Next Generation Rare Variant Discovery in Multiplex AD Families

多重 AD 家族中下一代罕见变异的发现

• 批准号: 9132156
• 负责人: David B. Goldstein
• 金额: $ 44.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132156
• 关键词: Adolescence; Affect; Alcohol dependence; Base Sequence; Bioinformatics; Biological; Brothers; Childhood; Clinical; Code; Complex; Conduct Disorder; DNA; DNA Library; Data; Development; Disease; Disease Outcome; Disinhibition; EP300 gene; Event; Event-Related Potentials; Exons; Family; Family member; Gene Frequency; Generations; Genes; Genetic; Genetic Recombination; Genetic Risk; Genetic Variation; Genome; Genomic DNA; Goals; Health; Heterogeneity; Human; Human Genetics; Individual; Interview; Laboratories; Location; Maps; Measures; Methods; Minor; Outcome; P300 Event-Related Potentials; Parents; Patients; Pattern; Personality; Personality Assessment; Persons; Pharmacotherapy; Phenotype; Play; Population; Predisposition; Proteins; Psychopathology; Recruitment Activity; Reporting; Risk; Role; Sampling; Series; Siblings; Signal Transduction; Single Nucleotide Polymorphism; Sister; Societies; Staging; Substance Use Disorder; Susceptibility Gene; Techniques; Technology; Testing; Time; Validation; Variant; Walkers; Woman; Work; base; brain morphology; cost; cost effective; density; early onset; endophenotype; exome; exome sequencing; genetic analysis; genetic linkage analysis; genetic pedigree; genetic risk factor; genetic variant; genome wide association study; genome-wide; genome-wide linkage; high risk; improved; meetings; member; men; neuronal growth; next generation; novel; offspring; phenotypic data; proband; rare variant; risk variant; screening; tool; trait; whole genome; young adult

 DESCRIPTION (provided by applicant): Despite the recognition that genetic factors play an important role in susceptibility to alcohol dependence (AD), few genes have been identified to date that have been replicated across studies. Because alcohol dependence is a common disorder affecting one in five men and one in twelve women, the prevailing thought has been that common genetic variants (those with minor allele frequency over 3% in the population) would be the appropriate place to look for susceptibility variants. The common disease/common variant hypothesis has provided the impetus for a large number of genome-wide association studies (GWAS) where a large number of common variants have been assessed. While some studies have reported findings meeting genome-wide significance, often the findings for AD cannot be replicated in other studies. Also, across a wide variety of diseases, it is now recognized that only 2-4% of the variance in disease outcome is explained by these common variants. Recent evidence suggests that variants that are rarer may be more penetrant and potentially explain a greater proportion of disease outcome. Members of families in which multiple cases of AD are seen are most likely to carry a burden of rare and highly penetrant risk variants. Using existing DNA collected from members of high density AD pedigrees, we will use next generation exome sequencing and novel bioinformatics tools to identify rare variation in these high risk individuals and examine the distribution of variants in the families in collaboratin with the Center for Human Genetic Variation at Duke. Aim 1 provides a discovery stage and is facilitated by the use of a subset of pedigrees in which DNA is available for parents and affected offspring. Aim 2 provides confirmation of the discovered variation using a larger set of pedigrees in which the existence of the variants and their distribution within the full pedigree will be determined. By focusing on individuals with a strong genetic burden with multigenerational involvement and including the entire exome, we expect to find rare highly penetrant variants that would be undetectable with other approaches. A search for early developmental indicators of AD susceptibility has revealed both clinical (e.g., presence of childhood conduct disorder) and biological endophenotypes (e.g., reduced amplitude of the P300 component of the event-related potential). In Aim 3,we will examine our newly discovered rare variants in a third generation sample of individuals followed from childhood through young adulthood and for whom developmental trajectories of P300 amplitude are available. This sample includes both high-risk offspring from multiplex for AD families and low-risk controls providing an opportunity to find variants associated with P300 trajectories, an endophenotype that is highly associated with AD.

 描述（由申请人提供）：尽管人们认识到遗传因素在酒精依赖（AD）易感性中发挥着重要作用，但迄今为止，几乎没有发现可在研究中重复的基因，因为酒精依赖是影响人们的一种常见疾病。五名男性和十二分之一的女性，普遍的想法是常见的遗传变异（人群中次要等位基因频率超过 3% 的变异）将是寻找易感性变异的适当位置常见疾病/常见变异假说。为大量全基因组关联研究 (GWAS) 提供了动力，其中评估了大量常见变异，虽然一些研究报告了符合全基因组意义的发现，但 AD 的发现通常无法在其他研究中复制。此外，在多种疾病中，现在人们认识到，只有 2-4% 的疾病结果差异是由这些常见变异引起的。家庭成员的疾病结果比例更大。多例 AD 病例最有可能携带罕见且高渗透性风险变异的负担，利用从高密度 AD 谱系成员收集的现有 DNA，我们将使用下一代外显子组测序和新型生物信息学工具来识别罕见变异。目标 1 与杜克大学人类遗传变异中心合作，对这些高风险个体进行研究，并检查家族中变异的分布，这提供了一个发现阶段，并通过使用包含 DNA 的谱系子集来促进。目标 2 使用更大的谱系来确认发现的变异，其中变异的存在及其在完整谱系中的分布将通过关注具有强烈遗传负担的个体来确定。多代参与并包括整个外显子组，我们期望找到其他方法无法检测到的罕见的高渗透性变异，对 AD 易感性的早期发育指标的搜索已揭示了临床（例如，儿童行为障碍的存在）。在目标 3 中，我们将在第三代个体样本中新发现的罕见变异（例如，事件相关电位的 P300 成分的幅度降低），这些样本从童年到成年早期进行跟踪，并检查其发育轨迹。该样本包括 AD 家族多重的高风险后代和低风险对照，为寻找与 P300 轨迹相关的变异提供了机会，P300 轨迹是一种与 P300 高度相关的内表型。广告。