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) 是一种严重致残且高度遗传的疾病，困扰着全球约 1% 的人 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许​​多疾病的发生。 针对从失明到癌症等疾病的突破性新疗法，SCZ 的基因研究已取得进展 因其遗传复杂性和表型异质性而受到阻碍：两个不共享单一基因的患者 一种方法是定义分子亚型，这是一种方法。 这在肿瘤学和其他医学领域取得了成功，但通常需要确定不同的 因此，我们建议研究该疾病最严重的形式——极度。 难治性 SCZ (ETRS)——因为具有重大影响的罕见遗传变异可能在这种情况下丰富 ETRS 患者是受影响最严重的前 1% 患者，通常需要住院治疗。 几十年来，通常不包括在基因研究中，部分原因是大多数人无法接触到它们 我们将从纽约州住院系统中彻底招募 400 名 ETRS 受试者。 表征他们的表型，并进行全基因组测序 (WGS)，我们的初步数据来自 75 个。 ETRS 患者的癫痫发作、畸形特征和认知障碍的患病率高于预期 损伤，这表明存在 60 种已知模仿 SCZ 的孟德尔疾病之一。 此外，之前的研究和我们的初步数据表明 SCZ 严重程度、认知障碍和 治疗耐药性与罕见单核苷酸变异（SNV）的更大负担相关，复制 因此，在目标 1 中，我们将使用诊断性 WGS。 识别 (a) 模拟 SCZ 的孟德尔病症，例如 C 型尼曼-匹克病，以及 (b) 降低任一类型抗精神病药物治疗效果的药物遗传学变异。 在目标 2 中，我们将 (a) 评估罕见 SNV 和罕见 CNV 的负担。 极端表型也可能是由于常见变异风险过高造成的，我们将 (b) 确定常见变异风险 通过计算 SCZ 多基因风险评分来计算变异负担 我们将使用 6,500 名具有典型 SCZ 和 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 医学中心，安东尼·佐格比（Anthony Zoghbi）医学博士，一位具有临床专业知识的精神病患者，其职业目标是成为一名 精神遗传学独立研究者，专注于 Zoghbi 博士的五年综合研究。 培训计划将使他能够发展统计遗传学和基因组学、认知评估方面的专业知识 SCZ 以及在 David Goldstein 博士（研究所所长）指导下的临床研究方法 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。 提出的目标与他的培训目标一致，并将阐明 ETRS 的遗传结构，揭示 SCZ 的病理生理学，并改善对因 SCZ 而致残最严重的人的护理。