Uncovering the genetic architecture of extremely treatment-resistant schizophrenia using whole genome sequencing

利用全基因组测序揭示极度难治性精神分裂症的遗传结构

• 批准号: 10483179
• 负责人: Anthony Zoghbi
• 金额: $ 19.56万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10483179
• 关键词: Academic Medical Centers; Acute Intermittent Porphyria; Affect; Antipsychotic Agents; Biological; Biology; Blindness; Caring; Clinical; Clinical Management; Clinical Research; Communities; Complex; Control Groups; Copy Number Polymorphism; Country; DNA; Data; Diabetes Mellitus; Diagnosis; Diagnostic; Disabled Persons; Disease; Doctor of Philosophy; Drug Kinetics; Family; Functional disorder; Genes; Genetic; Genetic Counseling; Genetic Variation; Genetic study; Genome; Genomic medicine; Genomics; Goals; Heritability; Heterogeneity; High Prevalence; Impaired cognition; Individual; Inpatients; Institutes; Lead; Light; Medicine; Mendelian disorder; Mental Health; Mental disorders; Mentorship; Microarray Analysis; Mutation; New York; Oncology; Participant; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Population; Prevalence; Psychiatrist; Psychiatry; Research; Research Methodology; Research Personnel; Resistance; Risk; Sample Size; Sampling; Schizophrenia; Seizures; Severities; Single Nucleotide Polymorphism; Supraoptic Vertical Ophthalmoplegia; Symptoms; System; Testing; Training; Variant; Work; actionable mutation; autism spectrum disorder; base; cancer genetics; career; clinically actionable; cognitive testing; cohort; dosage; genetic architecture; genetic disorder diagnosis; genetic variant; genome sequencing; improved; insight; loss of function; mental state; molecular subtypes; new therapeutic target; novel therapeutics; polygenic risk score; precision medicine; psychogenetics; rare variant; recruit; risk variant; therapeutic development; therapy resistant; whole genome

Schizophrenia (SCZ) is a severely disabling and highly heritable condition that afflicts ~1% of the global population. Despite the advances in genetics that have shed light on the biology of so many diseases and led to groundbreaking new treatments for conditions from blindness to cancer, genetic studies in SCZ have been hindered by its genetic complexity and phenotypic heterogeneity: two patients who do not share a single symptom can both receive the same diagnosis. One way forward is to define molecular subtypes, an approach that has been successful in oncology and other realms of medicine, but which often requires identifying distinct phenotypic subtypes. We therefore propose to study the most severe form of the disorder—extremely treatment-resistant SCZ (ETRS)—because rare genetic variants of large effects are likely to be enriched in this population. ETRS patients are the top 1% most severely affected patients, often remain hospitalized for decades, and are not usually included in genetic studies, in part because they are not accessible to most researchers. We will recruit 400 subjects with ETRS from the New York State inpatient system, thoroughly characterize their phenotype, and perform whole genome sequencing (WGS). Our preliminary data from 75 ETRS patients revealed a higher-than-expected prevalence of seizures, dysmorphic features, and cognitive impairment, which suggest the presence of one of the 60 Mendelian diseases known to mimic SCZ. Furthermore, prior research and our preliminary data indicate that SCZ severity, cognitive impairment, and treatment resistance are associated with a greater burden of rare single nucleotide variants (SNVs), copy number variants (CNVs), and common variant polygenic risk. Therefore, in Aim 1, we will use diagnostic WGS to identify (a) Mendelian conditions that mimic SCZ, such as Niemann-Pick disease type C, and (b) pharmacogenetic variants that reduce the efficacy of antipsychotic treatments. Patients with either type of mutation may be treatable. In Aim 2, we will (a) evaluate the burden of rare SNVs and rare CNVs. Since extreme phenotypes can also be due to an excess of common variant risk, we will (b) determine the common variant burden by calculating SCZ polygenic risk scores. We will use 6,500 individuals with typical SCZ and 165,000 healthy individuals as controls for Aims 1 and 2. The project will be conducted at Columbia University Medical Center by Anthony Zoghbi, MD, a psychiatrist with clinical expertise and a career goal of becoming an independent investigator in psychiatric genetics, focusing on SCZ. Dr. Zoghbi's comprehensive five-year training plan will enable him to develop expertise in statistical genetics and genomics, cognitive assessment of SCZ, and clinical research methods under the mentorship of David Goldstein, PhD (Director, Institute for Genomic Medicine), statistical geneticist Suzanne Leal, PhD, and neuropsychologist Terry Goldberg, PhD. The proposed aims align with his training goals and will elucidate the genetic architecture of ETRS, shed light on the pathophysiology of SCZ, and improve the care of those most disabled by SCZ.

精神分裂症（SCZ）是一种严重的残疾和高度可遗传的疾病，遭受了约1％的全球状况 人口。尽管遗传学的进步已经阐明了许多疾病的生物学，并导致了 从失明到癌症的疾病的开创性新疗法，SCZ中的遗传研究一直是 受到其遗传复杂性和表型异质性的阻碍：两名不共享一个单一的患者 症状都可以接受相同的诊断。前进的一种方法是定义分子亚型，一种方法 这在肿瘤学和其他医学领域都取得了成功，但通常需要确定独特的 表型亚型。因此，我们建议研究最严重的疾病形式 耐药性SCZ（ETRS） - 由于罕见的遗传变异很大，因此很可能会富集 人口。 ETRS患者是受影响最严重的最严重影响的患者，经常住院 数十年，通常不包含在遗传研究中，部分原因是大多数人无法使用它们 研究人员。我们将通过来自纽约州住院系统的ETR招募400名受试者，彻底 表征其表型并执行整个基因组测序（WGS）。我们的初步数据来自75 ETRS患者显示癫痫发作，营养不良特征和认知的患病率高于预期 障碍，这表明存在模仿SCZ已知的60种孟德尔疾病之一。 此外，先前的研究和我们的初步数据，表明SCZ严重程度，认知障碍和 治疗耐药性与稀有单核苷酸变体（SNV）更大的燃烧相关，复制 数字变体（CNV）和常见的多基因风险。因此，在AIM 1中，我们将使用诊断WGS 要确定（a）模仿niemann-pick疾病C型和（b）的孟德尔条件 降低抗精神病药效率的药物源性变体。两种类型的患者 突变可能是可以治疗的。在AIM 2中，我们将（a）评估稀有SNV和稀有CNV的燃烧。自从 极端表型也可能是由于过多的常见变异风险，我们将（b）确定常见 通过计算SCZ多基因风险评分的变体伯嫩。我们将使用6,500名具有典型SCZ的人，并且 165,000个健康个体作为目标1和2的控制。该项目将在哥伦比亚大学进行 医学中心Anthony Zoghbi，医学博士，具有临床专业知识的精神科医生，也是成为职业目标 精神遗传学的独立研究者，重点是SCZ。 Zoghbi博士的综合五年 培训计划将使他能够发展统计遗传学和基因组学方面的专业知识，认知评估 SCZ和临床研究方法是David Goldstein博士的心态（研究所主任 基因组医学），统计遗传学家Suzanne Leal博士和神经心理学家Terry Goldberg博士。这 拟议的目标与他的训练目标保持一致，并将阐明ETR的遗传结构，阐明 SCZ的病理生理学，并改善SCZ最残疾的人的护理。