Children's Hospital of Philadelphia, Pennsylvania, United States; Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China.
Children's Hospital of Philadelphia, Pennsylvania, United States.
J Am Acad Child Adolesc Psychiatry. 2024 Aug;63(8):835-844. doi: 10.1016/j.jaac.2023.09.550. Epub 2023 Dec 8.
Accumulative evidence indicates a critical role of mitochondrial function in autism spectrum disorders (ASD), implying that 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.
Two European cohorts and an Ashkenazi Jewish (AJ) cohort were analyzed, including 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 to ASD.
We observed that the ancient adaptive mtDNA haplogroup K was significantly associated with decreased risk of ASD by the investigation of 2 European cohorts including a total of 2,006 cases and 4,435 controls (odds ratio = 0.64, P=1.79 × 10), 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). 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 for ASD via regulation of expression levels of genes encoded by the mitochondrial genome.
This study helps to 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.
Increasing evidence indicates that mitochondrial dysfunction may be linked to autism spectrum disorder (ASD). This study investigated potential associations of mitochondrial DNA (mtDNA) variants in 2 European and Ashkenazi Jewish cohorts including 2,062 individuals with ASD and 4,632 healthy controls. Researchers found that the ancient mtDNA haplogroup K was linked to a reduced risk of ASD in both European and Ashkenazi Jewish populations. Additionally, specific mtDNA variants were associated with ASD risk and were shown to influence the expression of nearby genes in the brain. These findings highlight the potential involvement of mtDNA in ASD development, offering new insights into the genetic mechanisms underlying the disorder.
越来越多的证据表明线粒体功能在自闭症谱系障碍（ASD）中起着关键作用，这意味着 ASD 的风险可能与由于 DNA（mtDNA）变异导致的线粒体功能障碍有关。尽管一些研究已经探讨了 mtDNA 变异与 ASD 之间的关联，但 mtDNA 在 ASD 中的作用仍不清楚。在这里，我们旨在研究线粒体 DNA 单倍群是否与 ASD 的风险相关。
分析了两个欧洲队列和一个阿什肯纳兹犹太（AJ）队列，包括 2062 名 ASD 患者与 4632 名健康对照。使用 Illumina HumanHap550/610 和 Illumina 1M 阵列对 DNA 样本进行基因分型，包括线粒体标记物。使用 HaploGrep2 从基因分型数据中识别线粒体 DNA（mtDNA）单倍群。建立了一个线粒体基因组内插管道来检测 mtDNA 变体。我们进行了病例对照研究，以调查 mtDNA 单倍群和变体与 ASD 易感性的潜在关联。
我们观察到古老的适应性 mtDNA 单倍群 K 通过对包括 2006 例病例和 4435 例对照在内的两个欧洲队列的研究与 ASD 风险显著降低相关（比值比=0.64，P=1.79×10），并且我们在包括 56 例病例和 197 例对照的阿什肯纳兹犹太（AJ）队列中复制了这种关联（比值比=0.35，P=9.46×10）。此外，我们证明 mtDNA 变体 rs28358571、rs28358584 和 rs28358280 与 ASD 风险显著相关。进一步的表达数量性状基因座（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 变体可能通过调节线粒体基因组编码的基因的表达水平来导致 ASD 风险。
本研究有助于阐明线粒体在 ASD 中的贡献，并为 ASD 的遗传机制提供了新的见解，表明 mtDNA 编码蛋白可能参与 ASD 的发展。
