No evidence that ACE2 or TMPRSS2 drive population disparity in COVID risks

Abstract

Early in the SARS-CoV2 pandemic, in this journal, Hou et al. (BMC Med 18:216, 2020) interpreted public genotype data, run through functional prediction tools, as suggesting that members of particular human populations carry potentially COVID-risk-increasing variants in genes ACE2 and TMPRSS2 far more often than do members of other populations. Beyond resting on predictions rather than clinical outcomes, and focusing on variants too rare to typify population members even jointly, their claim mistook a well known artifact (that large samples reveal more of a population's variants than do small samples) as if showing real and congruent population differences for the two genes, rather than lopsided population sampling in their shared source data. We explain that artifact, and contrast it with empirical findings, now ample, that other loci shape personal COVID risks far more significantly than do ACE2 and TMPRSS2-and that variation in ACE2 and TMPRSS2 per se unlikely exacerbates any net population disparity in the effects of such more risk-informative loci.

Keywords: ACE2; TMPRSS2; COVID; COVID19; Functional prediction; GWAS; Host genetics; Human genes; Immunity; Infection; Polygenic risk; Population genetics; Population structure; Rare variants; SARS-CoV2; Sample design; Sample size; Sampling.

Fig. 1

Population-specific variant tallies in Hou et al. [6] reflect lopsided sampling. Scatterplots of population-specific tallies (y-axis) of shortlisted variants in ACE2 (orange) or TMPRSS2 (blue), by sample size (x-axis; values denote maximum sampled alleles among shortlisted variant-position genotypes for that gene in gnomAD (v.3.0) + NHLBI-GO ESP6500 genotypes, as pooled by Hou et al. [6]). Datapoints mark values for African/African-American (AFR; TMPRSS2 count excludes 1 variant (p.Pro444Leu) reported by Hou et al., but not in public data, and not consistent with reference variant at given protein residue); Amish (AMI); Ashkenazi (ASH); east Asian (EAS); south Asian (SAS); non-Finnish, non-Amish, non-Ashkenazi European (EUR; TMPRSS2 count excludes 1 variant (p.Gly6Arg) reported by Hou et al., but not in public data, and not consistent with reference variant at given protein residue); Finnish (FIN in Hou et al. [6]); Latino/Admixed American (AMR; ACE2 count includes 2 variants wrongly omitted from this population by Hou et al.); or other (oth; PNA in Hou et al. [6]; ACE2 count excludes 2 variants wrongly tallied in this population by Hou et al.). Best-fit trends (dashed) mark origin-rooted linear regression, conservatively proxying independent (versus cumulative) discovery of potentially selection-constrained (versus selectively neutral) variants in samples from variably sized, mutually diverged populations (versus one steady-sized randomly mating population). We note that even in the contrasting case of cumulative discovery in a steady-sized population, variants under selective constraint (as Hou et al. sought to tally) tend to accrue quasi-linearly, rather than strictly logarithmically, with increasing overall sample size [–11]

Fig. 2

Nearly everyone, in all studied populations, likely lacks all ostensibly population-distinctive variants shortlisted by Hou et al. [6]. Bar plot of estimated percentage of people in each studied population who likely have none of the 130 notionally population-distinctive (i.e., absent in sample data from at least one studied population) ACE2 and TMPRSS2 variants shortlisted (without empirical evidence for any effect on protein function or other physiology, and omitting many other potentially functionally relevant variants in all populations) by Hou et al. [6]. Estimates (product of binomial probabilities) presume variants assort randomly, independently, at sampled population-specific frequencies, in half-XX/half-XY populaces. AFR = African/African-American; AMI = Amish; ASH = Ashkenazi; EAS = east Asian; SAS = south Asian; EUR = non-Finnish, non-Amish, non-Ashkenazi European; FIN = Finnish; AMR = Latino/Admixed American; oth = other. Values may underestimate true minimum region-wide percentage, as (i) the least rare such variant (ACE2 p.L731F), which most strongly suppresses the AFR estimate, appears mainly in data from over-proportionately sampled west Africa, more so than in data yet sampled from likewise populous peoples elsewhere in Africa and diaspora [17]; and (ii) any pairwise linkage among shortlisted variants would increase the proportion of people inheriting neither variant in such pairs