Around 10% of adults infected with SARS-CoV-2 that survive a first episode of COVID-19 appear to experience long-term clinical manifestations. The signs and symptoms of this post-acute COVID-19 syndrome (PACS) include fatigue, dyspnea, joint pain, myalgia, chest pain, cough, anosmia, dysgeusia, headache, depression, anxiety, memory loss, concentration difficulties, and insomnia. These sequelae remind the constellation of clinical manifestations previously recognized as myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS). This condition has been described following distinct infectious events, mostly acute viral illnesses. In this way, the pathophysiology of PACS might overlap with mechanisms involved in other post-infectious fatigue syndromes. The risk of PACS is more frequent in women than men. Additional host genetic factors could be involved. There is a dysregulation of multiple body organs and systems, involving the immune system, the coagulation cascade, endocrine organs, autonomic nervous system, microbiota-gut-brain axis, hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-thyroid axis, etc. Hypothetically, an abnormal response to certain infectious agents could trigger the development of post-infectious fatigue syndromes.

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.