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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.

项目概要/摘要尽管最近取得了进展，但临床异质性可能阻碍了明确描述遗传因素的努力。精神分裂症和双相情感障碍等精神障碍的结构。然而，这种异质性也为研究具有极端表型、致命疾病形式的个体提供了机会推测病因更为同质。早发性精神病（EOP，18 岁之前发病）代表此类极端表型，EOP 中罕见有害突变的发生率比成人发病率高得多精神病。因此，研究 EOP 队列提供了发现罕见遗传位点的独特机会影响疾病风险。我们将对 1900 名 EOP 先证者和 1900 名非精神病患者进行深入表型分析和测序，人口统计上匹配的年轻人。对于 400 名先证者，将招募父母双方和一名非精神病兄弟姐妹促进寻找与 EOP 相关的遗传突变和新生突变（n=1200 名家庭成员）。儿童和青少年及其家人将从一个大型公立儿科精神病院招募墨西哥城的一家医院。迄今为止，大多数精神病学遗传学研究都集中在欧洲血统（EA）群体，同时排除其他血统群体。然而，没有一个种群足以充分阐明遗传因素精神病等复杂特征的架构以及 EA 焦点可能会加剧医疗保健差距。拉丁裔约占世界人口的 8%（约占美国人口的 18%），但在已发表的数据中所占比例不到 1% 全基因组研究。让事情变得更复杂的是，拉丁美洲人在遗传上具有异质性，中美洲、南美洲和加勒比地区人口之间的差异，反映了大陆层面祖先群体的混合和当地美国原住民人口的基础。作为 62% 的美国的拉丁裔是墨西哥裔，墨西哥人口的调查结果与大多数人直接相关全国最大的种族/族裔中的个人。在我们最初的 1 年项目中，我们招募了 1000 名来自同一家精神病医院的参与者并使用相同的程序，从而证明了当前研究的可行性。将这 1000 名个人与另外 5000 名参与者结合起来，我们现在提议获得，我们的目标是：1）在认知和认知方面描述 EOP 先证者和兄弟姐妹的特征。心理社会功能、不良生活事件的频率、社会决定因素和大麻使用； 2）记录了罕见的功能缺失突变和 CNV 的流行情况，这些突变和 CNV 以前与 EOP 参与者相对于未受影响的家庭成员患有精神分裂症或自闭症谱系障碍，以及人口和人口控制； 3) 利用祖先分析来识别染色体区域和多个不相关的 EOP 病例共有纯合性运行，但未受影响的个体则不然。 David Glahn (BCH)、Laura Almasy (CHOP)、Humberto Nicolini (Instituto Nacional de Medicina Genómica) 和 Carlos Bustamante（斯坦福大学）领导该项目。