A brain multi-omic approach to identify key molecular drivers of neuropsychiatric symptoms in Alzheimer's dementia

大脑多组学方法识别阿尔茨海默氏痴呆症神经精神症状的关键分子驱动因素

基本信息

批准号：
10611855
负责人：
Aliza Pham Wingo
金额：
$ 100.46万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611855
关键词：
Acceleration Accounting Address Affect Agitation Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Anxiety Autopsy Biological Process Bipolar Disorder Brain Caregiver Burden Caregivers Characteristics Data Delusions Dementia Disease Progression Disinhibition Drug Targeting Environment Future Genes Genetic Genetic Risk Genets Genotype Hallucinations Heritability Human Individual Institutionalization Knowledge Major Depressive Disorder Measures Mediator Medical Mendelian randomization Mental Depression Mental disorders Modeling Molecular Participant Pathogenesis Pathway Analysis Pathway interactions Pharmaceutical Preparations Phenotype Plasma Prefrontal Cortex Proteins Proteome Proteomics Public Health Publishing Role Schizophrenia Signal Transduction Sleep disturbances Testing Therapeutic Studies Transcript Translating United States Work brain tissue causal variant comorbidity differential expression disabling symptom effective therapy experience functional disability genetic variant genome wide association study genome-wide insight mild cognitive impairment mortality multiple omics neuropsychiatric symptom new therapeutic target novel pleiotropism potential biomarker protein expression risk variant side effect therapeutic target transcriptome transcriptomics variant detection

Acceleration Accounting Address Affect Agitation Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Anxiety Autopsy Biological Process Bipolar Disorder Brain Caregiver Burden Caregivers Characteristics Data Delusions Dementia Disease Progression Disinhibition Drug Targeting Environment Future Genes Genetic Genetic Risk Genets Genotype Hallucinations Heritability Human Individual Institutionalization Knowledge Major Depressive Disorder Measures Mediator Medical Mendelian randomization Mental Depression Mental disorders Modeling Molecular Participant Pathogenesis Pathway Analysis Pathway interactions Pharmaceutical Preparations Phenotype Plasma Prefrontal Cortex Proteins Proteome Proteomics Public Health Publishing Role Schizophrenia Signal Transduction Sleep disturbances Testing Therapeutic Studies Transcript Translating United States Work brain tissue causal variant comorbidity differential expression disabling symptom effective therapy experience functional disability genetic variant genome wide association study genome-wide insight mild cognitive impairment mortality multiple omics neuropsychiatric symptom new therapeutic target novel pleiotropism potential biomarker protein expression risk variant side effect therapeutic target transcriptome transcriptomics variant detection

展开

项目摘要

Approximately 65% of individuals with mild cognitive impairment (MCI), Alzheimer's disease (AD), or AD related dementias (ADRD) experience neuropsychiatric symptoms (NPS). These debilitating symptoms include depression, anxiety, apathy, delusions, hallucinations, agitation, sleep disturbances and are associated with faster disease progression, greater functional impairment, higher caregiver burden, and earlier institutionalization. Current treatments for NPS in MCI/dementia have limited efficacy but high rates of adverse side effects, including higher mortality. Therefore, safe and effective treatments for NPS are urgently needed. However, we have limited insights into molecular mechanisms of NPS in MCI/dementia to nominate therapeutic targets. To address this knowledge gap, we aim to elucidate the genetic and molecular mechanisms underlying NPS in MCI/dementia using two complementary but independent approaches. In the first approach, we will leverage the substantial genetic basis of NPS (heritability of ~61%) to identify novel genes involved in NPS. First, we will perform genome-wide association studies (GWAS) of NPS in ~32,000 individuals with MCI/AD/ADRD from across the United States. We will perform a GWAS of each NPS domain as well as a multivariate GWAS of all NPS collectively. Results of each GWAS will be integrated with reference human brain transcriptomic and proteomic profiles to identify individual brain transcripts and proteins that are consistent with being causal in NPS. We have applied these integrative approaches to AD and identified 11 genes that regulate their brain protein abundances to predispose to AD (Wingo et al. 2021, Nat Genet). Unlike GWAS results, these findings point to specific brain proteins that are consistent with a causal role in AD. Importantly, this approach does not solely depend on genome-wide significant signals, and the causal inference of this integrative strategy has been experimentally tested and found to be robust. Thus, we expect that findings from this approach will provide novel insights into the pathogenesis of NPS. Our second approach aims to identify brain transcripts, proteins, and co-expression networks associated with NPS. We will perform transcriptomic and proteomic sequencing of post-mortem brain tissues from 400 individuals with MCI/AD and longitudinal NPS assessment, as existing brain omics data do not have robust NPS measures. Then we will examine NPS domains individually as well as collectively in our differential expression and network analyses. We anticipate that molecular alterations at the brain transcript and protein levels identified with this approach will provide insights into NPS pathogenesis and progression. Studying both transcripts and proteins would provide complementary information and a more complete molecular picture. We view understanding proteins as particularly important since they are the vast majority of drug targets. The proposed project will likely lead to new insights into molecular mechanisms and novel therapeutic targets for NPS and thereby have an important and sustained impact on public health.

大约65％的轻度认知障碍（MCI），阿尔茨海默氏病（AD）或 AD相关的痴呆症（ADRD）经历神经精神症状（NPS）。这些使人衰弱的症状包括抑郁症，焦虑，冷漠，妄想，幻觉，躁动，睡眠障碍，并相关随着疾病进展的速度，功能障碍更大，护理人员负担更高，并且更早制度化。 MCI/痴呆症中NP的当前治疗方法有限，但不良率很高副作用，包括更高的死亡率。因此，迫切需要对NP的安全有效治疗。但是，我们对MCI/痴呆中NP的分子机制的见解有限治疗靶标。为了解决这一知识差距，我们旨在阐明遗传和分子使用两种互补但独立的方法，MCI/痴呆症中NP的机制。在第一种方法中，我们将利用NP的实质遗传基础（约61％）识别NP中涉及的新基因。首先，我们将进行全基因组的关联研究（GWAS）来自美国各地的约32,000名MCI/AD/ADRD的人。我们将执行每个 NPS域以及所有NP的多元GWA。每个GWA的结果将集成参考人脑转录组和蛋白质组学特征，以识别单个脑转录本和与NPS中因果关系一致的蛋白质。我们已经将这些综合方法应用于AD 并确定了11种调节其脑蛋白丰度易感AD的基因（Wingo等，2021， NAT基因）。与GWAS结果不同，这些发现指出了特定的脑蛋白与A 因果关系在AD中的作用。重要的是，这种方法不仅取决于全基因组的重要信号，并且该综合策略的因果推断已经经过实验测试，并被认为是健壮的。因此，我们期望这种方法的发现将为NP的发病机理提供新的见解。我们的第二种方法旨在识别大脑成绩单，蛋白质和共表达网络与NP相关。我们将对验尸后脑组织进行转录组和蛋白质组学测序从400名MCI/AD和纵向NPS评估的人中，由于现有的大脑OMICS数据没有强大的NPS测量。然后，我们将单独检查NPS域表达和网络分析。我们预计在脑转录和蛋白质上会发生分子改变使用这种方法确定的水平将提供有关NPS发病机理和进展的见解。两者都研究转录本和蛋白质将提供互补信息和更完整的分子图片。我们将理解蛋白质视为特别重要，因为它们是绝大多数药物靶标。拟议的项目可能会导致对分子机制和新型治疗的新见解 NPS的目标，因此对公共卫生产生了重要的持续影响。