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: 10409189
• 负责人: Anthony Zoghbi
• 金额: $ 19.66万
• 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/10409189
• 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）是一种严重致残和高度遗传的疾病，困扰着全球约1%的人。 人口尽管遗传学的进步已经揭示了许多疾病的生物学，并导致了 从失明到癌症的开创性新疗法，SCZ的遗传研究已经成为 受其遗传复杂性和表型异质性的阻碍：两名患者不共享单一的 两种症状可以得到相同的诊断。一种方法是定义分子亚型， 这在肿瘤学和其他医学领域已经取得了成功，但这通常需要识别不同的 表型亚型因此，我们建议研究最严重的形式的障碍-极端 治疗耐药SCZ（ETRS）-因为罕见的遗传变异的大的影响，很可能是丰富的， 人口ETRS患者是受影响最严重的前1%患者，通常仍在住院治疗， 几十年来，通常不包括在遗传研究中，部分原因是大多数人无法获得它们。 研究人员我们将从纽约州住院系统招募400名ETRS受试者， 表征其表型，并进行全基因组测序（WGS）。我们的初步数据来自75 ETRS患者的癫痫发作、畸形特征和认知功能的患病率高于预期。 损伤，这表明存在已知模拟SCZ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的严重程度，认知障碍， 治疗耐药性与罕见单核苷酸变异（SNV）的更大负担相关， 数字变异（CNVs）和常见变异多基因风险。因此，在目标1中，我们将使用诊断WGS 鉴定（a）模拟SCZ的孟德尔病症，如C型尼曼-匹克病，和（B） 降低抗精神病药物疗效的药物遗传学变异。任何类型的患者 突变是可以治疗的。在目标2中，我们将（a）评估罕见SNV和罕见CNV的负担。以来 极端的表型也可能是由于常见变异风险过高，我们将（B）确定常见的 通过计算SCZ多基因风险评分来评估变异负荷。我们将使用6,500名具有典型SCZ的个体， 165，000名健康个体作为目标1和2的对照。该项目将在哥伦比亚大学进行 医学博士安东尼·佐格比（Anthony Zoghbi）是一位具有临床专业知识的精神病学家，他的职业目标是成为一名 精神病遗传学的独立研究者，专注于SCZ。Zoghbi博士的全面五年 培训计划将使他能够发展在统计遗传学和基因组学，认知评估， SCZ和临床研究方法的指导下，大卫戈尔茨坦，博士（主任，研究所 统计遗传学家Suzanne Leal博士和神经心理学家Terry Goldberg博士。的 提出的目标与他的培训目标一致，并将阐明ETRS的遗传结构，阐明 SCZ的病理生理学，并改善那些最残疾的SCZ的护理。