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（如自闭症谱系障碍）的一个强有力的风险因素。然而，很少有人知道父亲在出生时的高龄可能会特别导致后代患这些疾病的风险增加。几项研究表明，随着年龄的增长，父亲精子中的从头突变率增加，并不足以解释在一些单基因疾病中观察到的风险增加。最近的一项研究发现，在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，这突出了另一种可能的机制，在疾病易感性的分子基础中发挥作用。在这项探索性研究中，我们假设父亲年龄的增加导致后代中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同胞组成的100对同胞中，我们将使用全血样本比较RNA和DNA序列差异。这些受试者在出生时有年轻（25岁）和年长（40岁）的父亲，因此我们可以确定父亲年龄以及疾病状态对RNA和DNA序列差异丰度的影响。