An association between advanced paternal age at birth and risk for autism spectrum disorders and the underlying biological mechanisms

背景和目的。父亲的出生年龄被认为与自闭症谱系障碍（ASD）有关。在这项研究中，我们旨在以回顾性的方式在日本样本中复制这种关联，并使用出生队列研究这种关联的生物学机制。这种机制的潜在候选是使用人工生殖技术。方法1。“回顾性研究”：84名高功能ASD患者和208名正常发展的对照患者被纳入研究。在控制性别、胎次和母亲出生年龄的情况下，寻求ASD诊断与父亲出生年龄之间的统计关联。方法2。“前瞻性研究”：在2007年11月19日至2009年7月1日期间出生的780名孕妇及其婴儿被纳入一项正在进行的出生队列研究。研究人员对参与研究的母子二人组进行了随访，直到2010年底，以检查是否有任何异常的发展。这些结果测量包括马伦早期学习量表、发育里程碑和疑似ASD诊断的分数。我们还研究了疑似ASD的风险与父亲出生年龄和人工生殖技术的关系。结果1。“回顾性研究”：在控制了协变量后，证实了父亲出生年龄与ASD风险之间的关联。还发现了剂量-反应关系。结果2。“前瞻性研究”：在单变量分析中，父亲的出生年龄不能预测运动/语言发育的延迟、发育里程碑的实现和疑似ASD的诊断。另一方面，人工生殖技术似乎可以预测发育迟缓和ASD，尽管这种关联没有达到统计学意义。由于缺乏统计能力，我们无法寻找父亲出生年龄和人工生殖治疗与自闭症风险之间的相互作用。虽然还有待确切的结论，但这项研究表明，人工生殖技术是父亲出生年龄与自闭症之间联系的潜在生物学机制。少

Background and aim. Paternal age at birth has been suggested to be associated with autism spectrum disorder (ASD). In this study, we aimed at replicating the association in a Japanese sample in a retrospective manner, and at investigating biological mechanisms underlying this association using a birth cohort. A potential candidate for this mechanism is a use of artificial reproductive technique.Method 1. "Retrospective study" : 84 individuals with high-functioning ASD and 208 typically developed control individuals were enrolled. A statistical association was sought between diagnosis of ASD and paternal age at birth, while controlling for gender, parity, and maternal age at birth.Method 2. "Prospective study" : 780 pregnant women and their babies were enrolled as a part of an ongoing birth cohort study who were born during the period of 19 November, 2007 and 1 July, 2009. The participating mother-and-child dyads were followed up until the end of 2010 to examine whether any aberrant dev … More elopmental trajectories would be found ; such outcome measures include scores of Mullen Scales of Early Learning, developmental milestones, and suspected diagnosis of ASD. We also examined a risk of suspected ASD in association with paternal age at birth, and artificial reproductive technique as well. Result 1. "Retrospective study" : The association between paternal age at birth and a risk for ASD was confirmed after controlling for covariates. The dose-response relationship was also found.Result 2. "Prospective study" : In univariate analyses, paternal age at birth did not predict delay in motor/language development, in achievement of developmental milestones, and suspected diagnosis of ASD. On the other hand, artificial reproductive technique appeared to predict delayed development and ASD, although the associations did not reach statistical significance. Due to lack of statistical power, we were unable to seek for interaction between paternal age at birth and artificial reproductive therapy in association with a risk for ASD.Conclusion. Although firm conclusions are awaited, this study suggested relevance of artificial reproductive techniques as an underlying biological mechanism for the association between paternal age at birth and ASD. Less