Genes for human chronic pain syndromes through whole genome sequencing

通过全基因组测序发现人类慢性疼痛综合征的基因

基本信息

批准号：
8675833
负责人：
Kari Stefansson
金额：
$ 52.67万
依托单位：
DECODE GENETICS, EHF
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-26 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675833
关键词：
Acute Acute Pain Alveolar Behavioral Bicuspid Biological Process Budgets Cardiac Surgery procedures Chronic Craniofacial Pain DNA Microarray Chip Data Databases Development Diabetic Neuropathies Dimensions Disease Association Drops Drug Utilization Etiology Family Frequencies Functional disorder Gene Frequency Genealogy Genes Genetic Genome Genomics Genotype Grant Haplotypes Heart Diseases High Prevalence Human Iceland Individual Injury Knowledge Lead Mastectomy Mechanics Medical Methods Modeling Molecular Neuropathy Online Systems Operative Surgical Procedures Opiates Oral Surgical Procedures Pain Pathway interactions Patients Peripheral Persistent pain Pharmaceutical Preparations Phase Phenotype Population Population Control Postherpetic neuralgia Process Public Health Questionnaires Reaction Recording of previous events Risk Sample Size Somatoform Disorders Syndrome System Temporomandibular Joint Disorders Temporomandibular joint disorder pain Thoracotomy Tissues Tooth Extraction Tooth structure Toothache Trauma Trigeminal Neuralgia Variant addiction base breast surgery case control chronic neuropathic pain chronic pain cohort cost cost effective density disability gabapentin genetic analysis genetic association genetic resource genetic variant genome sequencing genome wide association study high risk malignant breast neoplasm next generation sequencing painful neuropathy population based pregabalin programs risk variant somatosensory trait

项目摘要

DESCRIPTION (provided by applicant): Chronic neuropathic pain syndromes including craniofacial and dental pain syndromes represent large unmet medical needs and are inadequately treated with current drugs. Conversion from acute pain to chronic neuropathic pain syndromes may result from maladaptive changes in the peripheral and central somatosensory system in reaction to the initial tissue injury that caused the acute pain. This project proposes t generate new knowledge on the basic pathophysiology chronic neuropathic pain by determining the genetic differences between patients who develop chronic neuropathic pain after initial tissue injury versus those who do not despite having the same acute tissue injury. We propose here to leverage the unique genetic resources gathered and developed at deCODE Genetics for whole genome sequence-based human pain genetics studies to uncover high risk variants of low frequency significantly associated to conversion from acute to chronic pain. In this project, we propose to extensively re-phenotype large cohorts with chronic neuropathic pain including common forms of craniofacial pain. We already have lists of Icelandic patients who have or are likely to have certain chronic neuropathic pain syndromes totaling over 12,000 patients. We will study large cohorts of phantom tooth pain (persistent dento-alveolar pain (PDAP)), temporomandibular disorder (TMD), and post-mastectomy pain syndrome. We will also screen a large cohort of Icelanders taking gabapentin or pregabalin for common chronic pain syndromes including diabetic neuropathy and post-herpetic neuralgia. The extra phenotyping will give us additional dimensions beyond the basic pain symptomology including quality and intensity on which to condition the genetic analysis. It may also make it easier to replicate our findings in outside pain cohorts that have already been well-phenotyped by our collaborators. We can generate whole genome sequences for large cohorts of pain syndromes and controls in Iceland more quickly and cost-effectively than in other populations. Although costs are dropping rapidly, it is still very expensive to fully sequence the genomes of the thousands of individuals that are required for well-powered disease association studies. We leverage our genealogy database and high density DNA chip data to propagate all genomic variation down to rare allelic frequencies of 0.05% from thousands of fully sequenced Icelanders to over one hundred thousand Icelanders. Using these full sequences and by sequencing the whole-genomes of 150 individuals from families with a high prevalence of either PDAP or TMD, we plan to perform whole-genome association studies of chronic neuropathic pain syndromes with large effective sample sizes, studies that would otherwise be prohibitively costly. We expect to find many new genetic associations that will increase our understanding of conversion from acute to chronic neuropathic pain syndromes. The primary data generated in this grant will be made widely available for others to build on.

描述（由申请人提供）：慢性神经性疼痛综合征，包括颅面和牙齿疼痛综合征，代表着大量未满足的医疗需求，并且目前的药物治疗不足。从急性疼痛向慢性神经性疼痛综合征的转变可能是由于外周和中枢体感系统对引起急性疼痛的初始组织损伤的反应而发生的适应不良变化所致。该项目旨在通过确定在初始组织损伤后发生慢性神经性疼痛的患者与尽管具有相同的急性组织损伤但未发生慢性神经性疼痛的患者之间的遗传差异，产生关于慢性神经性疼痛的基本病理生理学的新知识。我们在此建议利用 deCODE Genetics 收集和开发的独特遗传资源进行基于全基因组序列的人类疼痛遗传学研究，以发现与从急性疼痛转变为慢性疼痛显着相关的低频高风险变异。在这个项目中，我们建议对患有慢性神经性疼痛（包括常见形式的颅面疼痛）的大群体进行广泛的重新表型分析。我们已经拥有患有或可能患有某些慢性神经性疼痛综合征的冰岛患者名单，总计超过 12,000 名患者。我们将研究大量幻牙痛（持续性牙槽痛 (PDAP)）、颞下颌关节紊乱病 (TMD) 和乳房切除术后疼痛综合征。我们还将对大量服用加巴喷丁或普瑞巴林的冰岛人进行筛查，以了解常见的慢性疼痛综合征，包括糖尿病神经病变和带状疱疹后神经痛。额外的表型分析将为我们提供基本疼痛症状学之外的额外维度，包括影响遗传分析的质量和强度。它还可能使我们更容易在外部疼痛队列中复制我们的发现，这些队列已经被我们的合作者很好地表现出来。与其他人群相比，我们可以更快、更经济地为冰岛的大量疼痛综合征和对照生成全基因组序列。尽管成本正在迅速下降，但对强大的疾病关联研究所需的数千人的基因组进行全面测序仍然非常昂贵。我们利用家谱数据库和高密度 DNA 芯片数据，将所有基因组变异传播到 0.05% 的罕见等位基因频率，从数千名完全测序的冰岛人传播到超过 10 万冰岛人。利用这些完整序列，并对来自 PDAP 或 TMD 高患病率家庭的 150 名个体进行全基因组测序，我们计划以大有效样本量进行慢性神经病理性疼痛综合征的全基因组关联研究，否则这些研究将无法进行。成本高昂。我们期望发现许多新的遗传关联，这将增加我们对急性神经病理性疼痛综合征向慢性神经病理性疼痛综合征转化的理解。这笔赠款中生成的主要数据将广泛可供其他人使用。