JAMA：儿童自闭症遗传风险因素可隔代累积

自闭症不仅会受到环境因素影响，也会受到遗传因素影响。过去有研究表明，老年得子者，其孩子患有自闭症的风险是早年得子者孩子的两倍。而研究人员对瑞典1932年后出生的5936名自闭症患者和超过3万名健康人士的精神疾病诊断细节、他们祖父和外祖父的生育年龄等数据进行对照研究后发现，祖父生育子女时的年龄与其第三代患自闭症的风险成正比。相关论文发表于国际权威杂志JAMA 2013年4月份最新一期在线版。

为进一步丰富父母年龄与孤独症风险之间的联系的知识，研究人员对父母年龄对儿童孤独症的影响进行了探索。这一基于人群的、多中心、病例对照研究，对瑞典国家世代人口和患者注册处信息进行了分析。研究人员纳入了1932年后出生的瑞典人口。这一队列中超过90%的人口出生时父母的年龄数据有记录可循。可获得出生时其祖父母年龄数据的人口被设定为一个小型数集（5936例受试者，30923例对照）。主要结局为患者注册数据中按国际疾病分类法诊断为儿童孤独症的数量。

研究发现父母出生时祖父母高龄与第三代孤独症风险存在统计学单调相关。数据显示，与20岁至24岁生育女儿的人相比，超过50岁生育女儿者，其第三代患自闭症的风险是前者第三代的1.79倍(95% CI, 1.35-2.37; P < .001)；而与20岁至24岁生育儿子的人相比，超过50岁生育儿子者，其第三代患自闭症的风险是前者的1.67倍(95% CI, 1.35-2.37; P < .001)。父母高龄与后代孤独症风险之间同样存在有统计学意义的单调相关性。敏感性分析指示上述发现并非缘于遗失祖父一代年龄引起的倚所致。

研究人员指出，过去有研究表明，父亲生育年龄过大是自闭症的风险因素之一，而新研究则表明，祖父的生育年龄过大同样是自闭症的一个风险因素。虽然这一关联背后的机制尚不十分清楚，但或许可通过男性精子细胞的突变得到解释：男性精子细胞会随着时间推移不断分裂，而每一次分裂，都会使得精子基因面临更多的突变可能。虽然大多数的基因突变并不会导致儿童患上自闭症，但这些“沉默的”突变在遗传给健康的第二代后，会影响第三代患上自闭症的风险几率。研究人员认为，这种自闭症的遗传风险会逐代累积，或与其他风险因素发生反应，直至达到导致精神疾病的阈值。

论文作者之一、伦敦国王学院精神病学研究所的亚伯拉罕·勒玄博格博士表示，这一发现对于全面理解自闭症十分重要，这是第一次在精神病学范畴内表明，祖父的生活方式选择会影响到第三代。“但这并不是说，如果你的父亲是老年得子有了你，因为有可能增加你孩子患自闭症的风险，你就不应该要孩子，毕竟这种风险几率很小。”勒玄博格博士说。

研究人员最终得出结论，第一代高龄与第三代孤独症风险增加相关，这预示着孤独症风险可隔代积累。这些结果与突变和/或遗传变异随年龄增加而积累的理论一致。

与自闭症相关的拓展阅读：

• J Pediatr ：幼时接种疫苗不会引发自闭症
• JAMA：自闭症风险可能延续多代
• PNAS：自闭症和精神分裂症的最新研究
• 维生素D可降低自闭症风险
• Cell：发现基因胚系突变与自闭症风险之间的关联
• Transl Psychiat：自闭症或有新疗法
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Autism Risk Across Generations: A Population-Based Study of Advancing Grandpaternal and Paternal Age.
IMPORTANCE
Advancing paternal age has been linked to autism. OBJECTIVE To further expand knowledge about the association between paternal age and autism by studying the effect of grandfathers' age on childhood autism.
DESIGN
Population-based, multigenerational, case-control study. SETTING Nationwide multigeneration and patient registers in Sweden. PARTICIPANTS We conducted a study of individuals born in Sweden since 1932. Parental age at birth was obtained for more than 90% of the cohort. Grandparental age at the time of birth of the parent was obtained for a smaller subset (5936 cases and 30 923 controls). MAIN OUTCOME AND MEASURE International Classification of Diseases diagnosis of childhood autism in the patient registry.
RESULTS
A statistically significant monotonic association was found between advancing grandpaternal age at the time of birth of the parent and risk of autism in grandchildren. Men who had fathered a daughter when they were 50 years or older were 1.79 times (95% CI, 1.35-2.37; P < .001) more likely to have a grandchild with autism, and men who had fathered a son when they were 50 years or older were 1.67 times (95% CI, 1.35-2.37; P < .001) more likely to have a grandchild with autism, compared with men who had fathered children when they were 20 to 24 years old, after controlling for birth year and sex of the child, age of the spouse, family history of psychiatric disorders, highest family educational level, and residential county. A statistically significant monotonic association was also found between advancing paternal age and risk of autism in the offspring. Sensitivity analyses indicated that these findings were not the result of bias due to missing data on grandparental age.
CONCLUSIONS AND RELEVANCE
Advanced grandparental age was associated with increased risk of autism, suggesting that risk of autism could develop over generations. The results are consistent with mutations and/or epigenetic alterations associated with advancing paternal age.