BACKGROUND Autism spectrum disorder (ASD) is highly familial, with a positively skewed male-to-female ratio that is purported to arise from the so-called female protective effect. A serious implication of a female protective effect is that familial ASD liability would be expected to aggregate asymptomatically in sisters of affected probands, who would incur elevated rates of ASD among their offspring. Currently, there exist no data on second-generation recurrence rates among families affected by ASD. METHODS We analyzed data from the Swedish National Patient Register and the Multi-Generation Register for a cohort of children born between 2003 and 2012. ASD was ascertained in both the child and parental generations. RESULTS Among 847,732 children, 13,103 (1.55%) children in the cohort were diagnosed with ASD. Among their maternal/paternal aunts and uncles, 1744 (0.24%) and 1374 (0.18%) were diagnosed with ASD, respectively. Offspring of mothers with a sibling(s) diagnosed with ASD had higher rates of ASD than the general population (relative risk, 3.05; 95% confidence interval, 2.52-3.64), but not more than would be predicted for second-degree relatives within a generation, and only slightly more than was observed for fathers with siblings with ASD (relative risk, 2.08; 95% confidence interval, 1.53-2.67). Models adjusting for temporal trends and for psychiatric history in the parental generation did not alter the results. CONCLUSIONS These findings establish a robust general estimate of ASD transmission risk for siblings of individuals affected by ASD, the first ever reported. Our findings do not suggest female protective factors as the principal mechanism underlying the male sex bias in ASD.

中文翻译：

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通过母系和父系血统遗传的自闭症风险

背景自闭症谱系障碍（ASD）是高度家族性的，男性与女性的比例呈正偏态，据称是由所谓的女性保护作用引起的。女性保护作用的一个严重含义是，家族性 ASD 责任预计会在受影响的先证者的姐妹中无症状地聚集，这些先证者的姐妹会导致其后代的 ASD 发病率升高。目前，没有关于受 ASD 影响的家庭的第二代复发率的数据。方法 我们分析了瑞典国家患者登记和多代登记中 2003 年至 2012 年出生的一组儿童的数据。在儿童和父母代中都确定了 ASD。结果 在 847,732 名儿童中，队列中有 13,103 (1.55%) 名儿童被诊断出患有 ASD。在他们的母亲/父亲阿姨和叔叔中，分别有 1744 名（0.24%）和 1374 名（0.18%）被诊断出患有 ASD。有兄弟姐妹被诊断为 ASD 的母亲的后代 ASD 发生率高于一般人群（相对风险，3.05；95% 置信区间，2.52-3.64），但不超过对二级亲属的预测一代，仅略高于有 ASD 兄弟姐妹的父亲的观察结果（相对风险，2.08；95% 置信区间，1.53-2.67）。调整父母一代的时间趋势和精神病史的模型并没有改变结果。结论 这些发现建立了对受 ASD 影响的个体的兄弟姐妹的 ASD 传播风险的可靠一般估计，这是有史以来首次报道。