The major genetic risk factor for severe COVID-19 is inherited from Neandertals

Abstract

A recent genetic association study (Ellinghaus et al. 2020) identified a gene cluster on chromosome 3 as a risk locus for respiratory failure in SARS-CoV-2. Recent data comprising 3,199 hospitalized COVID-19 patients and controls reproduce this and find that it is the major genetic risk factor for severe SARS-CoV-2 infection and hospitalization (COVID-19 Host Genetics Initiative). Here, we show that the risk is conferred by a genomic segment of ~50 kb that is inherited from Neandertals and occurs at a frequency of ~30% in south Asia and ~8% in Europe. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.03.186296; this version posted July 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. Main text The coronavirus SARS-CoV-2 pandemic has caused considerable morbidity and mortality, claiming the lives of more than half a million people to date (WHO 2020). The disease caused by the virus, COVID-19, is characterized by a wide spectrum of severity of clinical manifestations, ranging from asymptomatic virus carriers to individuals experiencing rapid progression to respiratory failure (Vetter et al. 2020). Early in the pandemic it became clear that advanced age is a major risk factor, as well as male sex and some co-morbidities (Zhou et al. 2020). These risk factors, however, do not fully explain why some have no or mild symptoms while others become seriously ill. Thus, genetic risk factors are being investigated. An early study (Ellinghaus et al. 2020) identified two genomic regions associated with severe COVID-19: one region on chromosome 3 containing six genes and one region on chromosome 9 that determines the ABO blood group. A recently released dataset from the COVID-19 Host Genetics Initiative finds that the region on chromosome 3 is the only region significantly associated with severe COVID-19 at the genome-wide level (Fig. 1A) while the signal from the region determining ABO-blood group is not replicated (The COVID-19 Host Genetics Initiative 2020). The genetic variants which are associated with severe COVID-19 on chromosome 3 (chr3: 45,859,651-45,909,024, hg19) are all in high linkage disequilibrium (LD), i.e. they are all strongly associated with each other in the population (r 2>0.99), and span 49.4 thousand bases (kb) (Fig. 1B). …