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）：尽管认识到遗传因素在酒精依赖（AD）的易感性中起重要作用，但迄今为止，很少有基因被确定为在研究中重复。由于酒精依赖是一种常见疾病，影响五分之一的男性和十二分之一的女性，因此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合适地点。常见疾病/常见变异假说为大量的全基因组关联研究（GWAS）提供了动力，其中大量的常见变异已被评估。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重复。此外，在各种各样的疾病中，现在认识到只有2 - 4%的疾病结局差异是由这些常见变异解释的。最近的证据表明，罕见的变异可能更具渗透性，并可能解释更大比例的疾病结果。多个AD病例的家庭成员最有可能携带罕见和高度渗透性风险变异的负担。利用从高密度AD家系成员中收集的现有DNA，我们将使用下一代外显子组测序和新的生物信息学工具来识别这些高危个体中的罕见变异，并与杜克人类遗传变异中心合作检查家族中变异的分布。目标1提供了一个发现阶段，并通过使用一个谱系子集来促进，其中父母和受影响的后代的DNA是可用的。目的2使用更大的谱系组来确认发现的变异，其中将确定变异的存在及其在全谱系中的分布。通过关注具有多代参与的强烈遗传负担的个体并包括整个外显子组，我们希望找到其他方法无法检测到的罕见的高度渗透性变体。对AD易感性的早期发育指标的研究已经揭示了临床（例如，存在儿童期品行障碍）和生物学内表型（例如，事件相关电位的P300分量的幅度降低）。在目标3中，我们将在第三代样本中研究我们新发现的罕见变异，这些样本是从儿童期到青年期的个体，并且可以获得P300振幅的发展轨迹。该样本包括来自AD家族的多重高风险后代和低风险对照，提供了发现与P300轨迹相关的变体的机会，P300轨迹是与AD高度相关的内表型。