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Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

ABSTRACT: Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

SUBMITTER: Shrine N

PROVIDER: S-EPMC10011137 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Shrine Nick N Izquierdo Abril G AG Chen Jing J Packer Richard R Hall Robert J RJ Guyatt Anna L AL Batini Chiara C Thompson Rebecca J RJ Pavuluri Chandan C Malik Vidhi V Hobbs Brian D BD Moll Matthew M Kim Wonji W Tal-Singer Ruth R Bakke Per P Fawcett Katherine A KA John Catherine C Coley Kayesha K Piga Noemi Nicole NN Pozarickij Alfred A Lin Kuang K Millwood Iona Y IY Chen Zhengming Z Li Liming L Wijnant Sara R A SRA Lahousse Lies L Brusselle Guy G Uitterlinden Andre G AG Manichaikul Ani A Oelsner Elizabeth C EC Rich Stephen S SS Barr R Graham RG Kerr Shona M SM Vitart Veronique V Brown Michael R MR Wielscher Matthias M Imboden Medea M Jeong Ayoung A Bartz Traci M TM Gharib Sina A SA Flexeder Claudia C Karrasch Stefan S Gieger Christian C Peters Annette A Stubbe Beate B Hu Xiaowei X Ortega Victor E VE Meyers Deborah A DA Bleecker Eugene R ER Gabriel Stacey B SB Gupta Namrata N Smith Albert Vernon AV Luan Jian'an J Zhao Jing-Hua JH Hansen Ailin F AF Langhammer Arnulf A Willer Cristen C Bhatta Laxmi L Porteous David D Smith Blair H BH Campbell Archie A Sofer Tamar T Lee Jiwon J Daviglus Martha L ML Yu Bing B Lim Elise E Xu Hanfei H O'Connor George T GT Thareja Gaurav G Albagha Omar M E OME Suhre Karsten K Granell Raquel R Faquih Tariq O TO Hiemstra Pieter S PS Slats Annelies M AM Mullin Benjamin H BH Hui Jennie J James Alan A Beilby John J Patasova Karina K Hysi Pirro P Koskela Jukka T JT Wyss Annah B AB Jin Jianping J Sikdar Sinjini S Lee Mikyeong M May-Wilson Sebastian S Pirastu Nicola N Kentistou Katherine A KA Joshi Peter K PK Timmers Paul R H J PRHJ Williams Alexander T AT Free Robert C RC Wang Xueyang X Morrison John L JL Gilliland Frank D FD Chen Zhanghua Z Wang Carol A CA Foong Rachel E RE Harris Sarah E SE Taylor Adele A Redmond Paul P Cook James P JP Mahajan Anubha A Lind Lars L Palviainen Teemu T Lehtimäki Terho T Raitakari Olli T OT Kaprio Jaakko J Rantanen Taina T Pietiläinen Kirsi H KH Cox Simon R SR Pennell Craig E CE Hall Graham L GL Gauderman W James WJ Brightling Chris C Wilson James F JF Vasankari Tuula T Laitinen Tarja T Salomaa Veikko V Mook-Kanamori Dennis O DO Timpson Nicholas J NJ Zeggini Eleftheria E Dupuis Josée J Hayward Caroline C Brumpton Ben B Langenberg Claudia C Weiss Stefan S Homuth Georg G Schmidt Carsten Oliver CO Probst-Hensch Nicole N Jarvelin Marjo-Riitta MR Morrison Alanna C AC Polasek Ozren O Rudan Igor I Lee Joo-Hyeon JH Sayers Ian I Rawlins Emma L EL Dudbridge Frank F Silverman Edwin K EK Strachan David P DP Walters Robin G RG Morris Andrew P AP London Stephanie J SJ Cho Michael H MH Wain Louise V LV Hall Ian P IP Tobin Martin D MD

Nature genetics 20230313 3

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking ...[more]

PMID: 36914875

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Project description:BackgroundThere is increasing need for effective incorporation of high-dimensional genetics data from individuals with varied ancestry in genome-wide association (GWAS) analyses. Classically, multi-ancestry GWAS analyses are performed using statistical meta-analysis to combine results conducted within homogeneous ancestry groups. The emergence of cosmopolitan reference panels makes collective preprocessing of GWAS data possible, but impact on downstream GWAS results in a mega-analysis framework merits investigation. We utilized GWAS data from the multi-national Hyperglycemia and Adverse Pregnancy Outcome Study to investigate differences in GWAS findings using a homogeneous ancestry meta-analysis versus a heterogeneous ancestry mega-analysis pipeline. Maternal fasting and 1-hr glucose and metabolomics measured during a 2-hr 75-gram oral glucose tolerance test during early third trimester pregnancy were evaluated as phenotypes.ResultsFor the homogeneous ancestry meta-analysis pipeline, variant data were prepared by identifying sets of individuals with similar ancestry and imputing to ancestry-specific reference panels. GWAS was conducted within each ancestry group and results were combined using random-effects meta-analysis. For the heterogeneous ancestry mega-analysis pipeline, data for all individuals were collectively imputed to the Trans-Omics for Precision Medicine (TOPMed) cosmopolitan reference panel, and GWAS was conducted using a unified mega-analysis. The meta-analysis pipeline identified genome-wide significant associations for 15 variants in a region close to GCK on chromosome 7 with maternal fasting glucose and no significant findings for 1-hr glucose. Associations in this same region were identified using the mega-analysis pipeline, along with a well-documented association at MTNR1B on chromosome 11 with both fasting and 1-hr maternal glucose. For metabolomics analyses, the number of significant findings in the heterogeneous ancestry mega-analysis far exceeded those from the homogeneous ancestry meta-analysis and confirmed many previously documented associations, but genomic inflation factors were much more variable.ConclusionsFor multi-ancestry GWAS, heterogeneous ancestry mega-analysis generates a rich set of variants for analysis using a cosmopolitan reference panel and results in vastly more significant, biologically credible and previously documented associations than a homogeneous ancestry meta-analysis approach. Genomic inflation factors do indicate that findings from the mega-analysis pipeline may merit cautious interpretation and further follow-up.

Dataset Information

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Publications

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

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