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

项目摘要/摘要 尽管最近取得了进展，但临床上的异质性可能阻碍了明确描述基因的努力。 精神分裂症和双相情感障碍等精神障碍的架构。然而，这种异质性也 为研究具有极端表型、致病形式的个体提供了一个机会 推定为更同质的病因。早发性精神病(EOP，发病早于18岁)就是这样的表现 一种极端的表型，在EOP中罕见的有害突变的比率显著高于成人发病 精神错乱。因此，研究EOP队列提供了发现罕见遗传基因座的独特机会 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的表型和测序， 在人口统计上与之相匹配的年轻人。对于400名先证者，父母和一个非精神病兄弟姐妹都将被招募 为了便于寻找与EOP相关的遗传和从头突变(n=1200个家系成员)。 儿童和青少年及其家人将从一家大型公立儿科精神科医院招募 墨西哥城的一家医院。到目前为止，大多数精神遗传学研究都集中在欧洲血统(EA)队列， 同时排除了其他祖先群体。然而，没有一个单一的种群足以完全阐明 精神病等复杂特征的架构，以及对电针的关注可能会加剧医疗保健方面的差距。拉丁裔 约占世界人口的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。让事情变得复杂的是，拉丁裔在基因上是不同的，有大量 中南美洲和加勒比人口之间的差异，反映了大陆一级的差异 祖先群体的混杂和当地土著美国人的亚结构。作为62%的 在美国的拉丁裔是墨西哥血统，来自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/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人 来自同一家精神病院的参与者，使用相同的程序，从而展示了 当前研究的可行性。将这1000人与我们现在增加的5000名参与者结合在一起 建议收购，我们的目标是：1)从认知和认知的角度描述EOP先证者和兄弟姐妹 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) 记录以前与以下疾病相关的罕见功能突变和CNV丢失的流行率 EOP参与者的精神分裂症或自闭症谱系障碍与其未受影响的家庭成员和 人口和人口控制；以及3)利用祖先分析来确定染色体区域和 多个无关的EOP病例有共同的纯合性，但不是未受影响的个体。 David Glahn(BCH)，Laura Almasy(CHOP)，Humberto Nicolini(Medicina Genómica国家研究所)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.