Genetic Architecture of Early-Onset Psychosis in Mexicans

墨西哥人早发性精神病的遗传结构

• 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
• 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

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.

项目总结/摘要 精神障碍，如精神分裂症和双相情感障碍，是与以下疾病相关的知之甚少的疾病： 增加死亡率和终身心理社会损害。不幸的是，目前的治疗方法仅部分 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， 有助于精神障碍的风险，应导致新的诊断和治疗的发展， 战略布局精神病的临床异质性可能限制了基因的发现。但这 异质性也为研究具有极端表型的个体提供了机会， 脓毒症的病因更为相似。早发性精神病（EOP）代表了这样一种精神病。 极端表型因此，研究EOP队列提供了一个独特的机会， 影响患病风险的基因位点。我们将获得迄今为止最大的EOP样本，并对这些样本进行表征。 个体在诊断表现，早期生活逆境（ELA），认知能力和罕见的负担方面 基因突变具体来说，我们将对2000例EOP先证者进行表型、基因型和外显子组深度测序 和2000名非精神病的人口统计学匹配的年轻人。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）将允许我们搜索遗传和新生 与疾病相关的突变。儿童和青少年及其家庭将从一个 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病 研究只集中在欧洲血统的人群，这限制了我们充分描述他们的能力。 这些复杂疾病的遗传结构，并可能增加医疗保健的差距。以帮助减少 这种差异，并促进发现，我们将进行我们的研究在拉丁美洲社区，单一最大的种族 少数民族在美国。为了确定与精神病易感性相关的罕见突变是否与单倍型有关， 来自其中一个祖先的创始人，2000个人口统计学匹配的对照将被 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n=10000）。我们的目标是：1）在认知和心理社会方面描述EOP先证者和同胞 ELA的运作和频率，以证明我们的服务不足的人口与以前相当 队列; 2）记录25例罕见但复发的CNV的患病率，这些CNV先前与精神分裂症相关 EOP参与者相对于其未受影响的家庭成员和人口统计学特征 和人口控制;和3）检查基因破坏和脓毒蛋白损伤的患病率 受影响的参与者相对于未受影响的家庭成员和对照组的罕见变异。 大卫Glahn和克里斯沃尔什（BCH），劳拉Almasy（CHOP）和Humberto Nicolini（国家研究所 Medicina Genómica）是共同主要研究者。卡洛斯布斯塔曼特（斯坦福大学）带领一个 进行混合物分析。我们的跨国团队根据PAR-20-026开发了此应用程序。