Female Sexual Orientation GWAS

7.项目概要/摘要 我们将对女性性取向的遗传学进行迄今为止规模最大、最全面的研究 (SO)这是一个具有重大科学和社会意义的遗传复杂性状。我们的研究将揭示 女性的生理特征。我们已经建立了一个大型的GWAS合作，以实现我们的特定目标： 1.对现有的GWAS数据集进行荟萃分析，总计约10,900名同性恋者，约6,800名双性恋者， 359,700名异性恋女性。我们提出了一项前所未有的规模和范围的遗传研究， 研究女性SO。我们将收集、协调和分析现有的全基因组基因分型数据， 对这些女性进行荟萃分析。 2.对新收集的女性样本（N= 8，000）进行GWAS， 与之前的样本（N= 1，949）相比，共有3，754名同性恋者，2，843名双性恋者和3，352名异性恋者 妇女这意味着非异性恋妇女进行基因研究的人数比2005年增加了40%。 目标1。拟议的研究将填补几个空白，因为它将提供更详细的表型SO和 与以前的研究相关的特征，允许在未来的研究中重新接触受试者，并迅速分享 通过NIH数据共享机制。这一新的样本集将发挥重要的统计作用， 增加总体样本量，更好地平衡非异性恋妇女与异性恋妇女的比例。 目标1和2合并的GWAS将> 387，000名女性（加上合并分析的> 347，000名男性）。 3.对目标1和2的数据进行多位点分析， 基因座的含义和鉴定其他可能的基因靶点。我们将执行路径 分析以测试功能相关基因座的累积效应，以及多基因评分分析以 描述女性SO的整体遗传结构。 4.将相关的表型/性状纳入分析，以评估混杂因素和潜在遗传因素 相关性，并定义共享的遗传景观。我们将重点关注表型相关性， 包括自杀倾向、抑郁、焦虑、物质使用、性别焦虑--来自文献和我们的 初步数据。将进行几项分析：（a）测试顶级变体/基因，包括相关的 表型作为协变量，以评估潜在的混杂，（B）评估遗传力和遗传相关性， 量化遗传效应并确定共有的遗传成分，以及（c）进行多性状分析， 利用相关表型中的信息。 通过定位和表征有助于性状变异的遗传变异，我们将提供重要的新方法。 以及关于女性SO遗传贡献的验证性见解，这是一个众所周知的研究不足的领域。 发现相关的并最终影响性状的遗传变异将为进一步的研究打开大门 对SO发展的遗传和环境机制的研究。

7. PROJECT SUMMARY / ABSTRACT We will conduct the largest and most comprehensive study to date on the genetics of female sexual orientation (SO), a genetically complex trait of major scientific and social interest. Our research will uncover fundamental biological aspects of female SO. We have built a large GWAS collaboration to conduct our specific aims: 1. Conduct a meta-analysis of available GWAS datasets totaling ~10,900 homosexual, ~6,800 bisexual, and ~359,700 heterosexual women. We propose a study of unprecedented size and scope for the genetic study of female SO. We will assemble, harmonize, and analyze available genome-wide genotyping data in order to perform a meta-analysis on these women. 2. Conduct a GWAS on a deeply phenotyped, newly collected sample of women (N=8,000) combined with a previous sample (N=1,949), totaling 3,754 homosexual, 2,843 bisexual, and 3,352 heterosexual women. This represents a ~40% increase in the number of non-heterosexual women for genetic research over Aim 1. The proposed research will fill several gaps as it will provide more detailed phenotyping for SO and correlated traits than previous studies, allow for recontact of subjects for future studies, and be rapidly shared through an NIH data-sharing mechanism. This new sample set will serve an important statistical role by increasing the overall sample size and better balancing the ratio of nonheterosexual to heterosexual women. Aims 1 & 2 combined GWAS will be >387,000 women (plus >347,000 men for combined analyses). 3. Perform multi-locus analyses on the data from Aims 1 & 2, providing insight into functional implications of the loci and identifying additional possible genic targets. We will perform pathway analyses to test for the cumulative effect of functionally related loci, and polygenic score analysis to characterize the overall genetic architecture of female SO. 4. Incorporate correlated phenotypes/traits into analyses to assess confounding and potential genetic correlations and define the shared genetic landscape. We will focus on phenotypic correlations—, including suicidality, depression, anxiety, substance use, gender dysphoria—from the literature and our preliminary data. Several analyses will be conducted: (a) test top variants/genes including correlated phenotypes as covariates to assess potential confounding, (b) evaluate heritability and genetic correlations to quantify genetic effects and identify shared genetic components, and (c) conduct multi-trait analysis to leverage information in correlated phenotypes. By mapping and characterizing genetic variants contributing to trait variation, we will provide important novel and confirmatory insights regarding genetic contributions to female SO, a notoriously understudied area. Finding associated and eventually trait-influencing genetic variants will open a gateway to additional research on both genetic and environmental mechanisms of SO development.