TY - JOUR
T1 - Host genetic effects in pneumonia
AU - Chen, Hung Hsin
AU - Shaw, Douglas M.
AU - Petty, Lauren E.
AU - Graff, Misa
AU - Bohlender, Ryan J.
AU - Polikowsky, Hannah G.
AU - Zhong, Xue
AU - Kim, Daeeun
AU - Buchanan, Victoria L.
AU - Preuss, Michael H.
AU - Shuey, Megan M.
AU - Loos, Ruth J.F.
AU - Huff, Chad D.
AU - Cox, Nancy J.
AU - Bastarache, Julie A.
AU - Bastarache, Lisa
AU - North, Kari E.
AU - Below, Jennifer E.
N1 - Publisher Copyright:
© 2020
PY - 2021/1/7
Y1 - 2021/1/7
N2 - Given the coronavirus disease 2019 (COVID-19) pandemic, investigations into host susceptibility to infectious diseases and downstream sequelae have never been more relevant. Pneumonia is a lung disease that can cause respiratory failure and hypoxia and is a common complication of infectious diseases, including COVID-19. Few genome-wide association studies (GWASs) of host susceptibility and severity of pneumonia have been conducted. We performed GWASs of pneumonia susceptibility and severity in the Vanderbilt University biobank (BioVU) with linked electronic health records (EHRs), including Illumina Expanded Multi-Ethnic Global Array (MEGAEX)-genotyped European ancestry (EA, n= 69,819) and African ancestry (AA, n = 15,603) individuals. Two regions of large effect were identified: the CFTR locus in EA (rs113827944; OR = 1.84, p value = 1.2 × 10−36) and HBB in AA (rs334 [p.Glu7Val]; OR = 1.63, p value = 3.5 × 10−13). Mutations in these genes cause cystic fibrosis (CF) and sickle cell disease (SCD), respectively. After removing individuals diagnosed with CF and SCD, we assessed heterozygosity effects at our lead variants. Further GWASs after removing individuals with CF uncovered an additional association in R3HCC1L (rs10786398; OR = 1.22, p value = 3.5 × 10−8), which was replicated in two independent datasets: UK Biobank (n = 459,741) and 7,985 non-overlapping BioVU subjects, who are genotyped on arrays other than MEGAEX. This variant was also validated in GWASs of COVID-19 hospitalization and lung function. Our results highlight the importance of the host genome in infectious disease susceptibility and severity and offer crucial insight into genetic effects that could potentially influence severity of COVID-19 sequelae.
AB - Given the coronavirus disease 2019 (COVID-19) pandemic, investigations into host susceptibility to infectious diseases and downstream sequelae have never been more relevant. Pneumonia is a lung disease that can cause respiratory failure and hypoxia and is a common complication of infectious diseases, including COVID-19. Few genome-wide association studies (GWASs) of host susceptibility and severity of pneumonia have been conducted. We performed GWASs of pneumonia susceptibility and severity in the Vanderbilt University biobank (BioVU) with linked electronic health records (EHRs), including Illumina Expanded Multi-Ethnic Global Array (MEGAEX)-genotyped European ancestry (EA, n= 69,819) and African ancestry (AA, n = 15,603) individuals. Two regions of large effect were identified: the CFTR locus in EA (rs113827944; OR = 1.84, p value = 1.2 × 10−36) and HBB in AA (rs334 [p.Glu7Val]; OR = 1.63, p value = 3.5 × 10−13). Mutations in these genes cause cystic fibrosis (CF) and sickle cell disease (SCD), respectively. After removing individuals diagnosed with CF and SCD, we assessed heterozygosity effects at our lead variants. Further GWASs after removing individuals with CF uncovered an additional association in R3HCC1L (rs10786398; OR = 1.22, p value = 3.5 × 10−8), which was replicated in two independent datasets: UK Biobank (n = 459,741) and 7,985 non-overlapping BioVU subjects, who are genotyped on arrays other than MEGAEX. This variant was also validated in GWASs of COVID-19 hospitalization and lung function. Our results highlight the importance of the host genome in infectious disease susceptibility and severity and offer crucial insight into genetic effects that could potentially influence severity of COVID-19 sequelae.
KW - GWAS
KW - biobank
KW - electronic health record
KW - host genetic effect
KW - pneumonia
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UR - http://www.scopus.com/inward/citedby.url?scp=85098482986&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2020.12.010
DO - 10.1016/j.ajhg.2020.12.010
M3 - Article
C2 - 33357513
AN - SCOPUS:85098482986
SN - 0002-9297
VL - 108
SP - 194
EP - 201
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -