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

摘要 这项应用是第一次大规模、协调一致地将性别作为人类的生物变量进行研究 通过一项世界性的大脑倡议进行神经科学研究。我们创建它是为了响应NIH的任务，以解决 对于为什么一些大脑疾病在女性中比男性更普遍，反之亦然，在知识上存在重大差距。 女性和男性在老龄化趋势以及严重抑郁症、焦虑症和精神疾病的患病率方面存在差异 虐待障碍(SODS)、酗酒、精神病、创伤后应激障碍(PTSD)和神经变性 阿尔茨海默氏症等疾病。脑部疾病患者的平均年龄存在显著的性别差异 发病、治疗反应、症状严重程度和疾病轨迹。然而，科学对此所知甚少，令人担忧。 为什么。为了回应这一点，我们发起了一项新的全球大脑倡议：“谜-SD：了解性爱” 全球大脑健康之谜的差异“。Enigma的性别差异倡议汇集数据 在全球范围内解决动力不足的研究带来的“可再现性危机”(Ioannidis 2014)。我们带了两个 创新来源：(1)一项覆盖35个国家的全球研究的巨大、前所未有的力量，产生了 对性别差异的特殊敏感性和(2)寿命方法，以绘制整个疾病出现的图表 生活，在脑部疾病的发病年龄、严重程度和轨迹上拾取特定性别的“变化”。我们会 始终如一地分析来自数百家机构的成像、基因组和临床数据-以了解(1) 一生中大脑结构和功能的性别差异；以及(2)五个性别中大脑异常的性别差异 主要精神疾病：重度抑郁症(MDD)、躁郁症(BD)、精神分裂症(SCZ)、创伤后应激障碍(PTSD)、 还有肥皂水。我们将利用我们谜团的成功--这是一项关于18种主要脑部疾病的全球研究。 我们的目标是：目标1。一生中大脑老化的性别差异图表。建立在我们有史以来最大的 对10,144人大脑的规范研究(谜-寿命；DIMA 2017)，我们将创建特定性别 寿命“图表”显示了女性和男性大脑的平均年龄。使用MRI、DTI和休息 在全球范围内，我们测量皮质/皮质下大脑结构、白质束和年龄- 大脑功能同步性的敏感指标。我们根据年龄和性别制定统计标准；我们测试 生物学性别和脑老化指标之间的相互作用。目标2.确定不同性别之间的差异 MDD、BD、SCZ、创伤后应激障碍和成瘾患者的大脑缺陷轨迹。以我们的全球神经成像为基础 对5种普遍存在的大脑疾病的研究-我们将问：(1)女性和男性的大脑缺陷是否相同 每种疾病？(2)在临床严重程度相同的女性中，大脑的差异更大吗？目标3.性和 遗传风险。在我们的5个全球财团-Enigma-MDD、-BD、-SCZ、-PTSD和 -SODS-我们将计算每种疾病的多基因风险评分，并询问： 这些疾病中的一种具有更高的遗传风险？这种影响因性别而异吗？我们会做好基础工作 在2022年提交一份关于大脑疾病性别差异的谜团U01。

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.