
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.25.24312558
preprint
1
Article
Multi-trait and multi-ancestry genetic analysis of comorbid lung diseases and traits improves genetic discovery and polygenic risk prediction
He Yixuan http://orcid.org/0000-0003-4033-6513

Lu Wenhan http://orcid.org/0000-0002-3048-9658

Jee Yon Ho http://orcid.org/0000-0003-4686-2186

Wang Ying
Tsuo Kristin
Qian David C http://orcid.org/0000-0002-8459-009X

Diao James A http://orcid.org/0000-0002-6134-4339

Huang Hailiang http://orcid.org/0000-0003-1461-5762

Patel Chirag J http://orcid.org/0000-0002-8756-8525

Byun Jinyoung
Pasaniuc Bogdan
Atkinson Elizabeth G. http://orcid.org/0000-0002-6308-776X

Amos Christopher I. http://orcid.org/0000-0002-8540-7023

Moll Matthew http://orcid.org/0000-0002-0683-0975

Cho Michael H. http://orcid.org/0000-0002-4907-1657

Martin Alicia R. http://orcid.org/0000-0003-0241-3522

26 8 2024
2024.08.25.24312558https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.08.25.24312558
nihpp-2024.08.25.24312558.pdf
Abstract

While respiratory diseases such as COPD and asthma share many risk factors, most studies investigate them in insolation and in predominantly European ancestry populations. Here, we conducted the most powerful multi-trait and -ancestry genetic analysis of respiratory diseases and auxiliary traits to date. Our approach improves the power of genetic discovery across traits and ancestries, identifying 44 novel loci associated with lung function in individuals of East Asian ancestry. Using these results, we developed PRSxtra (cross TRait and Ancestry), a multi-trait and -ancestry polygenic risk score approach that leverages shared components of heritable risk via pleiotropic effects. PRSxtra significantly improved the prediction of asthma, COPD, and lung cancer compared to trait- and ancestry-matched PRS in a multi-ancestry cohort from the All of Us Research Program, especially in diverse populations. PRSxtra identified individuals in the top decile with over four-fold odds of asthma and COPD compared to the first decile. Our results present a new framework for multi-trait and -ancestry studies of respiratory diseases to improve genetic discovery and polygenic prediction.
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