A Sex-Specific Dissection of Autism Genetics

描述（由申请人提供）：本申请涉及康复法案有限竞争：研究解决自闭症谱系障碍（R21）的异质性与RFA-MH-09-172。自闭症谱系障碍是最具遗传性的常见疾病之一，具有广泛的临床异质性，然而，其潜在的神经生物学基础和遗传结构都知之甚少。受影响的男性是女性的四倍，原因不明。因此，我们可能能够利用我们关于两性二态性的主要遗传和激素决定因素的知识，以剖析自闭症异质性的主要来源。长期目标是利用遗传工具更好地了解自闭症的生物学基础，从而在诊断、预防和治疗方面取得进展。这项提议的目的是调查男性患自闭症风险增加的遗传原因。核心假设是自闭症的两性二态易感性反映在自闭症基因结构的性别差异上。在初步数据的指导下，包括自闭症的性别特异性遗传因子和许多人类特征的广泛的两性二态遗传结构，本提案包括一个试点，招募受试者并比较男性和女性，以区分遗传模型和确定性别特异性易感性位点。具体目标包括：1)招募丰富的女性患病家庭样本；2)调查女性与男性自闭症的遗传结构；3)确定自闭症的性别特异性遗传机制或途径。第一个目标将通过从UCSF自闭症诊所回顾性和前瞻性地招募受试者，从在线自闭症社区招募受试者，并使用Affymetrix 6.0微阵列进行全基因组SNP和CNV基因分型来实现。第二个目标将通过比较家族史、确定和自闭症特征的测量，以及比较男性和女性之间的拷贝数概况和总结SNP关联信号来实现。第三个目标将通过分析性别特异性关联信号、上位性（包括X染色体位点）和激素调节基因通路关联来实现。这种方法是创新的，因为性别特异性遗传结构尚未在一个功能强大的数据集中得到全面分析，因此我们期望对自闭症异质性的重要来源获得新的见解。这一结果将具有重大意义，因为有关保护女性不患自闭症的信息可能会降低男性患自闭症的风险。

DESCRIPTION (provided by applicant): This application addresses Recovery Act Limited Competition: Research to Address the Heterogeneity in Autism Spectrum Disorders (R21) with RFA-MH-09-172. Autism spectrum disorders are among the most heritable common disorders and show extensive clinical heterogeneity, however, both the underlying neurobiological basis and genetic architecture are poorly understood. Four times as many males as females are affected, for unknown reasons. Thus, we may be able to leverage our knowledge about the primary genetic and hormonal determinants of sexual dimorphism in order to dissect a major source of heterogeneity in autism. The long-term goal is to use genetic tools to better understand the biological basis of autism, leading to advances in diagnosis, prevention and treatment. The objective of this proposal is to investigate genetic causes for increased male risk of autism. The central hypothesis is that sexually dimorphic susceptibility to autism is reflected in sex differences of the genetic architecture of autism. Guided by preliminary data including sex-specific genetic contributors to autism and extensive sexually dimorphic genetic architecture for numerous human traits, this proposal comprises a pilot to recruit subjects and compare males and females in order to distinguish genetic models and to identify sex-specific susceptibility loci. The specific aims include: 1) Recruitment of an enriched female-affected family sample, 2) Investigation of the genetic architecture of autism in females vs. males, and 3) Identification of the sex-specific genetic mechanisms or pathways involved in autism. The first aim will be accomplished by enrolling subjects retrospectively and prospectively from the UCSF Autism Clinic, enrolling subjects from an online autism community, and performing genome-wide SNP and CNV genotyping using the Affymetrix 6.0 microarray. The second aim will be accomplished by comparing family history, ascertainment, and measures of autism traits as well as comparing copy number profiles and summary SNP association signal between males and females. The third aim will be accomplished by analysis of sex-specific association signals, epistasis including X chromosome loci, and hormone-regulated gene pathway association. This approach is innovative, as sex-specific genetic architecture has not been comprehensively analyzed in a well-powered dataset, and we thus expect to gain novel insight into an important source of heterogeneity in autism. The results will be significant, as information about what protects females from developing autism could lead to reduction of male risk. PUBLIC HEALTH RELEVANCE: Autism is a common cause of severe disability to individuals and families across the lifespan with extremely limited treatment options. With better understanding of the biological basis and the genetic architecture of autism, diagnosis, prognosis, prevention and treatment options could be improved.