Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations
Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations
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DOI：
10.1038/ng.3577
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发表时间：
2016-07-01
期刊：
影响因子：
30.8
通讯作者：
Goddard, Michael E.
中科院分区：
文献类型：
--
作者：
Gratten, Jacob;Wray, Naomi R.;Goddard, Michael E.
年长父亲的后代患精神疾病的风险更高，如精神分裂症和自闭症。与父源年龄相关的新生突变被广泛认为是潜在的因果机制，尽管这些突变在逻辑上一定有一定的贡献，但也有其他解释（例如，精神疾病的易感性增加可能会推迟父亲身份）。我们使用基于关键参数（例如，突变率，患病率和遗传性）的经验观察的群体遗传模型来评估父亲年龄与精神疾病风险之间的遗传关系。这些模型表明，与年龄相关的突变不太可能解释高龄父亲的孩子患精神疾病风险增加的大部分原因。相反，一个模型纳入了第一个孩子的年龄和精神疾病的易感性之间的弱相关性匹配流行病学观察。我们的研究结果表明，年长父亲及其后代共享的遗传风险因素是对年长父亲子女风险的新生突变的可靠替代解释。
The offspring of older fathers have higher risk of psychiatric disorders such as schizophrenia and autism. Paternal-agerelated de novo mutations are widely assumed to be the underlying causal mechanism, and, although such mutations must logically make some contribution, there are alternative explanations (for example, elevated liability to psychiatric illness may delay fatherhood). We used population genetic models based on empirical observations of key parameters (for example, mutation rate, prevalence, and heritability) to assess the genetic relationship between paternal age and risk of psychiatric illness. These models suggest that age-related mutations are unlikely to explain much of the increased risk of psychiatric disorders in children of older fathers. Conversely, a model incorporating a weak correlation between age at first child and liability to psychiatric illness matched epidemiological observations. Our results suggest that genetic risk factors shared by older fathers and their offspring are a credible alternative explanation to de novo mutations for risk to children of older fathers.