Department of Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
JAMA Netw Open. 2020 Apr 1;3(4):e202868. doi: 10.1001/jamanetworkopen.2020.2868.
Advanced parental age has been associated with autism spectrum disorders (ASDs) in children. However, little is known about the association between grandparental age at the time of birth of the parent and the risk of ASD in the grandchildren.
To estimate the associations between parental and grandparental age and ASD risk in children.
DESIGN, SETTING, AND PARTICIPANTS: This population-based, multigenerational cohort study used data from Danish national health registries. A parental age cohort was constructed to evaluate the association between parental age and ASD in 1 476 783 singleton children born from 1990 to 2013, and a multigenerational cohort was also constructed including 362 438 fathers and 458 234 mothers born from 1973 to 1990 for whom information on grandparental age was available. Data analyses were conducted from November 1, 2018, through February 7, 2020.
Parental age at childbirth and grandparental age at the time of the birth of the parent.
Diagnoses of ASD in children were obtained from the Danish Psychiatric Central Register (1994-2017). Logistic regression analysis was used to estimate the associations between parental or grandparental age and ASD in children.
Of the 1 476 783 children born from 1990 to 2013, 758 066 (51.3%) were male, and 27 616 (1.9%) had ASD (20 467 [74.1%] were male). Advanced paternal or maternal age over 30 years was monotonically associated with increased ASD risk, with odds ratios (ORs) of 1.56 (95% CI, 1.45-1.68) for maternal age 40 years and older and 1.57 (95% CI, 1.39-1.78) for paternal age 50 years and older, compared with parents aged 25 to 29 years. In the multigenerational cohort, 9364 grandchildren (1.7%) had ASD. This study found U-shaped associations, in that ASD risk was higher among grandchildren of younger (≤19 years) maternal grandmothers (OR, 1.68; 95% CI, 1.52-1.85), younger maternal grandfathers (OR, 1.50; 95% CI, 1.26-1.78), and younger paternal grandmothers (OR, 1.18; 95% CI, 1.04-1.34), and older (≥40 years) paternal grandmothers (OR, 1.40; 95% CI, 1.03-1.90) compared with the grandchildren of grandparents who were aged 25 to 29 years at the time of giving birth to the parents.
These findings corroborate previous studies suggesting that advanced parental age is independently associated with increased ASD risk in children. This study also found that children with young maternal grandparents and children with young and old paternal grandparents had elevated ASD risk. Possible transmission of ASD risk across generations should be considered in etiological research on ASD.
高龄父母与儿童自闭症谱系障碍（ASD）有关。然而，关于父母年龄与孙辈患 ASD 风险之间的关系，知之甚少。
评估父母和祖父母年龄与儿童 ASD 风险之间的关联。
设计、地点和参与者：本基于人群的多代队列研究使用了丹麦国家健康登记处的数据。构建了一个父母年龄队列，以评估 1990 年至 2013 年期间出生的 1476783 名单胎儿童的父母年龄与 ASD 之间的关联，还构建了一个多代队列，包括 1973 年至 1990 年期间出生的 362438 名父亲和 458234 名母亲，这些父母的祖父母年龄信息可用。数据分析于 2018 年 11 月 1 日至 2020 年 2 月 7 日进行。
子女出生时父母的年龄和父母出生时祖父母的年龄。
通过丹麦精神病学中央登记处（1994-2017 年）获得儿童 ASD 的诊断。使用逻辑回归分析评估父母或祖父母年龄与儿童 ASD 之间的关联。
在 1990 年至 2013 年期间出生的 1476783 名儿童中，758066 名（51.3%）为男性，27616 名（1.9%）患有 ASD（20467 名[74.1%]为男性）。母亲年龄在 40 岁及以上或父亲年龄在 50 岁及以上与 ASD 风险呈单调递增相关，优势比（OR）分别为 1.56（95%CI，1.45-1.68）和 1.57（95%CI，1.39-1.78），与 25 至 29 岁的父母相比。在多代队列中，有 9364 名（1.7%）孙辈患有 ASD。本研究发现了 U 型关联，即祖母年龄≤19 岁（OR，1.68；95%CI，1.52-1.85）、母亲年龄≤19 岁（OR，1.50；95%CI，1.26-1.78）、父亲年龄≤19 岁（OR，1.18；95%CI，1.04-1.34）和祖母年龄≥40 岁（OR，1.40；95%CI，1.03-1.90）的孙辈患 ASD 的风险更高。
这些发现证实了先前的研究结果，即高龄父母与儿童 ASD 风险增加独立相关。本研究还发现，有年轻的外祖母和年轻及年长的祖父的儿童患 ASD 的风险增加。在 ASD 的病因学研究中，应考虑跨代传递 ASD 风险的可能性。
