Autism Genetics Phase II: Increasing Representation of Human Diversity

自闭症遗传学第二阶段：增加人类多样性的代表性

• 批准号: 10533955
• 负责人: DANIEL H GESCHWIND
• 金额: $ 243.37万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-25 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533955
• 关键词: Address; Adult; African American; African American population; African ancestry; Age; Behavior; Biological; Brain; Calendar; Child; Chromatin Structure; Chromosome abnormality; Clinical; Code; Cognition; Collaborations; Color; Communities; Consensus; Coupled; Data; Development; Developmental Gene; Diagnosis; Dideoxy Chain Termination DNA Sequencing; Disparity; Disparity in diagnosis; Early Diagnosis; Etiology; European; Event; Family; Family member; Frequencies; Future; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Research; Genetic Risk; Genetic Variation; Genetic study; Genotype; Goals; Health Services Accessibility; Heritability; Human; Internet; Interview; Investigation; Knowledge; Maps; Methods; Mutation; Neurocognitive; Neurodevelopmental Disorder; Outcome; Parents; Pathogenicity; Pathway Analysis; Pathway interactions; Patient Self-Report; Phase; Phenotype; Play; Population; Population Control; Population Heterogeneity; Predisposition; Quality of Care; Quantitative Trait Loci; RNA Splicing; Race; Recording of previous events; Recurrence; Research; Research Personnel; Resolution; Resources; Risk Factors; Role; Sample Size; Sampling; School-Age Population; Services; Severities; Siblings; Single Nucleotide Polymorphism; Site; Susceptibility Gene; Symptoms; Testing; Time; Toddler; Untranslated RNA; Update; Validation; Variant; Visual; Work; admixture mapping; autism spectrum disorder; burden of illness; clinical care; cohort; cost; data exchange; de novo mutation; disorder risk; early detection biomarkers; exome sequencing; gene discovery; gene network; genetic analysis; genetic architecture; genetic risk factor; genetic testing; genetic variant; genome sequencing; genome-wide; genomic data; genomic locus; health disparity; improved; improved outcome; insertion/deletion mutation; member; novel; polygenic risk score; population stratification; proband; rare variant; recruit; remediation; repository; risk variant; social; standard measure; transcriptome sequencing; transmission process; variant detection; visual tracking; whole genome

Abstract Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder whose genetic contributions are increasingly recognized. However, the vast majority of genetic research and discovery has occurred in populations of European (EU) origin, significantly underrepresenting communities of color and those of self- described African American (AA) ancestry. This disparity in genetics research, coupled with disparities in diagnosis and treatment, motivated the investigators in this Network to take a major new direction in their research, embarking on what has been a unique and highly successful recruitment of AA families with ASD (AA-ASD) into gene discovery research at multiple sites, conducted phenotyping—including information of critical relevance to the elucidation of race-based health disparities—while commencing genetic analysis to identify ASD susceptibility genes. Via this collaborative effort, we aim to fill significant gaps in ASD research by continuing to recruit and perform genetic research in this important population that has not previously been well represented in ASD genetics research. Our Network involves seven research sites and a DCC, collaborating in a systematic investigation of ASD genetics in order to identify rare mutations, chromosomal abnormalities, and common variation contributing to ASD susceptibility in the AA population, while leveraging this unique opportunity to understand and potentially remediate health disparities. Specifically, we will enrich existing resources by recruiting at least 720 AA probands and additional family members to ascertain a cohort of at least 2000 probands in total. Our recruitment plan includes an embedded health disparities project that continues to evaluate access and quality of care for AAs with ASD while increasing participation of AA individuals in genetic research. We will conduct whole-genome sequencing (WGS), which permits comprehensive investigation of genome-wide structural variation (SV) and coding and non-coding sequence variation (SNV) in ASD. We will employ novel methods to define the ancestral origin of specific chromosomal segments and ascertain the background on which susceptibility alleles occur and relate these features to quantitative phenotypes. In parallel, gene expression profiling and network analysis will be used to prioritize variants. Genetic risk factors identified in the mostly EU samples will be tested for association in the AA sample to determine whether these cohorts share the same genetic risk factors, using a sample size providing power to replicate previous associations and to identify rare, recurrent CNV and SNV. We will use local ancestry to boost power of polygenic risk scores derived from EU cohorts. The observation of new forms or different population frequencies of ASD-related variation in this sample as well as the sharing of most CNV and SNV with other cohorts are both outcomes that will have great significance for future studies and for clinical care. As has been our practice, our Network will make all phenotypic and genotype data accessible via the internet on a rolling basis, further enhancing the value of this resource to the community.

抽象的 自闭症谱系障碍 (ASD) 是一种常见的神经发育障碍，其遗传因素是 越来越被认可。然而，绝大多数基因研究和发现都发生在 欧洲 (EU) 血统的人口，有色人种和自卑群体的代表性明显不足 描述了非裔美国人 (AA) 血统。遗传学研究中的这种差异，加上 诊断和治疗，激励该网络中的研究人员在他们的研究中采取一个重要的新方向 研究，开始对患有 ASD 的 AA 家庭进行独特且非常成功的招募 （AA-ASD）在多个地点进行基因发现研究，进行表型分析——包括 与阐明基于种族的健康差异至关重要——同时开始基因分析 识别 ASD 易感基因。通过这项合作，我们的目标是通过以下方式填补 ASD 研究的重大空白： 继续在这个以前并不顺利的重要人群中招募和进行基因研究 代表自闭症谱系障碍遗传学研究。我们的网络包括七个研究中心和一个 DCC，在以下方面进行合作： 对 ASD 遗传学进行系统研究，以识别罕见突变、染色体异常和 共同变异导致 AA 人群中 ASD 易感性，同时利用这种独特的 了解并可能纠正健康差异的机会。具体来说，我们将丰富现有的 通过招募至少 720 名 AA 先证者和其他家庭成员来确定一组至少 总共2000名先证者。我们的招聘计划包括一个嵌入式健康差异项目，该项目将继续 评估患有 ASD 的 AA 的护理机会和质量，同时增加 AA 个体对遗传的参与 研究。我们将进行全基因组测序（WGS），从而可以全面调查 ASD 中的全基因组结构变异 (SV) 以及编码和非编码序列变异 (SNV)。我们将 采用新方法来定义特定染色体片段的祖先起源并确定 易感性等位基因发生的背景并将这些特征与定量表型联系起来。并联， 基因表达谱和网络分析将用于确定变异的优先顺序。确定的遗传风险因素 大多数欧盟样本将在 AA 样本中进行关联测试，以确定这些群体是否 共享相同的遗传风险因素，使用样本量提供复制先前关联的能力，并且 识别罕见、复发性 CNV 和 SNV。我们将利用当地血统来增强多基因风险评分的力量 来自欧盟队列。自闭症谱系障碍（ASD）相关新形式或不同人群频率的观察 该样本的变异以及与其他队列共享大多数 CNV 和 SNV 都是结果 对未来的研究和临床护理具有重要意义。按照我们的惯例，我们的网络将 使所有表型和基因型数据可通过互联网滚动访问，进一步提高价值 将该资源提供给社区。

项目成果

SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs).

• DOI: 10.1186/2040-2392-4-36
• 发表时间: 2013-10-03
• 期刊: Molecular autism
• 影响因子: 6.2
• 作者: Abrahams BS;Arking DE;Campbell DB;Mefford HC;Morrow EM;Weiss LA;Menashe I;Wadkins T;Banerjee-Basu S;Packer A
• 通讯作者: Packer A

Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder.

• DOI: 10.1186/2040-2392-5-13
• 发表时间: 2014-02-17
• 期刊: Molecular autism
• 影响因子: 6.2
• 作者: Werling DM;Lowe JK;Luo R;Cantor RM;Geschwind DH
• 通讯作者: Geschwind DH

A framework for the investigation of rare genetic disorders in neuropsychiatry.

• DOI: 10.1038/s41591-019-0581-5
• 发表时间: 2019-10
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Sanders SJ;Sahin M;Hostyk J;Thurm A;Jacquemont S;Avillach P;Douard E;Martin CL;Modi ME;Moreno-De-Luca A;Raznahan A;Anticevic A;Dolmetsch R;Feng G;Geschwind DH;Glahn DC;Goldstein DB;Ledbetter DH;Mulle JG;Pasca SP;Samaco R;Sebat J;Pariser A;Lehner T;Gur RE;Bearden CE
• 通讯作者: Bearden CE

High-Risk, High-Reward Genetics in ASD.

• DOI: 10.1016/j.neuron.2020.01.007
• 发表时间: 2020-02-05
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Castellani CA;Arking DE
• 通讯作者: Arking DE