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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.

项目概要/摘要精神障碍，如精神分裂症和双相情感障碍，是人们对与精神障碍相关的疾病知之甚少的疾病。死亡率增加和终身心理社会损害。不幸的是，目前的治疗仅部分有效尽管我们尽了最大努力，但许多精神病患者仍然残疾。识别基因增加精神障碍的风险应导致新的诊断和治疗方法的开发策略。精神病的临床异质性可能限制了基因的发现。然而，这异质性还为研究具有极端表型、有毒形式的个体提供了机会推测病因更为同质的疾病。早发性精神病（EOP）代表了这样一种极端表型。因此，研究 EOP 队列提供了一个独特的机会来发现罕见的影响疾病风险的遗传位点。我们将获取迄今为止最大的 EOP 样本并表征这些样本个人的诊断表现、早期生活逆境（ELA）、认知能力和罕见疾病负担基因突变。具体来说，我们将对2000名EOP先证者进行深度表型、基因型和外显子组测序以及 2000 名非精神病、人口统计相匹配的青少年。此外，核心家庭（未受影响的兄弟姐妹和 250 名 EOP 先证者（n = 750 名家庭成员）的父母双方）将允许我们寻找遗传性和新生与疾病相关的突变。儿童和青少年及其家人将从墨西哥城的一家大型公立儿科精神病医院。迄今为止，绝大多数精神病遗传研究仅集中于欧洲血统群体，这限制了我们充分描述欧洲血统群体特征的能力这些复杂疾病的遗传结构可能会增加医疗保健的差距。帮助减少为了消除这种差异并促进发现，我们将在拉丁裔社区进行研究，该社区是最大的单一种族在美国是少数。确定与精神病倾向相关的罕见突变是否与单倍型相关源自某一血统的创始人，2000 个人口统计匹配的对照将是补充了 5250 个具有精神病表型的档案样本，这些样本将作为“群体”对照（总数 n=10000）。我们的目标是：1）从认知和社会心理方面描述 EOP 先证者和兄弟姐妹的特征 ELA 的功能和频率，以证明我们服务不足的人口与以前的人口相当队列； 2) 记录了先前与精神分裂症相关的 25 种罕见但复发性 CNV 的患病率 EOP 参与者相对于未受影响的家庭成员和人口统计的自闭症谱系障碍或自闭症谱系障碍和人口控制； 3) 检查基因破坏性和推定蛋白质破坏性的发生率与未受影响的家庭成员和对照相比，受影响的参与者存在罕见变异。 David Glahn 和 Chris Walsh (BCH)、Laura Almasy (CHOP) 和 Humberto Nicolini (Instituto Nacional de Medicina Genómica）是联合首席研究员。卡洛斯·布斯塔曼特（斯坦福大学）领导了一份分包合同进行外加剂分析。我们的跨国团队根据 PAR-20-026 开发了此应用程序。