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Ethnicity-dependent allele frequencies are correlated with COVID-19 case fatality rate
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  • Sungwon Jeon,
  • Asta Blazyte,
  • Changhan Yoon,
  • Hyojung Ryu,
  • Yeonsu Jeon,
  • Youngjune Bhak,
  • Dan Bolser,
  • Andrea Manica,
  • Eun-Seok Shin,
  • Yun Sung Cho,
  • Byung Chul Kim,
  • Namhee Ryoo,
  • Jong Bhak
Sungwon Jeon
UNIST
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Asta Blazyte
UNIST
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Changhan Yoon
UNIST
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Hyojung Ryu
UNIST
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Yeonsu Jeon
UNIST
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Youngjune Bhak
UNIST
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Dan Bolser
Geromics Ltd.
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Andrea Manica
University of Cambridge
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Eun-Seok Shin
Ulsan Medical Center
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Yun Sung Cho
Clinomics Inc.
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Byung Chul Kim
Clinomics Inc.
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Namhee Ryoo
Keimyung University School of Medicine
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Jong Bhak
UNIST
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Abstract

Coronavirus disease (COVID-19), caused by SARS-CoV-2, has a higher case fatality rate (CFR) in European ethnic groups than in others, especially East Asians. One explanation to this phenomenon might be TMPRSS2, a key processing enzyme essential for viral infection. Here, we analyzed the allele frequencies of two nonsynonymous variants rs12329760 (V197M) and rs75603675 (G8V) in the TMPRSS2 gene using over 200,000 present-day and ancient genomic samples. We found a significant association between the CFR of COVID-19 and the allele frequencies of the two variants. Interestingly, they had opposing effects on the CFR: inverse correlation by V197M, proportional correlation by G8V. East Asians have higher V197M and lower G8V allele frequencies than Europeans, possibly endowing resistance against SARS-CoV-2. Structural and energy calculation analysis of the V197M amino acid change showed that it destabilizes the TMPRSS2 protein, possibly affecting its ACE2 and viral spike protein processing negatively, ultimately resulting in reduced SARS-CoV-2 infection efficiency and CFR in East Asian ethnic groups.