Tick-borne encephalitis (TBE) is a viral infection of the central nervous system, caused by the tick-borne encephalitis virus (TBEV) presenting clinically as meningitis, meningoencephalitis, and meningoencephalomyelitis. To investigate genetic susceptibility to TBE, and its severe forms, we conducted a genome-wide association study in the European population comprising 1,600 TBE cases and 9,699 controls. We identified several suggestive (p < 1 × 10-5) intronic and exonic variants in ABCG1, the only gene significantly associated with TBE susceptibility. These variants were shown to influence ABCG1 expression in peripheral blood, a finding corroborated by RNA expression analysis. In vitro inhibition or silencing of ABCG1 significantly reduced TBEV replication in both neuronal cells and macrophages, highlighting the potential role of ABCG1 in TBEV biology. Additionally, we detected a genome-wide significant variant within TEX41, located downstream of ZEB1, associated with severe forms of TBE. These findings provide novel insights into the genetic factors underlying TBE susceptibility and severity.

Center for Virology Medical University of Vienna Wien Austria

Core Facility Molecular Biology Center for Medical Research Medical University of Graz Graz Austria

Department of Children's Infectious Diseases Faculty of Medicine and University Hospital Brno Czech Republic

Department of Infection Biology Faculty of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine London UK

Department of Infectious Diseases and Neuroinfections Medical University of Białystok Białystok Poland

Department of Infectious Diseases and Travellers Medicine Medical Faculty Plzeň Charles University Prague Czech Republic

Department of Infectious Diseases Faculty of Medicine Masaryk University Brno and University Hospital Brno Brno Czech Republic

Department of Infectious Diseases Lithuanian University of Health Sciences Kaunas Lithuania

Department of Infectious Diseases University Medical Center Ljubljana Ljubljana Slovenia

Department of Internal Medicine Division of Endocrinology and Diabetology Medical University of Graz Graz Austria

Department of Neurology Medical University of Graz Graz Austria

Department of Paediatrics Children's Clinical University Hospital Rīgas Stradiņa Universitāte Riga Latvia

Department of Pediatrics and Adolescent Medicine Division of General Pediatrics Medical University of Graz Graz Austria

Estonian Genome Centre Institute of Genomics University of Tartu Tartu Estonia

Faculty of Science Masaryk University Brno Czech Republic

GSK Stevenage UK

Hospital Ceske Budejovice Ceske Budejovice Czech Republic

Infectious Diseases and Prevention Medicine Department Veterinary Research Institute Brno Czech Republic

Institute for Medical Informatics Statistics and Documentation Medical University of Graz Graz Austria

Institute of Human Genetics University of Bonn Bonn Germany

Institute of Parasitology Biology Centre of the Czech Academy of Sciences České Budějovice Czech Republic

Royal Liverpool University Hospital Liverpool UK

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