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. 2025 May 8;23(1):516.
doi: 10.1186/s12967-025-06535-x.

Reproducibility of genetic risk factors identified for long COVID using combinatorial analysis across US and UK patient cohorts with diverse ancestries

J Sardell  1 , M Pearson  1 , K Chocian  1 , S Das  1 , K Taylor  1 , M Strivens  1 , R Gupta  2 , A Rochlin #  3 , S Gardner #  4   5
Affiliations

Reproducibility of genetic risk factors identified for long COVID using combinatorial analysis across US and UK patient cohorts with diverse ancestries

J Sardell et al. J Transl Med. .

Abstract

Background: Long COVID is a major public health burden causing a diverse array of debilitating symptoms in tens of millions of patients globally. In spite of this overwhelming disease prevalence, staggering cost, severe impact on patients' lives and intense global research efforts, study of the disease has proved challenging due to its complexity. Genome-wide association studies (GWAS) have identified only four loci potentially associated with the disease, although these results did not statistically replicate between studies. A previous combinatorial analysis study identified a total of 73 genes that were highly associated with two long COVID cohorts in the predominantly (> 91%) white European ancestry Sano GOLD population, and we sought to reproduce these findings in the independent and ancestrally more diverse All of Us (AoU) population.

Methods: We assessed the reproducibility of the 5343 long COVID disease signatures from the original study in the AoU population. Because the very small population sizes provide very limited power to replicate findings, we initially tested whether we observed a statistically significant enrichment of the Sano GOLD disease signatures that are also positively correlated with long COVID in the AoU cohort after controlling for population substructure.

Results: For the Sano GOLD disease signatures that have a case frequency greater than 5% in AoU, we consistently observed a significant enrichment (77-83%, p < 0.01) of signatures that are also positively associated with long COVID in the AoU cohort. These encompassed 92% of the genes identified in the original study. At least five of the disease signatures found in Sano GOLD were also shown to be individually significantly associated with increased long COVID prevalence in the AoU population. Rates of signature reproducibility are strongest among self-identified white patients, but we also observe significant enrichment of reproducing disease associations in self-identified black/African-American and Hispanic/Latino cohorts. Signatures associated with 11 out of the 13 drug repurposing candidates identified in the original Sano GOLD study were reproduced in this study.

Conclusion: These results demonstrate the reproducibility of long COVID disease signal found by combinatorial analysis, broadly validating the results of the original analysis. They provide compelling evidence for a much broader array of genetic associations with long COVID than previously identified through traditional GWAS studies. This strongly supports the hypothesis that genetic factors play a critical role in determining an individual's susceptibility to long COVID following recovery from acute SARS-CoV-2 infection. It also lends weight to the drug repurposing candidates identified in the original analysis. Together these results may help to stimulate much needed new precision medicine approaches to more effectively diagnose and treat the disease. This is also the first reproduction of long COVID genetic associations across multiple populations with substantially different ancestry distributions. Given the high reproducibility rate across diverse populations, these findings may have broader clinical application and promote better health equity. We hope that this will provide confidence to explore some of these mechanisms and drug targets and help advance research into novel ways to diagnose the disease and accelerate the discovery and selection of better therapeutic options, both in the form of newly discovered drugs and/or the immediate prioritization of coordinated investigations into the efficacy of repurposed drug candidates.

Keywords: Combinatorial analytics; Genetics; Long COVID; PASC; Post COVID-19 condition; Post-acute COVID-19; Reproducibility; SARS-CoV-2.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The Sano GOLD study has approval from the Wales Research Ethics Committee (REC) (IRAS 291221). Consent to participate has been received from all participants. Institutional Reviewing Board (IRB) approval was obtained prior to enrollment of patients in the All of Us Research Program. Informed consent for all participants is conducted in person or through an eConsent platform that includes primary consent, HIPAA Authorization for Research use of EHRs and other external health data, and Consent for Return of Genomic Results. The protocol was reviewed by the Institutional Review Board (IRB) of the All of Us Research Program (IRB Approval Date: Dec 03, 2021). The All of Us IRB follows the regulations and guidance of the NIH Office for Human Research Protections for all studies, ensuring that the rights and welfare of research participants are overseen and protected uniformly. The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers (OT2 OD026549; OT2 OD026554; OT2 OD026557; OT2 OD026556; OT2 OD026550; OT2 OD 026552; OT2 OD026553; OT2 OD026548; OT2 OD026551; OT2 OD026555); Inter agency agreement AOD 16037; Federally Qualified Health Centers HHSN 263201600085U; Data and Research Center: U2 C OD023196; Genome Centers (OT2 OD002748; OT2 OD002750; OT2 OD002751); Biobank: U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: U24 OD023163; Communications and Engagement: OT2 OD023205; OT2 OD023206; and Community Partners (OT2 OD025277; OT2 OD025315; OT2 OD025337; OT2 OD025276). Results reported are in compliance with the All of Us Data and Statistics Dissemination Policy disallowing disclosure of group counts under 20 to protect participant privacy. Competing interest: AR is an employee of the Complex Disorders Alliance, SG and RG are co-chairs of the Complex Disorders Alliance's Scientific Advisory Board. JS, SD, KT, KC, MP and SG are employees of PrecisionLife Ltd. S.G. is a shareholder of PrecisionLife, Ltd.

Figures

Fig. 1
Fig. 1
Study flow and overview reproducing disease signatures identified in the original combinatorial analysis of the Sano GOLD dataset30 in a disjoint and more ancestrally diverse AoU cohort
Fig. 2
Fig. 2
Distribution of observed odds ratios in AoU for reproducing signatures with high case frequencies (> 5%) in the Severe (top), Fatigue Dominant (middle) and General (bottom) cohorts
Fig. 3
Fig. 3
Venn diagram showing overlap of genes identified in three Sano GOLD sub-cohorts (Severe, Fatigue Dominant and General) that were positively correlated with long COVID in AoU
See this image and copyright information in PMC

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