Mendelian Variants Associated with Psychosis

与精神病相关的孟德尔变异

基本信息

批准号：
10053078
负责人：
Sadaf Naz
金额：
$ 34.02万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-17 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053078
关键词：
Affect American Amish Awareness Benign Binding Brain Diseases Bypass Cell model Clinical Clinical Medicine Collaborations Complex Consensus Copy Number Polymorphism Country DNA Development Diagnosis Diagnostic Disease Dopamine Egypt Enrollment Etiology Family Family Sizes Family member Future Genes Genetic Genome Genotype Goals Heritability Heterogeneity High Prevalence Human Genome Inbreeding Individual Informatics Inherited Intellectual functioning disability International Knock-out Laboratories Major Depressive Disorder Marriage Medicine Mental Depression Mental disorders Methods Molecular Molecular and Cellular Biology Morocco Movement Disorders Mus Mutation Neurotransmitters Oligogenic Traits Pakistan Parkinson Disease Pathogenicity Patient Recruitments Patients Phase Phenotype Point Mutation Population Prevention Prevention strategy Preventive Process Proteins Psyche structure Psychiatric Diagnosis Psychiatrist Psychiatry Psychotic Disorders Reporting Research Research Infrastructure Rodent Model Saudi Arabia Schizophrenia Serotonin Specificity Stretching Symptoms Synapses Synaptic Vesicles Syndrome System Therapeutic Training Translations Variant Woman Work base brain health causal variant cognitive neuroscience consanguineous family deafness depression model design disease classification exome gene discovery gene environment interaction genetic architecture genetic linkage analysis genetic pedigree genetic variant genome sequencing genome wide association study human disease hypercholesterolemia infancy medical specialties molecular modeling monoamine neglect neuroimaging neuropsychiatric disorder neuropsychiatry next generation novel personalized medicine prevent programs rare variant recruit risk variant skeletal dysplasia social stigma success whole genome

项目摘要

Psychiatry remains the only medical specialty with diagnosis based solely on reported symptoms. For progress in personalized medicine, diagnosis must be reliable, sensitive, and specific. Consensus exists the current diagnostic system (DSM), although useful for clinical description, lacks these requirements. Genetics offers potential in psychiatric nosology and in the development of novel prevention strategies and treatments. Numerous variants associated with psychiatric disorders have been discovered recently. These variants if common have low effects sizes and lack disease specificity; if rare, they typically involve genes with broad functions and neuropsychiatric phenotypes (e.g., intellectual disability). Historically in medicine, Mendelian variants have been the first step in understanding the genetic bases of diseases. No single Mendelian variant has been discovered for any psychiatric disease. Across the world (e.g., Saudi Human Genome Program), the most successful approach for mutation discovery used whole exome or whole genome sequencing (WES, WGS) along with homozygosity mapping of consanguineous multiplex pedigrees. US population isolates do not have the requisite coefficient of inbreeding to apply these methods successfully. However, there is a high prevalence of marriages between first cousins in several countries: the highest occurs in Pakistan (>60%). This proposal exploits a newly developed international collaboration (PK, USA): molecular biologists with a track record of successful gene discovery in consanguineous pedigrees; neuropsychiatrists; clinical neuroscientists; bioinformaticians; and neuroimagers. The goals are twofold: 1) To find and characterize Mendelian genes associated with a mental illness; 2) To increase awareness and treatment of mental disorders and to grow Pakistan’s existing research infrastructure including a Pakistani Human Genome Program focusing on the study of mental disorders. Were no Mendelian genes found where they are most expected, this result would provide practical evidence of absence, highly significant in and of itself. If found and because single pedigrees are likely to have only one rare variant, the mutation would essentially define a homogeneous disorder that can be studied with methods such as neuroimaging, molecular/cellular biology, and cognitive neuroscience. Aim one involves the recruitment and characterization of multigenerational, multiplex, consanguineous families afflicted with psychosis. WES will be followed by informatic analyses including only variants that are rare; nonsynonymous; protein altering or likely pathogenic; and showing Mendelian in-heritance (homozygous in affected; heterozygous in obligate carriers). Aim 2 involves increasing within Pakistan the participation of women in STEM; training the next generation of geneticists; educating about mental diseases; collaborating and impacting clinical psychiatry; and decreasing stigma. These goals will deliver significance for psychiatry by radically transforming its nosology and by expanding the Pakistani research enterprise to diagnose, prevent, or cure neuropsychiatric diseases—neglected in Pakistan but impacting over 10% of the Pakistani population.

精神病学仍然是唯一仅根据报告的症状进行诊断的医学专业。在个性化医疗中，诊断必须是可靠的、灵敏的和具体的。诊断系统（DSM）虽然对临床描述有用，但缺乏遗传学提供的这些要求。在精神病学和开发新型预防策略和治疗方面具有潜力。最近发现了许多与精神疾病相关的变异。常见的效应较小且缺乏疾病特异性；如果罕见，它们通常涉及广泛的基因功能和神经精神表型（例如，智力障碍）在医学史上，孟德尔。变异是了解疾病遗传基础的第一步。没有单一的孟德尔变异。世界各地已发现任何精神疾病（例如沙特人类基因组计划）。最成功的突变发现方法是使用全外显子组或全基因组测序（WES、 WGS）以及美国群体的近亲多重谱系的纯合性图谱可以做到这一点。不具备成功应用这些方法所需的近亲繁殖系数，但存在较高的近交系数。几个国家中表兄弟姐妹之间的婚姻发生率最高：巴基斯坦最高（>60%）。提案利用了新开发的国际合作（PK，美国）：分子生物学家与轨道近亲血统中成功发现基因的记录；生物信息学家和神经影像学家的目标有两个：1）寻找并表征孟德尔基因。与精神疾病相关；2) 提高对精神疾病的认识和治疗并成长巴基斯坦现有的研究基础设施，包括巴基斯坦人类基因组计划，重点关注如果没有在最期望的地方发现孟德尔基因，这个结果就会提供实际的缺席证据，如果被发现的话，并且因为单一的血统，其本身就非常重要。很可能只有一种罕见的变异，该突变本质上将定义一种同质疾病，可以通过神经影像学、分子/细胞生物学和认知神经科学等方法进行研究。其中之一涉及多代、多重、近亲家庭的招募和特征描述患有精神病的 WES 将进行信息分析，仅包括罕见的变异；非同义；蛋白质改变或可能致病；并显示孟德尔遗传（纯合）目标 2 涉及增加巴基斯坦境内的参与； STEM 领域的女性；培训下一代遗传学家；开展有关精神疾病的教育；影响临床精神病学；并减少耻辱感，这些目标将为精神病学带来意义。从根本上改变其疾病分类学，并通过扩大巴基斯坦研究事业来诊断、预防或治愈神经精神疾病——在巴基斯坦被忽视，但影响了超过 10% 的巴基斯坦人口。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

RGS3 and IL1RAPL1 missense variants implicate defective neurotransmission in early-onset inherited schizophrenias.

RGS3 和 IL1RAPL1 错义变异表明早发性遗传性精神分裂症存在神经传递缺陷。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Kanwal, Ambreen;Pardo, José V;Naz, Sadaf
通讯作者：
Naz, Sadaf

Genome Sequencing of Consanguineous Family Implicates Ubiquitin-Specific Protease 53 (USP53) Variant in Psychosis/Schizophrenia: Wild-Type Expression in Murine Hippocampal CA 1-3 and Granular Dentate with AMPA Synapse Interactions.

近亲家族的基因组测序表明泛素特异性蛋白酶 53 (USP53) 变异与精神病/精神分裂症有关：小鼠海马 CA 1-3 和颗粒状齿状细胞中的野生型表达与 AMPA 突触相互作用。

DOI：
发表时间：
2023-10-09
期刊：
影响因子：
3.5
作者：
Kanwal, Ambreen;Sheikh, Sohail A;Aslam, Faiza;Yaseen, Samina;Beetham, Zachary;Pankratz, Nathan;Clabots, Connie R;Naz, Sadaf;Pardo, José V
通讯作者：
Pardo, José V

A preliminary study of resting brain metabolism in treatment-resistant depression before and after treatment with olanzapine-fluoxetine combination.

奥氮平-氟西汀联合治疗前后难治性抑郁症静息脑代谢的初步研究。

DOI：
发表时间：
2020
期刊：
影响因子：
3.7
作者：
Pardo, José V;Sheikh, Sohail A;Schwindt, Graeme;Lee, Joel T;Adson, David E;Rittberg, Barry;Abuzzahab Sr, Faruk S
通讯作者：
Abuzzahab Sr, Faruk S

Preliminary studies on apparent mendelian psychotic disorders in consanguineous families.

近亲家庭中明显孟德尔精神障碍的初步研究。