key: cord-0325655-828s0mtz authors: Zeberg, Hugo; Pääbo, Svante title: The major genetic risk factor for severe COVID-19 is inherited from Neandertals date: 2020-07-03 journal: bioRxiv DOI: 10.1101/2020.07.03.186296 sha: 9578520100307e264cb64642a343d4d37fb3bc39 doc_id: 325655 cord_uid: 828s0mtz 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. 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. 1B) . Four of these variants occur the "Altai" as well as in the Chagyrskaya 8 Neandertals, both of whom come from the Altai Mountains in southern Siberia and are ~120,000 and ~50,000 years old, respectively (Table S1) while none occur in the Denisovan genome. Thus, the risk haplotype is similar to the corresponding genomic region in the Neandertal from Croatia and less similar to the Neandertals from Siberia. We next investigated whether the risk haplotype of 49.4 kb might be inherited by both Neandertals and present-day people from the common ancestors of the two groups that lived in the order of 500,000 years ago (Prüfer et al. 2014 ). The longer a present-day haplotype that shared with Neandertals is, the less likely this is to be the case as recombination in each generations will tend to break up haplotypes into smaller segments. Assuming a generational time of 29 years (Langergraber Figure 2 shows a phylogenetic tree relating such haplotypes found more than 10 times (see Fig. S1 for all haplotypes). We find that all risk haplotypes Arabic numbers indicate bootstrap support (100 replicates). Phylogenies were constructed using maximum-likelihood and the Hasegawa-Kishino-Yano-85 model (Hasegawa et al. 1985) . The tree is rooted with the inferred ancestral sequence of present-day humans from Ensembl (Yates et al. 2020 ). There are no heterozygous positions in this region in the three Neandertal genomes. Figure S1 . A phylogenetic tree estimating the relationships of all haplotypes in 1000 Genomes individuals covering the genomic region of the core Neandertal risk haplotype. Table S1 . Genetic variants in LD (r2>0.99) with rs11385942. Identifying and Interpreting Apparent Neanderthal Ancestryy in African Individuals Genome-wide Association Study of Severe Covid-19 with Respiratory Failure The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic Dating of the human-ape splitting by a molecular clock of mitochondrial DNA Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA Generation times in wild chimpanzees and gorillas suggest earlier divergence times in great ape and human evolution A high-resolution recombination map of the human genome A high-coverage Neandertal genome from Chagyrskaya Cave The complete genome sequence of a Neanderthal from the Altai Mountains A high-coverage Neandertal genome from Vindija Cave in Croatia The date of interbreeding between Neandertals and modern humans Clinical features of covid-19 WHO Coronavirus disease (COVID-2019) situation report 2 Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study We are indebted to the COVID-19 Host Genetics Initiative (HGI) for making the GWAS data available, to the Max Planck Society and the NOMIS Foundation for funding, and to Nordforsk for funding to sequence patients for the COVID-19 HGI.