Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program

Xiaowei Hu; Dandi Qiao; Wonji Kim; Matthew Moll; Pallavi P Balte; Leslie A Lange; Traci M Bartz; Rajesh Kumar; Xingnan Li; Bing Yu; Brian E Cade; Cecelia A Laurie; Tamar Sofer; Ingo Ruczinski; Deborah A Nickerson; Donna M Muzny; Ginger A Metcalf; Harshavardhan Doddapaneni; Stacy Gabriel; Namrata Gupta; Shannon Dugan-Perez; L Adrienne Cupples; Laura R Loehr; Deepti Jain; Jerome I Rotter; James G Wilson; Bruce M Psaty; Myriam Fornage; Alanna C Morrison; Ramachandran S Vasan; George Washko; Stephen S Rich; George T O'Connor; Eugene Bleecker; Robert C Kaplan; Ravi Kalhan; Susan Redline; Sina A Gharib; Deborah Meyers; Victor Ortega; Josée Dupuis; Stephanie J London; Tuuli Lappalainen; Elizabeth C Oelsner; Edwin K Silverman; R Graham Barr; Timothy A Thornton; Heather E Wheeler; TOPMed Lung Working Group; Michael H Cho; Hae Kyung Im; Ani Manichaikul

doi:10.1016/j.ajhg.2022.03.007

Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program

Am J Hum Genet. 2022 May 5;109(5):857-870. doi: 10.1016/j.ajhg.2022.03.007. Epub 2022 Apr 5.

Authors

Xiaowei Hu¹, Dandi Qiao², Wonji Kim², Matthew Moll³, Pallavi P Balte⁴, Leslie A Lange⁵, Traci M Bartz⁶, Rajesh Kumar⁷, Xingnan Li⁸, Bing Yu⁹, Brian E Cade¹⁰, Cecelia A Laurie¹¹, Tamar Sofer¹⁰, Ingo Ruczinski¹², Deborah A Nickerson¹³, Donna M Muzny¹⁴, Ginger A Metcalf¹⁴, Harshavardhan Doddapaneni¹⁴, Stacy Gabriel¹⁵, Namrata Gupta¹⁵, Shannon Dugan-Perez¹⁴, L Adrienne Cupples¹⁶, Laura R Loehr¹⁷, Deepti Jain¹¹, Jerome I Rotter¹⁸, James G Wilson¹⁹, Bruce M Psaty²⁰, Myriam Fornage²¹, Alanna C Morrison⁹, Ramachandran S Vasan²², George Washko²³, Stephen S Rich¹, George T O'Connor²⁴, Eugene Bleecker⁸, Robert C Kaplan²⁵, Ravi Kalhan²⁶, Susan Redline¹⁰, Sina A Gharib²⁷, Deborah Meyers⁸, Victor Ortega²⁸, Josée Dupuis¹⁶, Stephanie J London²⁹, Tuuli Lappalainen³⁰, Elizabeth C Oelsner⁴, Edwin K Silverman³, R Graham Barr⁴, Timothy A Thornton¹¹, Heather E Wheeler³¹; TOPMed Lung Working Group; Michael H Cho³, Hae Kyung Im³², Ani Manichaikul³³

Affiliations

¹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
² Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
³ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁴ Departments of Medicine and Epidemiology, Columbia University Medical Center, New York, NY 10032, USA.
⁵ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO 80045, USA.
⁶ Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
⁷ Division of Allergy and Clinical Immunology, Ann and Robert H. Lurie Children's Hospital, Chicago, IL 60611, USA; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁸ Department of Medicine, University of Arizona, Tucson, AZ 85724, USA.
⁹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
¹⁰ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹¹ Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
¹² Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
¹³ Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
¹⁴ The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁶ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
¹⁷ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
¹⁸ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
¹⁹ Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
²⁰ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA 98101, USA.
²¹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
²² Boston University and the National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA; Department of Preventive Medicine and Epidemiology, School of Medicine and Public Health, Boston University, Boston, MA 02118, USA.
²³ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
²⁴ Pulmonary Center, Boston University, School of Medicine, Boston, MA 02118, USA.
²⁵ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
²⁶ Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
²⁷ Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA 98109, USA.
²⁸ Pulmonary and Critical Care, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.
²⁹ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Durham, NC 27709, USA.
³⁰ New York Genome Center, New York, NY 10013, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA.
³¹ Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA.
³² Section of Genetic Medicine, The University of Chicago, Chicago, IL 60637, USA.
³³ Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: am3xa@virginia.edu.

Abstract

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV₁] and its ratio to forced vital capacity [FEV₁/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV₁ and FEV₁/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10^-16 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.

Keywords: cross-ethnic portability; gene expression; integrative analysis; polygenic transcriptome risk score; pulmonary disease; risk prediction.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Humans
Lung
National Heart, Lung, and Blood Institute (U.S.)
Pulmonary Disease, Chronic Obstructive* / genetics
Risk Factors
Transcriptome*
United States / epidemiology

Abstract

Publication types

MeSH terms

Grants and funding