Parental Age and Schizophrenia Susceptibility

父母年龄和精神分裂症易感性

• 批准号: 8511320
• 负责人: Roel A Ophoff
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-10 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511320
• 关键词: Accounting; Achondroplasia; Affect; Age; Apert syndrome; Autistic Disorder; Birth; Blood specimen; Child; Code; DNA; DNA Sequence; Data; Delayed Childbearing; Disease; Disease susceptibility; Elderly; Event; Fathers; Gene Expression Profile; Gene Mutation; Genetic Transcription; Genetic Variation; Human; Incidence; Individual; Link; Molecular; Molecular Biology; Monozygotic Twinning; Monozygotic twins; Morphologic artifacts; Mutation; Neurodevelopmental Disorder; Parental Ages; Paternal Age; Patients; Personality Traits; Play; Predisposition; Psychosocial Factor; RNA; RNA Editing; RNA Sequences; Reporting; Risk; Risk Factors; Role; Sample Size; Sampling; Schizophrenia; Siblings; Testing; Time; Variant; Whole Blood; age effect; autism spectrum disorder; base; exome; exome sequencing; high risk; insight; instrument; offspring; paralogous gene; proband; public health relevance; sperm cell

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.

描述（由申请人提供）：父亲出生时的年龄是精神分裂症和相关神经发育障碍（例如自闭症谱系障碍）的重要危险因素。然而，人们很少知道父亲出生时的高龄如何具体导致精神分裂症和自闭症谱系障碍。一些研究表明，随着年龄的增长，父亲精子的新生突变率增加，并不能充分解释许多单基因疾病中观察到的风险增加。人类转录组中 DNA 序列的差异以及丰度的个体差异凸显了在疾病易感性的分子基础中发挥作用的另一种可能机制。在这项探索性研究中，我们发现父亲年龄的增加会导致 RNA-DNA 丰度的增加。在由精神分裂症患者和未受影响的兄弟姐妹组成的数百对兄弟姐妹中，我们将使用全血样本比较 RNA 和 DNA 序列差异。因年龄较小（年龄 ¿ 25）和出生时年龄较大（40岁）的父亲，以便我们可以确定父亲年龄以及疾病状况对RNA和DNA序列差异丰度的影响。