Parental Age and Schizophrenia Susceptibility

描述(由申请人提供)：出生时的父亲年龄是精神分裂症和相关神经发育障碍(如自闭症谱系障碍)的强烈风险因素。然而，人们很少知道父亲出生时的高龄如何具体导致后代患上这些疾病的风险增加。几项研究表明，随着年龄的增长，父亲精子中新生突变的增加并不能充分解释许多单基因疾病的风险增加。最近的一项发现表明，人类转录组中存在广泛的RNA和DNA序列差异，这些差异的个体差异丰富，这突显了另一种可能的机制，在疾病易感性的分子基础上发挥作用。在这项探索性研究中，我们假设父亲年龄的增加会导致后代中RNA-DNA差异的增加，这有助于精神分裂症的疾病易感性。在由精神分裂症患者和未受影响的兄弟姐妹组成的100对兄弟姐妹中，我们将使用全血样本比较RNA和DNA序列的差异。这些受试者在出生时有较年轻(25岁)和较大(40岁)的父亲，因此我们可以确定父亲的年龄以及疾病状况对RNA和DNA序列差异丰度的影响。

DESCRIPTION (provided by applicant): Paternal age at time of birth is a robust risk factor for schizophrenia and related neurodevelopmental disorders such as autism spectrum disorder. However, very little is known how advanced age of the father at time of birth may specifically result in increased risk to develop these diseases in the offspring. Several studies have shown that the increased de novo mutation rate in sperm of fathers with advancing age does insufficiently explain the increased risk observed in a number of monogenic diseases. A recent finding that there are widespread RNA and DNA sequence differences in the human transcriptome with individual variation in abundance of these differences has highlighted another possible mechanism playing a role in the molecular basis of disease susceptibility. In this explorative study we hypothesize that increased paternal age leads to increased abundance of RNA-DNA differences in the offspring, which contributes to disease susceptibility of schizophrenia. In hundred sibling pairs consisting of schizophrenia patient and unaffected sibling we will compare RNA and DNA sequence differences using whole blood samples. These subjects are selected for having younger (ages ¿25) and older (ages ¿40) fathers at time of birth, so that we can establish the effects of paternal age as well as disease status on the abundance of RNA and DNA sequence differences.