Genomic Determinants of Long COVID

Abstract

Around 5–10% of adults may experience persistence of symptoms/signs beyond 4 to 12 weeks after acute SARS-CoV-2 infection. According to the World Health Organization, up to 40 million people suffer from Long COVID in Europe and the USA alone. The Centers for Disease Control and Prevention have encouraged the recognition of predictors for Long COVID. Any genetic markers associated to the disease have remained elusive to date. Here we explore the potential contribution of genetic traits to Long COVID. We used a well characterized cohort of 50 individuals with definitive diagnostic criteria for Long COVID from an initial set of patients of more than 1,200 with suspected Long COVID. All were attended at Hospital Puerta de Hierro, a large regional hospital in Madrid, Spain. All subjects had tested positive for SARS-CoV-2 RNA and/or antibodies, showed clinical manifestations for more than 6 months, and developed more than 5 persistent symptoms/signs. Low pass whole genome sequencing was performed in blood specimens for our selected cohort. From hundreds of polygenic risk scores (PRS) recorded at the PGS Catalog, we tested in our selected cohort a total of 12 PRS that passed our filtering criteria. Selected PRS encompassed distinct medical conditions, including cancers, hematologic, cardiovascular, endocrine, immunologic and neurological disorders. The calculated PRS in our patients produced a distribution of scores that was compared to a control ancestry-matched general population. We found significant differences for the PRS of traits ‘Tiredness/lethargy in the last 2 weeks’ and suggestive significance for ‘Depression’ when comparing Long COVID patients and controls. Our results strongly support a genetic susceptibility for Long COVID, with those scoring high in genetic predisposition for ‘tiredness’ as more likely to develop the disease. Results shed new light into the physiopathological basis for Long COVID, contrary to opinions considering it a subjective condition.