Genetic Architecture of Early-Onset Psychosis in Mexicans

墨西哥人早发性精神病的遗传结构

基本信息

批准号：
10264286
负责人：
Laura A. Almasy
金额：
$ 289.98万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10264286
关键词：
Admixture Adolescent Adult Affect Alleles Biological Bipolar Disorder Brain Central America Child Childhood Cities Cognitive Communities Complex Copy Number Polymorphism DNA Sequence Alteration Development Diagnosis Diagnostic Diagnostic Procedure Disabled Persons Etiology European Exclusion Family Family member Frequencies Genes Genetic study Genotype Haplotypes Heterogeneity Hispanics Hospitals Impaired cognition Impairment Indigenous American Individual Inherited Interview Latino Lead Link Methods Mexican Mexico Mutation Neurons Nuclear Family Outpatients Parents Participant Phenotype Population Population Control Prevalence Principal Investigator Proteins Psychiatric Hospitals Psychoses Psychotic Disorders Publishing Recurrence Risk Sampling Schizophrenia Siblings South America Testing Therapeutic Underserved Population Variant Virulent Visit Youth admixture mapping autism spectrum disorder case control clinical heterogeneity cognitive ability cognitive load cohort comorbidity de novo mutation density design disparity reduction early life adversity early onset ethnic minority population exome exome sequencing gene discovery genetic architecture genome-wide genome-wide analysis genomic locus health care disparity insight mortality neurocognitive test nonsynonymous mutation novel novel diagnostics novel therapeutic intervention proband psychogenetics psychosocial rare variant recruit response sample archive trait

项目摘要

PROJECT SUMMARY/ABSTRACT Psychotic disorders, like schizophrenia and bipolar disorder, are poorly understood illnesses associated with increased mortality and lifelong psychosocial impairment. Unfortunately, current treatments are only partially effective and many individuals with psychosis remain disabled despite our best efforts. Identifying genes that contribute to risk for psychotic disorders should lead to the development of novel diagnostic and therapeutic strategies. It is likely that the clinical heterogeneity of psychosis has limited gene discovery. However, this heterogeneity also presents an opportunity for studying individuals with extreme phenotypes, virulent forms of the illness with putatively more homogeneous etiologies. Early onset psychosis (EOP) represents such an extreme phenotype. Consequently, studying EOP cohorts provides a unique opportunity to discover rare genetic loci influencing illness risk. We will acquire the largest EOP sample to date and characterize these individuals in terms of diagnostic presentation, early life adversity (ELA), cognitive ability and burden of rare genetic mutations. Specifically, we will deep phenotype, genotype and exome sequencing 2000 EOP probands and 2000 non-psychotic, demographically matched youth. In addition, nuclear families (unaffected sibling and both parents) for 250 EOP probands (n=750 family members) will allow us to search for inherited and de novo mutations associated with the illness. Children and adolescents and their families will be recruited from a single, large public pediatric psychiatric hospital in Mexico City. To date, the vast majority of psychiatric genetic studies have focused on European-ancestry cohorts alone, which limits our ability to fully characterize the genetic architecture of these complex illnesses and potentially adds to health care disparities. To help reduce this disparity and facilitate discovery, we will conduct our study in a Latino community, the single largest ethnic minority in the US. To determine if rare mutations associated with psychosis liability are linked to haplotypes originating from founders in one of the ancestries, the 2000 demographically matched controls will be supplemented with 5250 archival samples with psychiatric phenotypes who will serve as “population” controls (total n=10000). We aim to: 1) characterize EOP probands and siblings in terms of cognitive and psychosocial functioning and frequency of ELAs to demonstrate that our underserved population is comparable to prior cohorts; 2) document the prevalence of 25 rare but recurrent CNVs previously associated with schizophrenia or autism spectrum disorder in EOP participants relative to their unaffected family members and demographic and population controls; and 3) examine the prevalence of gene-disruptive and putatively protein-damaging rare variants in affected participants relative to unaffected family members and controls. David Glahn and Chris Walsh (BCH), Laura Almasy (CHOP) and Humberto Nicolini (Instituto Nacional de Medicina Genómica) are co-principal investigators. Carlos Bustamante (Stanford) leads a subcontract to conduct admixture analyses. Our multinational team developed this application in response to PAR-20-026.

项目摘要/摘要精神病患者，如精神分裂症和躁郁症，对与之相关的疾病知之甚少增加死亡率和终生的社会心理障碍。不幸的是，当前的治疗只是部分治疗尽管我们尽了最大的努力，但许多精神病患者仍然残疾。识别那个基因导致精神病风险的贡献应导致新的诊断和治疗的发展策略。精神病的临床异质性可能有限，基因发现有限。但是，这个异质性还为研究具有极端表型的个体，有毒形式的人提供了机会该疾病具有更均匀的病因。早期发作精神病（EOP）代表了这样的极端表型。因此，学习EOP队列提供了一个独特的机会来发现稀有遗传基因座影响风险。迄今为止，我们将获得最大的EOP样本，并将其描述个人在诊断表现，早期逆境（ELA），认知能力和罕见的燃烧方面遗传突变。特别是，我们将深层表型，基因型和外显子组测序2000 EOP概率以及2000年非精神病性，人口统计学匹配的年轻人。此外，核心家庭（不受影响的兄弟姐妹和父母双方）对于250个EOP问题（n = 750个家庭成员）将使我们能够搜索继承和从头搜索与疾病相关的突变。儿童和青少年及其家人将从墨西哥城的单身，大型的小儿精神病医院。迄今为止，绝大多数精神病通用研究的重点是仅欧洲委员会，这限制了我们完全表征的能力这些复杂疾病的遗传结构，并有可能增加医疗保健分布。帮助减少这种差异和促进发现，我们将在拉丁裔社区进行研究，这是最大的族裔美国的少数派。确定与精神病责任相关的罕见突变是否与单倍型有关源自其中一个祖先的创始人，2000年人口统计学匹配的控件将是补充了5250个具有精神病表型的档案样本，它们将充当“人口”对照（总n = 10000）。我们的目标是：1）在认知和社会心理方面表征EOP问题和兄弟姐妹 ELA的功能和频率证明我们服务不足的人口与先验相当队列； 2）记录25种罕见但复发性的CNV的患病率先前与精神分裂症相关 EOP参与者的自闭症谱系障碍相对于未受影响的家庭成员和人群和人口控制； 3）检查基因降低和抑制蛋白质破坏的患病率相对于未受影响的家庭成员和对照组，受影响参与者的罕见变体。 David Glahn和Chris Walsh（BCH），Laura Almasy（Chop）和Humberto Nicolini（Instituto Nacional de Instituto Medicinagenómica）是联合主管研究人员。卡洛斯·布斯曼特（Carlos Bustamante）（斯坦福大学）领导分包合同进行混合分析。我们的跨国公司为响应Par-20-026制定了此应用程序。