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

项目总结/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学特征的努力。 像精神分裂症和双相情感障碍这样的精神疾病的结构。然而，这种异质性也 为研究具有极端表型的个体提供了机会， 更为同质的病因。早发性精神病（EOP，在18岁之前发病）代表了这种 一个极端的表型，与成人发病相比，EOP中罕见的有害突变率显着更高 精神病因此，研究EOP队列提供了一个独特的机会，发现罕见的遗传位点 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度表型和测序， 人口统计学上匹配的年轻人。对于400名先证者，将招募父母和非精神病兄弟姐妹 以便于寻找与EOP相关的遗传和新生突变（n=1200个家庭成员）。 儿童和青少年及其家人将从一个单一的，大型公共儿科精神病招募 墨西哥城的医院迄今为止，大多数精神病遗传学研究集中在欧洲血统（EA）队列， 而排除其他祖先群体。然而，没有一个单一的群体足以完全阐明遗传 精神病等复杂特征的结构，以及EA的重点可能会加剧医疗保健的差距。拉丁裔 占世界人口的~8%（约占美国人口的18%），但出现在出版物中的不到1% 全基因组研究更复杂的是，拉丁美洲人的基因是异质的， 中美洲、南美洲和加勒比人口之间的差异，反映了大陆一级的 祖先群体混合物和当地土著美国人口的子结构。62%的 在美国的拉丁美洲人是墨西哥裔，来自墨西哥人口的调查结果与大多数人直接相关。 美国最大的种族/少数民族。在我们最初的一年项目中，我们招募了1000名 参与者来自同一家精神病医院，使用相同的程序，从而证明了 目前研究的可行性。把这1000个人和另外5000名参与者结合起来，我们现在 建议获得，我们的目标是：1）表征EOP先证者和兄弟姐妹的认知和 社会心理功能、不良生活事件的频率、社会决定因素和大麻使用; 2） 记录了以前与以下疾病相关的罕见功能缺失突变和CNV的患病率： EOP参与者相对于其未受影响的家庭成员的精神分裂症或自闭症谱系障碍， 人口统计学和人口控制;以及3）利用祖先分析来识别染色体区域， 多个不相关的EOP病例共有的纯合性序列，但未受影响的个体则没有。 大卫Glahn（BCH），Laura Almasy（CHOP），Humberto Nicolini（Instituto Nacional de Medicina Genómica）和 卡洛斯布斯塔曼特（斯坦福大学）领导这个项目。

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.