Autism Genetics Phase II: Increasing Representation of Human Diversity

摘要 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，绝大多数的基因研究和发现都发生在 欧洲（欧盟）血统的人口，显着代表社区的颜色和那些自我， 描述了非洲裔美国人（AA）的祖先。遗传学研究的这种差异，加上 诊断和治疗，促使该网络的研究人员采取一个主要的新方向， 研究，着手进行一项独特而非常成功的招募患有ASD的AA家庭的工作 （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问题至关重要，同时开始进行基因分析， 确定ASD易感基因。通过这种合作努力，我们的目标是填补ASD研究的重大空白， 继续招募并在这一重要人群中进行遗传研究， ASD遗传学研究的代表。我们的网络包括七个研究中心和一个DCC， ASD遗传学的系统调查，以确定罕见的突变，染色体异常， 在AA人群中导致ASD易感性的常见变异，同时利用这种独特的 有机会了解和潜在的补救健康差距。具体而言，我们将丰富现有的 招募至少720名AA先证者和其他家庭成员，以确定一个至少 总共有2000名先证者。我们的招募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的获得和护理质量，同时增加AA个体在遗传学方面的参与 research.我们将进行全基因组测序（WGS），这允许全面调查， 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 采用新的方法来确定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，并将这些特征与数量表型相关联。同时， 基因表达谱和网络分析将用于区分变异体的优先次序。确定的遗传风险因素 将在AA样本中检测主要EU样本中的相关性，以确定这些队列是否 共享相同的遗传风险因素，使用样本大小提供复制先前关联的能力， 以鉴别罕见的复发性CNV和SNV。我们将使用本地血统来提高多基因风险评分的效力 来自欧盟队列。ASD相关的新形式或不同人群频率的观察 该样本中的变异以及与其他队列共享大多数CNV和SNV都是结果， 将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 通过互联网滚动访问所有表型和基因型数据，进一步提高价值 这一资源对社区的贡献。

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.