Whole genome sequence meta-analyses reveal common and rare genetic associations with critical COVID-19
In susceptible patients, COVID-19 causes life-threatening disease driven by immune-mediated inflammatory lung injury. We have previously shown that multiple common host genetic variants are significantly associated with susceptibility to critical Covid-19, and in one case, we demonstrated that such variants can inform development of new, effective drug treatment.
Here we report an association analysis of whole-genome sequences (WGS) from 11,423 cases from the GenOMICC study and 60,628 controls, together with meta-analyses with available genome-wide data. We identify a rare association signal at SLC50A1, primarily driven by a missense variant rs147850817 (1:155138217:G:T, Arg201Leu) that may interfere with transport function, and we identify four common association signals near ARF1, ZNF462, KLF13 and MVP genes.
Finally, we build a WGS-derived polygenic risk score (PRS) for critical Covid-19, which offers only marginal improvement in risk estimation for the general population but may provide clinically-valuable discrimination for extreme susceptibility.
Web | DOI | PDF | Preprint: MedRxiv | Open Access
Athanasios Kousathanas; Konrad Rawlik; Erola Pairo-Castineira; Fiona Griffiths; Wilna Oosthuyzen; Sara Clohisey Hendry; Tomas Malinauskas; Guillaume Butler-Laporte; Prabhu Arumugam; Colin Begg; Marc Chadeau-Hyam; Georgia Chan; Graham Cooke; Sally Donovan; Greg Elgar; Tom A Fowler; Peter Goddard; Charles Hinds; Peter Horby; Lowell Ling; Emma F Magavern; Fiona Maleady-Crowe; Hugh Montgomery; Christopher A Odhams; Peter Jm Openshaw; Christine Patch; Augusto Rendon; Shahla Salehi; Richard H Scott; Malcolm G Semple; Manu Shankar-Hari; Afshan Siddiq; Alex Stuckey; Charlotte Summers; Linda Todd; Susan Walker; Timothy Walsh; Helen Ward; Tala Zainy; GenOMICC Investigators; Isaricc Investigators; Bqc Investigators; Gencovid Investigators; DeCOI Investigators; Polcovid Investigators; Pmbb Investigators; Angie Fawkes; Lee Murphy; Andy Law; Veronique Vitart; Patrick F Chinnery; James F Wilson; Matthew A Brown; Paul Elliott; Loukas Moutsianas; Mark J Caulfield; J Kenneth Baillie
In susceptible patients, COVID-19 causes life-threatening disease driven by immune-mediated inflammatory lung injury. We have previously shown that multiple common host genetic variants are significantly associated with susceptibility to critical Covid-19, and in one case, we demonstrated that such variants can inform development of new, effective drug treatment.
Here we report an association analysis of whole-genome sequences (WGS) from 11,423 cases from the GenOMICC study and 60,628 controls, together with meta-analyses with available genome-wide data. We identify a rare association signal at SLC50A1, primarily driven by a missense variant rs147850817 (1:155138217:G:T, Arg201Leu) that may interfere with transport function, and we identify four common association signals near ARF1, ZNF462, KLF13 and MVP genes.
Finally, we build a WGS-derived polygenic risk score (PRS) for critical Covid-19, which offers only marginal improvement in risk estimation for the general population but may provide clinically-valuable discrimination for extreme susceptibility.
Web | DOI | PDF | Preprint: MedRxiv | Open Access