Brent Richards of McGill University and colleagues had a different take on how to define cases of COVID-19 susceptible individuals and controls than what I previously advocated. They analysed only UK Biobank participants who had a test result, defining cases as those with at least one positive test, and controls as anyone whose test results were all negative (whether one test or multiple).
They and Andrea Ganna suggested I take a look at this definition, and the new analyses throws up at least one very suggestive finding: a non-coding variant on the X chromosome in the XPNPEP2 gene. X-linked genes are of special interest because of the known elevated risk in males (who carry only one X chromosome) and the co-location of the ACE2 gene on chromosome X. ACE2 is a transmembrane protein by which SARS-CoV-2 (the COVID-19 virus) gains entry to cells.
Interestingly, variation in XPNPEP2 is said to confer susceptibility to ACE-inhibitor-induced angioedema, an inflammatory reaction which causes swelling and can lead to respiratory distress. It is also interesting that ACE inhibitor drugs forge a connection between the X-linked ACE2 and XPNPEP2 genes.
Here are details of the analyses. I performed two analyses, one of which was focused only on white Europeans. The case:control ratios were 387:522 and 535:636 respectively. I controlled only for age, sex, and interaction between age and sex, and the first 10 or 40 principal components of genetic variation respectively. I controlled for population structure using SAIGE.
The Manhattan plot - where bigger numbers mean greater strength of evidence - for white Europeans shows two distinct peaks in chromsomes 3 and X. The most significant variant in both has a p-value of one in 10 million, which does not quite reach the conventionally agreed threshold for statistically interesting signals by a factor of two. However, sample sizes are set to increase.
The hit on chromosome 3 (rs7637558) occurs in the PTPRG gene, apparently involved in tumour suppression in some tissues. I have not yet looked into this signal in any detail. Brent and colleagues previously noted on twitter this hit at a similar level of significance. They did not analyse the X chromosome.
Here is a close-up of the X chromosome, with ACE2 marked by a grey vertical line. The peak of blue points is in XPNPEP2, with the most significant occuring at variant rs2076205.
I have made initial efforts to check the results by re-analysing each variant using a simple logistic regression, which shows an expected dosage effect whereby individuals homozygous for the risk allele have a higher risk of being COVID-19 positive than heterozygotes.
Reassuringly, the top hit variant has a similar signal when analysing individuals of any ancestry.
These results are as yet preliminary, and are subject to scrutiny via meta-analysis of different studies in the COVID-19 Hg consortium and as the number of cases continues to rise, as regrettably it will, in the UK Biobank cohort.
For aficionados, the SAIGE output for the top two hits is here:
SAIGE results, white Europeans:
CHR POS rsid SNPID Allele1 Allele2 AC_Allele2 AF_Allele2 imputationInfo N BETA SE Tstat p.value p.value.NA Is.SPA.converge varT varTstar AF.Cases AF.Controls
X 128893417 rs2076205 X:128893417_C_T C T 490.125490196078 0.269595979205764 0.990731443602318 909 -0.467221760698161 0.0880842712142245 -59.6888627031124 1.1313178853627e-07 1.28548802524349e-07 1 127.752745535483 130.654411688048 0.188812889496884 0.329486890541657
03 61708608 rs7637558 3:61708608_A_G A G 516.086274509803 0.283875838564248 0.989045376208952 909 -0.552085056361661 0.103915060855678 -50.6246662875149 1.07924297975498e-07 1.24547474669322e-07 1 91.6972225641108 93.7799545311091 0.218731316816132 0.332172639170611
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