COVID-19 genetic risk and Neanderthals: A case study highlighting the importance of scrutinizing diversity

Abstract

13 14 Recent genome wide association studies (GWAS) have identified genetic risk factors 15 for developing severe COVID-19 symptoms. The first published study reported a 1bp 16 insertion rs11385942 on chromosome 3 (1) and subsequent studies single nucleotide 17 variants (SNVs) such as rs35044562, rs67959919 (2) and rs13078854 (3), all highly 18 correlated with each other. Zeberg and Pääbo (4) subsequently traced them back to 19 Neanderthal origin. They found that a 49.4 kb genomic region including the risk allele 20 of rs35044562 is inherited from Neanderthals of Vindija in Croatia. Here we add a 21 differently focused evaluation of this major genetic risk factor to these recent analyses. 22 We show that (i) COVID-19-related genetic factors of three previously assessed 23 Neanderthals deviate from those of modern humans and that (ii) they differ among 24 world-wide human populations, which compromises risk prediction in non-Europeans. 25 Currently, caution is thus advised in the genetic risk assessment of non-Europeans 26 during this world-wide COVID-19 pandemic. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.02.365551; this version posted November 20, 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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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-NC-ND 4.0 International license. 27 Main 28 29 In general, GWAS relate genotypes to phenotypes such as disease susceptibility and 30 severity. However, association does not imply causality. To pinpoint causal variant(s) 31 underlying a GWAS association signal which typically comprises many correlated 32 variants, a so-called fine-mapping is performed in a first step. And ultimately, fine- 33 mapping must be followed by experimental validation to eventually identify causal 34 variant(s) and mechanisms. While GWAS are based on cohort data, a personal risk 35 can be assessed nonetheless, via associated variants as proxies for causal variants. 36 For this, the cohort’s genetic linkage patterns need to be representative of the 37 individuum’s genetic background. This requirement, however, is often violated, 38 especially for individuals having non-European ancestry. In a world-wide COVID-19 39 pandemic this might jeopardize individual genetic risk prediction and requires current 40 risk factors to be used with caution as we show below. …