Genome-wide association study of long COVID

Vilma Lammi; Tomoko Nakanishi; Samuel E Jones; Shea J Andrews; Juha Karjalainen; Beatriz Cortés; Heath E O'Brien; Ana Ochoa-Guzman; Brian E Fulton-Howard; Martin Broberg; Hele H Haapaniemi; Masahiro Kanai; Matti Pirinen; Axel Schmidt; Ruth E Mitchell; Abdou Mousas; Massimo Mangino; Alicia Huerta-Chagoya; Nasa Sinnott-Armstrong; Elizabeth T Cirulli; Marc Vaudel; Alex S F Kwong; Amit K Maiti; Minttu M Marttila; Daniel C Posner; Alexis A Rodriguez; Chiara Batini; Francesca Minnai; Anna R Dearman; C A Robert Warmerdam; Celia B Sequeros; Thomas W Winkler; Daniel M Jordan; Raimonds Rešcenko; Lorenzo Miano; Jacqueline M Lane; Ryan K Chung; Beatriz Guillen-Guio; Olivia C Leavy; Laura Carvajal-Silva; Kevin Aguilar-Valdés; Erika Frangione; Lindsay Guare; Ekaterina Vergasova; Eirini Marouli; Pasquale Striano; Ummu Afeera Zainulabid; Ashutosh Kumar; Hajar Fauzan Ahmad; Ole B V Pedersen; Hugo Zeberg; Hanna M Ollila; Long COVID Host Genetics Initiative

doi:10.1038/s41588-025-02100-w

Genome-wide association study of long COVID

Vilma Lammi
, Tomoko Nakanishi
, Samuel E Jones
, Shea J Andrews
, Juha Karjalainen
, Beatriz Cortés
, Heath E O'Brien
, Ana Ochoa-Guzman
, Brian E Fulton-Howard
, Martin Broberg
, Hele H Haapaniemi
, Masahiro Kanai
, Matti Pirinen
, Axel Schmidt
, Ruth E Mitchell
, Abdou Mousas
, Massimo Mangino
, Alicia Huerta-Chagoya
, Nasa Sinnott-Armstrong
, Elizabeth T Cirulli

Marc Vaudel, Alex S F Kwong, Amit K Maiti, Minttu M Marttila, Daniel C Posner, Alexis A Rodriguez, Chiara Batini, Francesca Minnai, Anna R Dearman, C A Robert Warmerdam, Celia B Sequeros, Thomas W Winkler, Daniel M Jordan, Raimonds Rešcenko, Lorenzo Miano, Jacqueline M Lane, Ryan K Chung, Beatriz Guillen-Guio, Olivia C Leavy, Laura Carvajal-Silva, Kevin Aguilar-Valdés, Erika Frangione, Lindsay Guare, Ekaterina Vergasova, Eirini Marouli, Pasquale Striano, Ummu Afeera Zainulabid, Ashutosh Kumar, Hajar Fauzan Ahmad, Ole B V Pedersen, Hugo Zeberg^*, Hanna M Ollila^*, Long COVID Host Genetics Initiative

^*Corresponding author for this work

Clinical Immunology

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

Abstract

Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association of FOXP4 with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4's role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.

Original language	English
Pages (from-to)	1402-1417
Number of pages	16
Journal	Nature Genetics
Volume	57
Issue number	6
Early online date	21 May 2025
DOIs	https://doi.org/10.1038/s41588-025-02100-w
Publication status	Published - Jun 2025

Funding

Funders
Academy of Finland
National Institutes of Health
European Union (HORIZON Europe SERENA project)

Keywords

Genetic Predisposition to Disease
Genome-Wide Association Study
Pandemics
Humans
Middle Aged
Male
Forkhead Transcription Factors/genetics
Case-Control Studies
SARS-CoV-2
Pneumonia, Viral/genetics
COVID-19/genetics
Female
Polymorphism, Single Nucleotide
Post-Acute COVID-19 Syndrome
Metaanalysis
Expression
Foxp4
Pulmonary

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10.1038/s41588-025-02100-w

Cite this

Lammi, V., Nakanishi, T., Jones, S. E., Andrews, S. J., Karjalainen, J., Cortés, B., O'Brien, H. E., Ochoa-Guzman, A., Fulton-Howard, B. E., Broberg, M., Haapaniemi, H. H., Kanai, M., Pirinen, M., Schmidt, A., Mitchell, R. E., Mousas, A., Mangino, M., Huerta-Chagoya, A., Sinnott-Armstrong, N., ... Long COVID Host Genetics Initiative (2025). Genome-wide association study of long COVID. Nature Genetics, 57(6), 1402-1417. https://doi.org/10.1038/s41588-025-02100-w

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abstract = "Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association of FOXP4 with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4's role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.",

keywords = "Genetic Predisposition to Disease, Genome-Wide Association Study, Pandemics, Humans, Middle Aged, Male, Forkhead Transcription Factors/genetics, Case-Control Studies, SARS-CoV-2, Pneumonia, Viral/genetics, COVID-19/genetics, Female, Polymorphism, Single Nucleotide, Post-Acute COVID-19 Syndrome, Metaanalysis, Expression, Foxp4, Pulmonary",

author = "Vilma Lammi and Tomoko Nakanishi and Jones, \{Samuel E\} and Andrews, \{Shea J\} and Juha Karjalainen and Beatriz Cort{\'e}s and O'Brien, \{Heath E\} and Ana Ochoa-Guzman and Fulton-Howard, \{Brian E\} and Martin Broberg and Haapaniemi, \{Hele H\} and Masahiro Kanai and Matti Pirinen and Axel Schmidt and Mitchell, \{Ruth E\} and Abdou Mousas and Massimo Mangino and Alicia Huerta-Chagoya and Nasa Sinnott-Armstrong and Cirulli, \{Elizabeth T\} and Marc Vaudel and Kwong, \{Alex S F\} and Maiti, \{Amit K\} and Marttila, \{Minttu M\} and Posner, \{Daniel C\} and Rodriguez, \{Alexis A\} and Chiara Batini and Francesca Minnai and Dearman, \{Anna R\} and Warmerdam, \{C A Robert\} and Sequeros, \{Celia B\} and Winkler, \{Thomas W\} and Jordan, \{Daniel M\} and Raimonds Re{\v s}cenko and Lorenzo Miano and Lane, \{Jacqueline M\} and Chung, \{Ryan K\} and Beatriz Guillen-Guio and Leavy, \{Olivia C\} and Laura Carvajal-Silva and Kevin Aguilar-Vald{\'e}s and Erika Frangione and Lindsay Guare and Ekaterina Vergasova and Eirini Marouli and Pasquale Striano and Zainulabid, \{Ummu Afeera\} and Ashutosh Kumar and Ahmad, \{Hajar Fauzan\} and Pedersen, \{Ole B V\} and Hugo Zeberg and Ollila, \{Hanna M\} and \{Long COVID Host Genetics Initiative\}",

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year = "2025",

month = jun,

doi = "10.1038/s41588-025-02100-w",

language = "English",

volume = "57",

pages = "1402--1417",

journal = "Nature Genetics",

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Lammi, V, Nakanishi, T, Jones, SE, Andrews, SJ, Karjalainen, J, Cortés, B, O'Brien, HE, Ochoa-Guzman, A, Fulton-Howard, BE, Broberg, M, Haapaniemi, HH, Kanai, M, Pirinen, M, Schmidt, A, Mitchell, RE, Mousas, A, Mangino, M, Huerta-Chagoya, A, Sinnott-Armstrong, N, Cirulli, ET, Vaudel, M, Kwong, ASF, Maiti, AK, Marttila, MM, Posner, DC, Rodriguez, AA, Batini, C, Minnai, F, Dearman, AR, Warmerdam, CAR, Sequeros, CB, Winkler, TW, Jordan, DM, Rešcenko, R, Miano, L, Lane, JM, Chung, RK, Guillen-Guio, B, Leavy, OC, Carvajal-Silva, L, Aguilar-Valdés, K, Frangione, E, Guare, L, Vergasova, E, Marouli, E, Striano, P, Zainulabid, UA, Kumar, A, Ahmad, HF, Pedersen, OBV, Zeberg, H, Ollila, HM & Long COVID Host Genetics Initiative 2025, 'Genome-wide association study of long COVID', Nature Genetics, vol. 57, no. 6, pp. 1402-1417. https://doi.org/10.1038/s41588-025-02100-w

TY - JOUR

T1 - Genome-wide association study of long COVID

AU - Lammi, Vilma

AU - Nakanishi, Tomoko

AU - Jones, Samuel E

AU - Andrews, Shea J

AU - Karjalainen, Juha

AU - Cortés, Beatriz

AU - O'Brien, Heath E

AU - Ochoa-Guzman, Ana

AU - Fulton-Howard, Brian E

AU - Broberg, Martin

AU - Haapaniemi, Hele H

AU - Kanai, Masahiro

AU - Pirinen, Matti

AU - Schmidt, Axel

AU - Mitchell, Ruth E

AU - Mousas, Abdou

AU - Mangino, Massimo

AU - Huerta-Chagoya, Alicia

AU - Sinnott-Armstrong, Nasa

AU - Cirulli, Elizabeth T

AU - Vaudel, Marc

AU - Kwong, Alex S F

AU - Maiti, Amit K

AU - Marttila, Minttu M

AU - Posner, Daniel C

AU - Rodriguez, Alexis A

AU - Batini, Chiara

AU - Minnai, Francesca

AU - Dearman, Anna R

AU - Warmerdam, C A Robert

AU - Sequeros, Celia B

AU - Winkler, Thomas W

AU - Jordan, Daniel M

AU - Rešcenko, Raimonds

AU - Miano, Lorenzo

AU - Lane, Jacqueline M

AU - Chung, Ryan K

AU - Guillen-Guio, Beatriz

AU - Leavy, Olivia C

AU - Carvajal-Silva, Laura

AU - Aguilar-Valdés, Kevin

AU - Frangione, Erika

AU - Guare, Lindsay

AU - Vergasova, Ekaterina

AU - Marouli, Eirini

AU - Striano, Pasquale

AU - Zainulabid, Ummu Afeera

AU - Kumar, Ashutosh

AU - Ahmad, Hajar Fauzan

AU - Pedersen, Ole B V

AU - Zeberg, Hugo

AU - Ollila, Hanna M

AU - Long COVID Host Genetics Initiative

PY - 2025/6

Y1 - 2025/6

N2 - Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association of FOXP4 with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4's role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.

AB - Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association of FOXP4 with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4's role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Pandemics

KW - Humans

KW - Middle Aged

KW - Male

KW - Forkhead Transcription Factors/genetics

KW - Case-Control Studies

KW - SARS-CoV-2

KW - Pneumonia, Viral/genetics

KW - COVID-19/genetics

KW - Female

KW - Polymorphism, Single Nucleotide

KW - Post-Acute COVID-19 Syndrome

KW - Metaanalysis

KW - Expression

KW - Foxp4

KW - Pulmonary

U2 - 10.1038/s41588-025-02100-w

DO - 10.1038/s41588-025-02100-w

M3 - Article

C2 - 40399555

SN - 1061-4036

VL - 57

SP - 1402

EP - 1417

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Genome-wide association study of long COVID

Abstract

Funding

Keywords

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