Genome-Wide Pleiotropy Study Identifies Association of PDGFB with Age-Related Macular Degeneration and COVID-19 Infection Outcomes

Jaeyoon Chung; Viha Vig; Xinyu Sun; Xudong Han; George T O'Connor; Xuejing Chen; Margaret M DeAngelis; Lindsay A Farrer; Manju L Subramanian

doi:10.3390/jcm12010109

Genome-Wide Pleiotropy Study Identifies Association of PDGFB with Age-Related Macular Degeneration and COVID-19 Infection Outcomes

J Clin Med. 2022 Dec 23;12(1):109. doi: 10.3390/jcm12010109.

Authors

Jaeyoon Chung¹, Viha Vig², Xinyu Sun¹, Xudong Han¹, George T O'Connor³, Xuejing Chen², Margaret M DeAngelis^{4

5}, Lindsay A Farrer^{1

2

6

7}, Manju L Subramanian²

Affiliations

¹ Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.
² Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.
³ Department of Medicine (Pulmonary & Critical Care), Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.
⁴ Department of Population Health Sciences and Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
⁵ Department of Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo and VA Research Service, Veterans Affairs Western New York Healthcare System, Buffalo, NY 14203, USA.
⁶ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.
⁷ Departments of Epidemiology and Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.

Abstract

Age-related macular degeneration (AMD) has been implicated as a risk factor for severe consequences from COVID-19. We evaluated the genetic architecture shared between AMD and COVID-19 (critical illness, hospitalization, and infections) using analyses of genetic correlations and pleiotropy (i.e., cross-phenotype meta-analysis) of AMD (n = 33,976) and COVID-19 (n ≥ 1,388,342) and subsequent analyses including expression quantitative trait locus (eQTL), differential gene expression, and Mendelian randomization (MR). We observed a significant genetic correlation between AMD and COVID-19 infection (r_G = 0.10, p = 0.02) and identified novel genome-wide significant associations near PDGFB (best SNP: rs130651; p = 2.4 × 10^-8) in the pleiotropy analysis of the two diseases. The disease-risk allele of rs130651 was significantly associated with increased gene expression levels of PDGFB in multiple tissues (best eQTL p = 1.8 × 10^-11 in whole blood) and immune cells (best eQTL p = 7.1 × 10^-20 in T-cells). PDGFB expression was observed to be higher in AMD cases than AMD controls {fold change (FC) = 1.02; p = 0.067}, as well as in the peak COVID-19 symptom stage (11-20 days after the symptom onset) compared to early/progressive stage (0-10 days) among COVID-19 patients over age 40 (FC = 2.17; p = 0.03) and age 50 (FC = 2.15; p = 0.04). Our MR analysis found that the liability of AMD risk derived from complement system dysfunction {OR (95% CI); hospitalization = 1.02 (1.01-1.03), infection = 1.02 (1.01-1.03) and increased levels of serum cytokine PDGF-BB {β (95% CI); critical illness = 0.07 (0.02-0.11)} are significantly associated with COVID-19 outcomes. Our study demonstrated that the liability of AMD is associated with an increased risk of COVID-19, and PDGFB may be responsible for the severe COVID-19 outcomes among AMD patients.

Keywords: AMD; COVID-19; GWAS; Mendelian randomization; PDGFB.

Grants and funding

J.C., X.H. and L.A.F. were supported in this work by National Institutes of Health grants RF1 AG057519, R01 AG069453, R01 AG048927, U19 AG068753, and U01 AG062602.