Genetic Architecture of Early-Onset Psychosis in Mexicans (EPIMex)

墨西哥人早发性精神病的遗传结构 (EPIMex)

基本信息

批准号：
10716496
负责人：
Laura A. Almasy
金额：
$ 244.67万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-14 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716496
关键词：
Admixture Adolescent Adult African Alleles Bipolar Disorder Brain Caribbean region Central American Characteristics Child Childhood Cities Clinical Cognitive Complex Control Groups DNA Sequence Alteration Diagnosis Diagnostic Diagnostic Procedure Environmental Risk Factor Etiology European European ancestry Event Exclusion Family Family Demographies Family member Frequencies Gene Frequency Genes Genetic study Genome Haplotypes Heterogeneity High Prevalence Hospitals Impaired cognition Impairment Income Indigenous American Individual Inherited Interview Latino Population Lead Life Mexican Mexico Mutation National Institute of Mental Health Neighborhoods Neurodevelopmental Disorder Neurons Outcome Outpatients Parents Participant Phenotype Population Population Control Prevalence Privatization Procedures Proteins Psychiatric Hospitals Psychoses Psychosocial Assessment and Care Psychotic Disorders Publishing Recurrence Risk Running Sampling Schizophrenia Severities Siblings Socioeconomic Status South American Testing Variant Virulent Visit Youth admixture mapping ancestry analysis autism spectrum disorder clinical heterogeneity cohort comparison control de novo mutation dosage early life adversity early onset ethnic minority exome exome sequencing gene environment interaction genetic architecture genetic association genome-wide genome-wide analysis genomic locus health care disparity indexing loss of function loss of function mutation marijuana use neurocognitive test proband psychogenetics psychosis risk psychosocial racial minority recruit risk variant social determinants trait whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Despite recent progress, clinical heterogeneity has likely hindered efforts to clearly delineate the genetic architecture of psychotic disorders like schizophrenia and bipolar disorder. 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, onset prior to 18 years) represents such an extreme phenotype, with dramatically higher rates of rare deleterious mutations in EOP than adult-onset psychosis. Consequently, studying EOP cohorts provides a unique opportunity to discover rare genetic loci influencing illness risk. We will deep phenotype and sequence 1900 EOP probands and 1900 non-psychotic, demographically matched youth. For 400 probands, both parents and a non-psychotic sibling will be recruited to facilitate the search for inherited and de novo mutations associated with EOP (n=1200 family members). Children and adolescents and their families will be recruited from a single, large public pediatric psychiatric hospital in Mexico City. To date, most psychiatric genetic studies focus on European-ancestry (EA) cohorts, while excluding of other ancestry groups. Yet, no single population is sufficient to fully illuminate the genetic architecture of complex traits like psychosis, and the EA focus could exacerbate health care disparities. Latinos make up ~8% of the world population (~18% of the US population) but appear in less than 1% of published genome-wide studies. Complicating matters, Latinos are genetically heterogeneous, with substantial differences between Central and South American and Caribbean populations, reflecting continental-level ancestral group admixture and the substructure of local Indigenous American populations. As 62% of the Latinos in the US are of Mexican origin findings from the Mexican population are directly relevant for most individuals in the nation’s largest racial/ethnic minority. During our initial 1-year project, we recruited 1000 participants from the same psychiatric hospital and using identical procedures, thus demonstrating the feasibility of the current study. Combining these 1000 individuals with the additional 5000 participants we now propose to acquire, we aim to: 1) characterize EOP probands and siblings in terms of cognitive and psychosocial functioning, frequency of adverse life events, social determinants, and cannabis use; 2) document the prevalence of rare loss of function mutations and 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) utilize ancestry analysis to identify chromosomal regions and runs of homozygosity shared in common by multiple unrelated EOP cases but not by unaffected individuals. David Glahn (BCH), Laura Almasy (CHOP), Humberto Nicolini (Instituto Nacional de Medicina Genómica) and Carlos Bustamante (Stanford) lead this project.

项目摘要/摘要尽管最近取得了进展，但临床异质性可能阻碍了清楚地描述遗传的努力精神分裂症和躁郁症等精神病的结构。但是，这种异质性也为研究具有极端表型的人，有毒的疾病形式提供了机会推理的更均匀的病因。早期发作精神病（EOP，18年以前发病）代表极端表型，EOP中罕见有害突变的速率明显高于成人发作精神病。因此，研究EOP队列提供了一个独特的机会来发现罕见的遗传基因座影响疾病风险。我们将深入表型和序列1900 EOP概率和1900个非精神病学，人口匹配的年轻人。对于400个问题，将招募父母和非精神病兄弟姐妹为了促进与EOP相关的遗传和从头突变（n = 1200个家庭成员）。儿童和青少年及其家人将从一个大型的公共儿科精神病学中招募墨西哥城的医院。迄今同时排除其他祖先。然而，没有一个人口足以完全照亮遗传精神病等复杂特征的建筑和EA重点会加剧医疗保健分布。拉丁美洲人占世界人口的约8％（占美国人口的18％），但出现不到1％全基因组研究。使事情复杂化，拉丁美洲人是遗传异质性的，很大中美洲和加勒比海人口之间的差异，反映了大陆级别祖先组混合和当地土著美国人口的子结构。为62％美国的拉丁美洲人是墨西哥人口的墨西哥起源发现与大多数人的直接相关该国最大的种族/族裔少数民族中的个人。在我们最初的一年项目中，我们招募了1000 来自同一精神病医院并使用相同程序的参与者，从而证明了当前研究的可行性。将这1000个人与额外的5000名参与者相结合我们的提议是：1）从认知和社会心理功能，不良生活事件的频率，社会决定者和大麻使用； 2）记录罕见的功能突变丧失和与先前相关的CNV的患病率 EOP参与者的精神分裂症或自闭症谱系障碍相对于其未受影响的家庭成员和人口统计和人口控制； 3）利用祖先分析来识别染色体区域和多个无关的EOP案例共有的纯合性共享，但没有受到影响的个体。 David Glahn（BCH），Laura Almasy（Chop），Humberto Nicolini（Instituto nacional de Medicinagenómica）和卡洛斯·布斯曼特（Carlos Bustamante）（斯坦福大学）领导该项目。