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

TOPMed Lung Working Group

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

TOPMed Lung Working Group

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English (US)
Pages (from-to)	857-870
Number of pages	14
Journal	American journal of human genetics
Volume	109
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2022.03.007
State	Published - May 5 2022

Funding

We dedicate this manuscript to our co-authors, long-time collaborators, and dear friends Dr. Debbie Ann Nickerson and Dr. L. Adrienne Cupples. Debbie was a pioneer in human genomics and advocate for diversity and inclusion in science and research. Adrienne was committed to excellence in statistical methodology and collaborative consortium-based genomic research, with major contributions to teaching and service in biostatistics. This research was supported by NIH/NHLBI R01 HL131565 (X.H. and A.M.); R01 HL153248 (A.M. and M.H.C.); R01 HL135142, R01 HL137927, R01 HL089856, and R01 HL147148 (M.H.C.); and K01-HL129039 (D.Q.). Study-specific acknowledgments are given in the supplemental information. We gratefully acknowledge the cohorts and participants who provided biological samples and data for TOPMed. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. A full list of authors for the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium is provided at https://www.nhlbiwgs.org/topmed-banner-authorship. In the past three years, E.K.S. and M.H.C. have received institutional grant support from GlaxoSmithKline and Bayer. M.H.C. has received consulting and speaking fees from Illumina and AstraZeneca. B.M.P. serves on the Steering Committee of the Yale Open Data Access project funded by Johnson & Johnson. T.L. is an advisor for Variant Bio, Goldfinch Bio, and GSK. T.L. also has stock in Variant Bio. All other authors have declared no competing interests. In the past three years, E.K.S. and M.H.C. have received institutional grant support from GlaxoSmithKline and Bayer. M.H.C. has received consulting and speaking fees from Illumina and AstraZeneca. B.M.P. serves on the Steering Committee of the Yale Open Data Access project funded by Johnson & Johnson. T.L. is an advisor for Variant Bio, Goldfinch Bio, and GSK. T.L. also has stock in Variant Bio. All other authors have declared no competing interests. We dedicate this manuscript to our co-authors, long-time collaborators, and dear friends Dr. Debbie Ann Nickerson and Dr. L. Adrienne Cupples. Debbie was a pioneer in human genomics and advocate for diversity and inclusion in science and research. Adrienne was committed to excellence in statistical methodology and collaborative consortium-based genomic research, with major contributions to teaching and service in biostatistics. This research was supported by NIH / NHLBI R01 HL131565 (X.H. and A.M.); R01 HL153248 (A.M. and M.H.C.); R01 HL135142 , R01 HL137927 , R01 HL089856 , and R01 HL147148 (M.H.C.); and K01-HL129039 (D.Q.). Study-specific acknowledgments are given in the supplemental information . We gratefully acknowledge the cohorts and participants who provided biological samples and data for TOPMed. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. A full list of authors for the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium is provided at https://www.nhlbiwgs.org/topmed-banner-authorship .

Keywords

cross-ethnic portability
gene expression
integrative analysis
polygenic transcriptome risk score
pulmonary disease
risk prediction

ASJC Scopus subject areas

Genetics
Genetics(clinical)

Access to Document

10.1016/j.ajhg.2022.03.007

Cite this

@article{c7859b86ab9549fa8fc417e8acbb674c,

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2022 American Society of Human Genetics",

year = "2022",

month = may,

day = "5",

doi = "10.1016/j.ajhg.2022.03.007",

language = "English (US)",

volume = "109",

pages = "857--870",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program

AU - TOPMed Lung Working Group

AU - Hu, Xiaowei

AU - Qiao, Dandi

AU - Kim, Wonji

AU - Moll, Matthew

AU - Balte, Pallavi P.

AU - Lange, Leslie A.

AU - Bartz, Traci M.

AU - Kumar, Rajesh

AU - Li, Xingnan

AU - Yu, Bing

AU - Cade, Brian E.

AU - Laurie, Cecelia A.

AU - Sofer, Tamar

AU - Ruczinski, Ingo

AU - Nickerson, Deborah A.

AU - Muzny, Donna M.

AU - Metcalf, Ginger A.

AU - Doddapaneni, Harshavardhan

AU - Gabriel, Stacy

AU - Gupta, Namrata

AU - Dugan-Perez, Shannon

AU - Cupples, L. Adrienne

AU - Loehr, Laura R.

AU - Jain, Deepti

AU - Rotter, Jerome I.

AU - Wilson, James G.

AU - Psaty, Bruce M.

AU - Fornage, Myriam

AU - Morrison, Alanna C.

AU - Vasan, Ramachandran S.

AU - Washko, George

AU - Rich, Stephen S.

AU - O'Connor, George T.

AU - Bleecker, Eugene

AU - Kaplan, Robert C.

AU - Kalhan, Ravi

AU - Redline, Susan

AU - Gharib, Sina A.

AU - Meyers, Deborah

AU - Ortega, Victor

AU - Dupuis, Josée

AU - London, Stephanie J.

AU - Lappalainen, Tuuli

AU - Oelsner, Elizabeth C.

AU - Silverman, Edwin K.

AU - Barr, R. Graham

AU - Thornton, Timothy A.

AU - Wheeler, Heather E.

AU - Cho, Michael H.

AU - Im, Hae Kyung

PY - 2022/5/5

Y1 - 2022/5/5

N2 - 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.

AB - 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.

KW - cross-ethnic portability

KW - gene expression

KW - integrative analysis

KW - polygenic transcriptome risk score

KW - pulmonary disease

KW - risk prediction

UR - http://www.scopus.com/inward/record.url?scp=85129668045&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85129668045&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2022.03.007

DO - 10.1016/j.ajhg.2022.03.007

M3 - Article

C2 - 35385699

AN - SCOPUS:85129668045

SN - 0002-9297

VL - 109

SP - 857

EP - 870

JO - American journal of human genetics

JF - American journal of human genetics

IS - 5

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this