Road Map to Precision Psychiatry: Comprehensive Investigation of Chromosomal Anomalies (PsychMap)

摘要 背景：虽然过去十年提供了对复杂性状的遗传结构和 疾病，已识别的遗传关联充满了复杂的异质性和临床模式 多效性的，尤指在精神病学中。此外，人们对疾病的致病和社会影响知之甚少-- 在个人或整个群体的水平上诱发基因组变异，因为它们中的许多赋予 疾病风险的增加非常温和。重复拷贝数变异(CNV)与性染色体 非整倍体(SCA)非常适合于打破僵局，并用他们的 合理的流行率和相当大的疾病风险。 目标：我们将首先提供对流行率以及与年龄相关的危险和疾病的真正公正的估计 复发性CNV和SCA的外显率；第二，决定这些患者的全球疾病负担(GBD) 基因组改变；第三，将这些发现转化为可操作的基因的临床建议 医疗保健服务的测试和规划。此外，我们将确定病理变化的程度 CNV/SCA的特征在临床确诊的携带者之间不同(这些携带者构成了迄今为止大多数研究的基础 CNV/SCA的致病性)和医疗保健系统未知的携带者。 方法：我们将(A)利用一个真正代表丹麦人的基因分型病例队列精神病学样本 群体(n[心理]=90.000；n[队列]=50,000)以确定54个基因组座位上复发CNV的携带者状态 以及(B)相互参照详细的临床、人口和社会经济人口级数据 以(C)估计每一种染色体异常(I) 个人精神和躯体诊断的人群流行率、外显率和危害，(2) 相应的终生疾病轨迹和(3)疾病负担，使用(D)(1)COX比例风险 具有逆抽样概率权重的模型，(Ii)序列分析和(Iii)标准卫生经济学 措施，包括DALY以及直接和间接的医疗成本。其中一些方法已经被开发出来 特别是在过去的几年里，丹麦和美国的研究小组合作 申请者。为了确定确定偏差对携带者可感知的发病率的影响，我们将交叉- 将丹麦人口样本携带者与丹麦细胞遗传学登记处的记录进行比较 临床已知携带者与未知携带者，并比较丹麦人群样本中的总体发病率 从美国获得大量SCA携带者临床样本的携带者

Summary Background: While the past decade has provided insight into the genetic architecture of complex traits and disorders, the identified genetic associations are fraught with complex patterns of heterogeneity and clinical pleiotropy, especially in psychiatry. Also, little is yet known about pathogenic and societal impact of disease- predisposing genomic variants at the level of an individual or an entire population, since many of them confer very modest increases in disease risk. Recurrent copy number variants (CNVs) and sex chromosome aneuploidies (SCAs) are well suited to break the impasse and pilot efforts in precision psychiatry with their reasonable prevalence and sizable disease risk. Aims: We will first provide truly unbiased estimates of prevalence, as well as age-dependent hazard and disease penetrance, of recurrent CNVs and SCA; second, determine the global burden of disease (GBD) of these genomic alterations; and third, transform these findings into clinical recommendations for actionable genetic testing and planning of healthcare provision. Additionally, we will determine the degree to which pathologic profiles of CNV/SCA differ between clinically ascertained carriers (who form the basis of most hitherto research of pathogenicity of CNVs/SCAs) and carriers whose carrier status is unknown by the healthcare system. Methods: We will (a) leverage a genotyped case-cohort psychiatric sample truly representative of the Danish population (n[psych]=90.000; n[cohort]=50,000) to determine carrier status of recurrent CNVs at 54 genomic loci as well as for SCA, (b) cross-reference detailed clinical, demographic and socio-economic person-level data from public, nationwide registries, in order to (c) estimate for each of the chromosomal anomalies (i) the Population prevalence, Penetrance and Hazards for individual psychiatric and somatic diagnoses, (ii) the corresponding life-time disease trajectories and (iii) the disease burden, using (d) (i) Cox Proportional Hazards models with inverse sampling probability weights, (ii) Sequence Analysis and (iii) standard health economic measures, incl. DALY and direct and indirect healthcare costs. Some of these methods have been developed specifically over the last years in cooperation between the research groups of the Danish and U.S. based applicants. To determine the impact of ascertainment bias on perceived disease rates of carriers, we’ll cross- reference the Danish population sample carriers with records from the Danish cytogenetic register and compare clinically known vs. unknown carriers, and also compare overall disease rate in the Danish population sample carriers with a large clinical sample of SCA carriers from the U.S.