,632 名健康对照者进行比较。使用 Illumina HumanHap550/610 和 Illumina 1M 阵列对 DNA 样本进行基因分型，包括线粒体标记。使用 HaploGrep2 从基因分型数据中鉴定线粒体 DNA (mtDNA) 单倍群。建立了线粒体基因组插补流程来检测 mtDNA 变异。我们进行了一项病例对照研究，以调查 mtDNA 单倍群和变异与 ASD 易感性的潜在关联。

结果

通过对两个欧洲队列（包括总共 2,006 例病例和 4,435 名对照）的调查，我们观察到古代适应性 mtDNA 单倍群 K 与 ASD 风险降低显着相关（比值比 0.64，P= 1.79 × 10 ^-5），并且我们重复了这种关联出现在德系犹太人 (AJ) 队列中，包括 56 例病例和 197 名对照（比值比 0.35，P= 9.46 × 10 ^-3）。此外，我们证明 mtDNA 变异 rs28358571、rs28358584 和 rs28358280 与 ASD 风险显着相关。进一步的表达数量性状位点（eQTL）分析表明，rs28358584和rs28358280基因型与脑组织中附近基因的表达水平相关，表明这些mtDNA变异可能通过调节线粒体基因组编码的基因的表达水平而赋予自闭症谱系障碍（ASD）风险。

结论

这项研究有助于阐明线粒体在自闭症谱系障碍中的作用，并为自闭症谱系障碍的遗传机制提供新的见解，表明线粒体DNA编码的蛋白质可能参与自闭症谱系障碍的发展。