Air-pollution risk for Autism and ADHD - cross-disorder insights and genetic liability
自闭症和多动症的空气污染风险——跨疾病洞察和遗传责任
基本信息
- 批准号:10090141
- 负责人:
- 金额:$ 2.85万
- 依托单位:
- 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:2020-08-01 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAir PollutantsAir PollutionAttention Deficit DisorderAttention deficit hyperactivity disorderBiologicalBiologyChemical ExposureChildDataDenmarkDevelopmentDevelopmental DisabilitiesDiagnosisDiseaseEmotionalEmploymentEnvironmentEnvironmental ImpactEtiologyExposure toFinancial HardshipGenesGeneticGenetic MarkersGenetic VariationGenotypeHeritabilityHumanInvestigationKnowledgeLocationModificationNervous system structureNeurodevelopmental DisorderNitrogen DioxideParticulate MatterPathogenicityPathway interactionsPhenotypePlayPopulation StudyPreventionPrimary PreventionPublic HealthRiskRisk AssessmentRisk FactorsRoleSourceSpecificitySubgroupWorkautism spectrum disorderautistic childrencritical developmental perioddisabilitydisorder preventionenvironmental chemicalenvironmental chemical exposurefamily geneticsfine particlesgenome-wideimprovedinnovationinsightmodifiable riskneurodevelopmentneurotoxicitynoveltraffic-related air pollution
项目摘要
ABSTRACT
Neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity
Disorder (ADHD) are a major source of disability and loss of potential, as well as emotional and financial
hardship. Primary prevention of these disorders is of great public health importance, calling for the
identification of modifiable risk factors, such as environmental chemical exposures. ASD and ADHD are both
heritable but there is growing evidence that environment plays a role, and that environmental impact may be
influenced by genetics. Traffic-related air pollutants, including fine particulate matter (PM2.5) and nitrogen
dioxide (NO2) have biological evidence of neurotoxicity and human evidence that they may be risk factors for
ASD and ADHD. Only two prior studies have considered the influence of genetics on air pollutant risk in
neurodevelopmental disorders – each addressing a single gene – despite the fact that gene*environment
investigation can improve ability to detect the impact of environmental chemicals and add pathophysiological
insights. Prior studies are also limited in failing to consider co-diagnosis of ASD and ADHD, which is common,
and other sub-phenotypes that may better reflect etiologically homogenous groups impacted by air pollutant
exposure. The objective of this application is to conduct the largest single study of air pollutants with ASD
and ADHD to date, in the context of genetic variation. The central hypotheses are that higher exposure
during critical developmental windows to PM2.5 and NO2 will be associated with ASD and ADHD, the
associations will be influenced by genetic factors, and will vary according to neurodevelopmental sub-
phenotype. Our aims are: SA1: Deepen the mechanistic understanding of air pollutant risk on ASD, SA2:
Clarify a potential role of air pollutant risk in ADHD, and SA3: Investigate the specificity of
neurodevelopmental phenotypic subgroup associations with air pollutants, leading to cross-disorder
insights. For each aim, we will (A) estimate air pollutant main effects, (B) account for child and family genetic
modification of air pollution effects using a multi-faceted targeted approach among hundreds of loci, including
genes related to exposure biology and neurodevelopment, and (C) estimate these associations in an
exploratory genome-wide agnostic analysis using all available genetic markers. We will use a large,
population-based study in Denmark with existing genome-wide genotyping data – iPSYCH, including 16,146
children with ASD, 18,726 with ADHD (3033 with both), and 28,768 controls. We will add innovative well-
validated weekly estimates of PM2.5 and NO2 air pollution exposures during critical developmental periods at
both residential and employment locations. This work introduces key innovations including incorporation of
novel genetic markers in exposure risk assessment and considering neurodevelopmental sub-phenotypes. It
is significant in addressing modifiable causes of developmental disabilities, leading to elucidation of
pathogenic mechanisms and specificity of effects, accelerating discovery for prevention and treatment.
摘要
神经发育障碍,如自闭症谱系障碍(ASD)和注意缺陷多动障碍
注意力缺陷多动障碍(ADHD)是残疾和丧失潜力的主要来源,也是情感和经济损失的主要来源
艰苦创业这些疾病的初级预防具有重大的公共卫生重要性,呼吁
确定可改变的风险因素,如环境化学品暴露。ASD和ADHD都是
遗传,但越来越多的证据表明,环境发挥作用,环境影响可能是
受基因影响。与空气污染物有关的空气污染物,包括细颗粒物(PM2.5)和氮
二氧化物(NO2)有神经毒性的生物学证据和人类证据表明,它们可能是
ASD和ADHD。只有两项先前的研究考虑了遗传对空气污染风险的影响,
神经发育障碍-每一个解决一个单一的基因-尽管事实上,
调查可以提高检测环境化学品影响的能力,
见解.先前的研究也局限于未能考虑ASD和ADHD的共同诊断,这是常见的,
以及其他可能更好地反映受空气污染物影响的病因同质群体的亚表型
exposure.这项申请的目的是进行最大的单一研究的空气污染物与ASD
和多动症的基因变异。核心假设是,
在PM2.5和NO2的关键发育窗口期间,
关联将受到遗传因素的影响,并将根据神经发育亚组而变化。
表型我们的目标是:SA 1:加深对ASD的空气污染物风险的机制理解,SA 2:
阐明空气污染物风险在ADHD中的潜在作用,SA 3:调查
神经发育表型亚组与空气污染物相关,导致交叉障碍
见解.对于每个目标,我们将(A)估计空气污染物的主要影响,(B)考虑儿童和家庭遗传因素,
在数百个地点采用多方面的有针对性的方法来改变空气污染的影响,包括
与暴露生物学和神经发育相关的基因,以及(C)估计这些关联,
使用所有可用的遗传标记进行探索性全基因组不可知分析。我们将使用一个大的,
一项在丹麦进行的基于人群的研究,使用现有的全基因组基因分型数据- iPSYCH,包括16,146例
ASD儿童,18,726名ADHD儿童(3033名两者都有)和28,768名对照组。我们将增加创新的井-
关键发展时期PM2.5和NO2空气污染暴露的每周有效估计值,
包括居住和工作地点。这项工作介绍了关键的创新,包括纳入
新的遗传标记在暴露风险评估和考虑神经发育亚表型。它
在解决发育障碍的可改变原因方面具有重要意义,从而阐明了
致病机制和特异性的影响,加速发现预防和治疗。
项目成果
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