Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human host cells via angiotensin-converting enzyme 2 (ACE2) and causes coronavirus disease 2019 (COVID-19). Here, through a genome-wide association study, we identify a variant (rs190509934, minor allele frequency 0.2–2%) that downregulates ACE2 expression by 37% (P = 2.7 × 10−8) and reduces the risk of SARS-CoV-2 infection by 40% (odds ratio = 0.60, P = 4.5 × 10−13), providing human genetic evidence that ACE2 expression levels influence COVID-19 risk. We also replicate the associations of six previously reported risk variants, of which four were further associated with worse outcomes in individuals infected with the virus (in/near LZTFL1, MHC, DPP9 and IFNAR2). Lastly, we show that common variants define a risk score that is strongly associated with severe disease among cases and modestly improves the prediction of disease severity relative to demographic and clinical factors alone.

Randomized controlled trials (RCTs) are regarded as the most reputable source of evidence. In some studies, factors beyond the intervention itself may contribute to the measured effect, an occurrence known as heterogeneity of treatment effect (HTE). If the RCT population differs from the real-world population on factors that induce HTE, the trials effect will not replicate. The RCTs eligibility criteria should identify the sub-population in which its evidence will replicate. However, the extent to which the eligibility criteria identify the appropriate population is unknown, which raises concerns for generalizability. We compared reported data from RCTs with real-world data from the electronic health records of a large, academic medical center that was curated according to RCT eligibility criteria. Our results show fundamental differences between the RCT population and our observational cohorts, which suggests that eligibility criteria may be insufficient for identifying the applicable real-world population in which RCT evidence will replicate.

This study was funded by Allergan. The authors received no compensation related to the development of the manuscript. Buono and Andrae are employees of Allergan. Mathur is an employee of Axtria. Averitt was an employee of Axtria at the time this study was conducted. Data from this manuscript have previously been presented in poster format by Buono at the American College of Gastroenterology Annual Scientific Meeting; Honolulu, Hawaii; October 16-21, 2015. Mathur and Averitt were involved in conducting the study analyses. All authors were involved in the study design, interpretation of the data, and preparation of the manuscript. The authors take full responsibility for the scope, direction, and content of the manuscript and have approved the submitted manuscript.

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Inadequate symptom control associated with available IBS-D therapies represents a significant economic burden for both payers and IBS-D patients.