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JAMA Psych:自闭症风险可能延续多代

来源:医脉通 2013-04-02 18:30

发表在3月20日《美国医学会杂志·精神病学》(JAMA Psychiatry)杂志上的2项新的研究表明,童年受虐的女性以及以后做父亲的男性,其所生育下一代及第三代子女的自闭症风险分别升高。

在第一项研究中,马萨诸塞州波士顿哈佛大学公共卫生学院的研究人员发现,受虐待可引起儿童自闭症风险升高,且呈一路攀升趋势。

瑞典斯德哥尔摩卡罗林斯卡研究所的研究人员进行的第二项研究显示,父母出生时,祖父母年龄较大与第三代子女自闭症风险间有显著统计学关联,这表明自闭症的风险可以延续多代。

母方虐待

在第一项研究中,Andrea L. Roberts博士和他的同事利用“护士健康研究II,对母源性儿童虐待与后代自闭症之间的风险进行了检测。

受试者包括451名患有自闭症儿童的母亲与52,498名没有自闭症儿童的母亲。

他们写道,“围产期环境不佳与后代自闭症风险升高有关。童年受虐待的女性出现围产期环境不佳的情况比未受虐待女性多,但母源性虐待是否与后代自闭症有关尚未知晓。”

虐待的程度越重,则自闭症患病率就越高(1.8%:0.7%,P = 0.005),人口因素调整后的自闭症风险也越高(受虐最严重危险比为3.7; 95%的可信区间[CI],2.3 - 5.8)。

围产期因素调整后,只略微减弱了母亲童年受虐与后代自闭症之间的关联(受虐最严重风险比,3.0; 95%CI,1.9 - 4.8)。

Roberts博士说,“重要的是要记住,受虐最严重女性生育自闭症儿童的几率为1/50。”

她告诉WebMD医学新闻说,“因为我们还不了解为什么受虐待的女性更易生育自闭症孩子,所以对于预防自闭症有临床意义还言之过早”。

北卡罗莱州达勒姆杜克大学医学院儿童发育和行为健康科主任,Richard E. D‘Alli(他没有参与这项研究)对此发表了评论告诫称,这项研究并没有促进科学向前发展。

D’Alli 博士说,“这是钻研那些巨型母子数据库的研究之一,如果你够硬,你将继续去寻找规律。另外,如果你观察受虐待的女性,那将有很多其他的东西需要研究,“如使用选择性5 - 羟色胺再摄取抑制剂和药物滥用,这些也可能是风险因素。

“我们已经进入临床认识阶段,”他补充说,“基本上是一种大脑神经回路缺陷,它的遗传程序出了问题,这种可能的遗传程序被环境因素推向边缘。

然而,分出这一点非常困难。

他补充说,“我不知道一个曾受虐待的女性对大脑的最终发育有什么影响,有那么多被虐待但未生育出患有自闭症孩子的女性存在。”

等待的结果?

在第二项研究中,研究人员使用了多代和患者登记,通过研究祖父的年龄对儿童自闭症的影响来了解父母年龄与自闭症之间的关联。

卡罗林斯卡学院的Emma Frans 对WebMD医学新闻说,“在这项研究中,我们不仅可以复制先前发现的父亲年龄与孩子自闭症之间的联系,而且我们还发现,老年男性出现第三代自闭症子女的风险升高”。

受试者包括5936名自闭症个体及30,923名非自闭症个体。研究人员确定了每个人出生时其父母的祖父的年龄。

控制潜在的混杂因素后,与20多岁当上父亲的男性相比,50多岁生了一个女儿的男性出现第三代自闭症子女的风险高1.79倍(95%CI,1.35 - 2.37,P <0.001),50多岁生了一个儿子的男性则为1.67倍(95%CI,1.35 - 2.37,P <0.001)。

这项研究还证实了以前WebMD医学新闻报道所称的父亲年龄大与后代自闭症风险升高之间存在显著统计学相关的结论。

研究人员说,敏感性分析表明,这些发现并非由祖父祖母年龄数据缺失引起的偏倚所致。

他们得出结论称,这些调查结果显示,自闭症风险“能延续多代。研究结果与父亲年龄较大引起的突变和/或表遗传学改变一致。

Frans告诉WebMD医学新闻说,“新的基因突变风险随父亲年龄而增加。突变遗传给子孙后代,因此可能影响第二代及第三代子女的健康。”

然而,研究人员提醒说,老年男性“不应该据此对生育后代表示灰心,因为这些结果可能对了解儿童孤独症与其他精神和神经发育障碍背后的机制很重要。”

我们已经知道,母亲年龄大,则生育能力下降,后代某些先天性疾病的风险增加。最近有研究重点研究了父亲年龄大的影响,”Frans说,“这项研究将有望增加对较大年龄当上父亲的风险以及给子孙后代所带来的后果的了解。”

Roberts博士和他的同事进行的这项研究受到了国防部和美国国立卫生研究院的资助。作者们皆宣告没有相关财务关系。瑞典研究受瑞典研究委员会,瑞典工作生活和社会研究理事会和卡罗林斯卡学院的支持。作者们皆宣告没有相关财务关系。(生物谷Bioon.com)

Association of Maternal Exposure to Childhood Abuse With Elevated Risk for Autism in Offspring

Andrea L. Roberts, Kristen Lyall, Janet W. Rich-Edwards, Alberto Ascherio, Marc G. Weisskopf.

Importance:  Adverse perinatal circumstances have been associated with increased risk for autism in offspring. Women exposed to childhood abuse experience more adverse perinatal circumstances than women unexposed, but whether maternal abuse is associated with autism in offspring is unknown.
Objectives: To determine whether maternal exposure to childhood abuse is associated with risk for autism in offspring and whether possible increased risk is accounted for by a higher prevalence of adverse perinatal circumstances among abused women, including toxemia, low birth weight, gestational diabetes, previous induced abortion, intimate partner abuse, pregnancy length shorter than 37 weeks, selective serotonin reuptake inhibitor use, and alcohol use and smoking during pregnancy.
Design and Setting: Nurses' Health Study II, a population-based longitudinal cohort of 116 430 women.
Participants: Nurses with data on maternal childhood abuse and child's autism status (97.0% were of white race/ethnicity). Controls were randomly selected from among children of women who did not report autism in offspring (participants included 451 mothers of children with autism and 52 498 mothers of children without autism).
Main Outcome Measures: Autism spectrum disorder in offspring, assessed by maternal report and validated with the Autism Diagnostic Interview–Revised in a subsample.
Results: Exposure to abuse was associated with increased risk for autism in children in a monotonically increasing fashion. The highest level of abuse was associated with the greatest prevalence of autism (1.8% vs 0.7% among women not abused, P = .005) and with the greatest risk for autism adjusted for demographic factors (risk ratio, 3.7; 95% CI, 2.3-5.8). All adverse perinatal circumstances except low birth weight were more prevalent among women abused in childhood. Adjusted for perinatal factors, the association of maternal childhood abuse with autism in offspring was slightly attenuated (risk ratio for highest level of abuse, 3.0; 95% CI, 1.9-4.8).
Conclusions and Relevance: We identify an intergenerational association between maternal exposure to childhood abuse and risk for autism in the subsequent generation. Adverse perinatal circumstances accounted for only a small portion of this increased risk.

Autism Risk Across Generations: A Population-Based Study of Advancing Grandpaternal and Paternal Age

Emma M. Frans, Sven Sandin,  Abraham Reichenberg, Niklas Langstrom, Paul Lichtenstein, John J. McGrath, Christina M. Hultman.

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.

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