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

总结 背景：虽然过去十年提供了对复杂性状遗传结构的深入了解， 在这些疾病中，所确定的遗传关联充满了复杂的异质性模式和临床特征。 多效性，特别是在精神病学中。此外，对疾病的致病性和社会影响知之甚少- 在个体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（CNVs）和性染色体 非整倍体（SCA）非常适合打破僵局，并在精确精神病学方面进行试点工作， 合理的患病率和相当大的疾病风险。 目的：我们将首先提供真正公正的估计流行率，以及年龄依赖的危险和疾病 第二，确定这些疾病的全球疾病负担（GBD）。 基因组改变;第三，将这些发现转化为临床建议， 测试和规划医疗保健服务。此外，我们将确定病理性 CNV/SCA的特征在临床确定的携带者之间是不同的（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）和携带者状态不为医疗保健系统所知的携带者。 方法：我们将（a）利用一个真正代表丹麦人的基因型病例队列精神病样本， 群体（n[心理学]=90.000; n[队列]= 50，000），以确定54个基因组位点复发性CNV的携带者状态 以及SCA，（B）交叉引用详细的临床、人口统计学和社会经济学个人水平数据 从公共的，全国性的登记，以（c）估计每一个染色体异常（i）， 人口患病率、外显率和个体精神病和躯体疾病诊断的危险，（ii） 相应的终生疾病轨迹和（iii）疾病负担，使用（d）（i）考克斯比例风险 模型与反抽样概率权重，（ii）序列分析和（iii）标准卫生经济 措施，包括DALY以及直接和间接医疗保健费用。其中一些方法已经被开发出来 特别是在过去几年中，丹麦和美国的研究小组合作， 申请者为了确定确认偏差对携带者感知疾病率的影响，我们将交叉- 参考丹麦人口样本携带者与丹麦细胞遗传学登记处的记录， 临床已知与未知携带者，并比较丹麦人口样本的总体疾病率 携带者与来自美国的大量SCA携带者临床样本。

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.