Pulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis.
Mi Kyeong LeeTianxiao HuanDaniel L McCartneyGeetha ChittoorMaaike M De VriesLies LahousseJennifer N NguyenJennifer A BrodyJuan E Castillo-FernandezNatalie TerzikhanCancan QiRoby JoehanesJosine L MinGordon J SmilnakJessica R ShawChen Xi YangElena ColicinoThanh T HoangMairead L BerminghamHanfei XuAnne E JusticeCheng-Jian XuStephen S RichSimon R CoxJudith M VonkIvana ProkicNona SotoodehniaPei-Chien TsaiJoel D SchwartzJanice M LeungSinjini SikdarRosie M WalkerSarah E HarrisDiana A van der PlaatDavid Van Den BergTraci M BartzTim D SpectorPantel S VokonasRiccardo E MarioniAdele M TaylorYongmei LiuR Graham BarrLeslie A LangeAndrea A BaccarelliMa'en ObeidatMyriam FornageTianyuan WangJames M WardAllison A Motsinger-ReifGibran HemaniGerard H KoppelmannJordana T BellSina A GharibGuy BrusselleH Marike BoezenKari E NorthDaniel LevyKathryn L EvansJosée DupuisCharles E BreezeAni W ManichaikulStephanie J LondonPublished in: American journal of respiratory and critical care medicine (2022)
Rationale: Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication. Objectives: To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function. Methods: Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina 450K or EPIC/850K arrays, with FEV 1 , FVC, and FEV 1 /FVC. We performed multiancestry epigenome-wide meta-analyses (total of 17,503 individuals; 14,761 European, 2,549 African, and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics. Measurements and Main Results: We identified 1,267 CpGs (1,042 genes) differentially methylated (false discovery rate, <0.025) in relation to FEV 1 , FVC, or FEV 1 /FVC, including 1,240 novel and 73 also related to chronic obstructive pulmonary disease (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that epigenome-wide association study signals capture causal regulatory genomic loci. Conclusions: We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies, providing insights into lung pathogenesis.
Keyphrases
- genome wide
- dna methylation
- meta analyses
- gene expression
- copy number
- systematic review
- lung function
- chronic obstructive pulmonary disease
- small molecule
- case control
- genome wide association
- randomized controlled trial
- transcription factor
- cystic fibrosis
- high throughput
- air pollution
- healthcare
- african american
- clinical trial
- study protocol
- fluorescence imaging
- dna damage
- gestational age
- risk assessment
- pregnancy outcomes