ENIGMA-SD: Understanding Sex Differences in Global Mental Health through ENIGMA

摘要 这项应用是第一次大规模的，协调一致的努力，研究性别作为一个生物变量在人类 通过一个全球性的大脑倡议。我们创建它是为了响应NIH的要求， 关于为什么某些脑部疾病在女性中比男性更普遍，反之亦然的知识存在重大差距。 女性和男性在老龄化趋势和严重抑郁症、焦虑症、物质依赖性疾病的患病率方面存在差异。 滥用障碍（SUD）、酒精中毒、精神病、创伤后应激障碍（PTSD）和神经退行性疾病 老年痴呆症等疾病。在大脑疾病的平均年龄方面有显著的性别差异， 发病、治疗反应、症状严重程度和疾病轨迹。然而，科学界对这一现象知之甚少， 为什么.为了应对这一问题，我们发起了一项新的全球大脑倡议：“ENIGMA-SD：了解性 通过ENIGMA全球大脑健康的差异。ENIGMA的性别差异倡议汇集了数据 在全球范围内解决动力不足研究的“再现性危机”（Ioanner 2014）。我们带两个 创新的源泉：（1）在35个国家进行的全球研究的巨大、前所未有的力量， 对性别差异的特殊敏感性和（2）寿命方法，以图表疾病的出现， 生活中，拿起性别特异性的'转变'的发病年龄，严重程度，和脑疾病的轨迹。我们将 始终如一地分析来自数百家研究所的成像、基因组和临床数据-以了解（1） 大脑结构和功能在一生中的性别差异;（2）大脑异常在五个方面如何因性别而异 主要精神疾病：严重抑郁症（MDD），双相情感障碍（BD），精神分裂症（SCZ），创伤后应激障碍， 和SUD。我们将利用我们的ENIGMA联盟的成功-一项针对18种主要脑部疾病的全球研究。 我们的目标是：目标1。图表在整个生命过程中大脑老化的性别差异。建立在我们有史以来最大的 在10，144人的大脑规范性研究（ENIGMA-Lifespan; Dima 2017）中，我们将创建性别特异性 寿命“图表”显示了大脑的年龄，平均而言，在女性和男性。使用MRI、DTI和静息 在世界范围内的功能磁共振成像，我们测量皮质/皮质下大脑结构，白色物质束，和年龄- 大脑同步功能的敏感指标我们根据年龄和性别制定统计标准;我们测试 生理性别和大脑老化指标之间的相互作用。目标二。确定性别差异 MDD、BD、SCZ、PTSD和成瘾中脑缺陷的轨迹。基于我们的全球神经成像 5种常见的大脑疾病的研究-我们会问：（1）大脑缺陷在女性和男性中是一样的吗？ 每种疾病？(2)在相同的临床严重程度下，女性的大脑差异更大吗？目标3：性别和 遗传风险。在我们5个全球联盟的独特合作中- ENIGMA-MDD，-BD，-SCZ，-PTSD，和 -SUDs -我们将计算每种疾病的多基因风险评分，并询问： 携带这些疾病的遗传风险更高吗这种影响是否因性别而异？我们会做好基础工作 在2022年提交关于脑部疾病性别差异的ENIGMA范围U 01。

ABSTRACT This application is the first, large scale, concerted effort to study sex as a biological variable in human neuroscience through a worldwide brain initiative. We created it to respond to the NIH mandate to address major gaps in knowledge on why some brain disorders are more prevalent in women than men, and vice versa. Women and men differ in aging trends and in the prevalence of major depression, anxiety disorders, substance abuse disorders (SUDs), alcoholism, psychosis, post-traumatic stress disorder (PTSD), and neurodegenerative diseases such as Alzheimer's disease. There are significant sex differences in the brain disorders' mean age of onset, treatment response, symptom severity and disease trajectory. Yet science knows alarmingly little about why. To respond to this, we launch a new worldwide brain initiative: “ENIGMA-SD: Understanding Sex Differences in Global Brain Health through ENIGMA”. ENIGMA's Sex Differences Initiative pools data worldwide to address the “crisis of reproducibility” from underpowered studies (Ioannidis 2014). We bring two sources of innovation: (1) the vast, unprecedented power of a global study across 35 countries, yielding exceptional sensitivity to sex differences and (2) a lifespan approach, to chart disease emergence throughout life, to pick up sex-specific `shifts' in the age of onset, severity, and trajectory of brain disease. We will consistently analyze imaging, genomic, and clinical data from hundreds of institutes - to understand (1) sex differences in brain structure and function across life; and (2) how brain abnormalities differ by sex in five major psychiatric illnesses: major depression (MDD), bipolar disorder (BD), schizophrenia (SCZ), PTSD, and SUDs. We will leverage the success of our ENIGMA consortium - a global study of 18 major brain diseases. Our Aims are: Aim 1. Chart Sex Differences in Brain Aging throughout Life. Building on our largest-ever normative study of the brain in 10,144 people (ENIGMA-Lifespan; Dima 2017), we will create sex-specific lifespan “charts” showing how the brain ages, on average, in women and in men. Using MRI, DTI and resting state fMRI on a worldwide scale, we measure cortical/subcortical brain structures, white matter tracts, and age- sensitive metrics of functional brain synchrony. We develop statistical norms based on age and sex; we test interactions between biological sex and brain aging metrics. Aim 2. Determine Sex Differences in the Trajectory of Brain Deficits in MDD, BD, SCZ, PTSD, and Addictions. Building on our global neuroimaging studies of 5 prevalent brain disorders - we will ask: (1) Are the brain deficits the same in women and men with each disease? (2) Are brain differences greater in women at the same level of clinical severity? Aim 3. Sex and Genetic Risk. In a unique collaboration across our 5 global consortia – ENIGMA-MDD, -BD, -SCZ, -PTSD, and -SUDs – we will compute polygenic risk scores for each disease, and ask: What is the effect on the brain of carrying a higher genetic risk for one of these disorders? Does this effect differ by sex? We will do the groundwork to submit an ENIGMA-wide U01 on Sex Differences in Brain Disease, in 2022.