Letter to the Editor
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World J Psychiatry. Mar 19, 2022; 12(3): 536-540
Published online Mar 19, 2022. doi: 10.5498/wjp.v12.i3.536
Does COVID-19 increase the risk of neuropsychiatric sequelae? Evidence from a mendelian randomization approach
Alfonsina Tirozzi, Federica Santonastaso, Giovanni de Gaetano, Licia Iacoviello, Alessandro Gialluisi
Alfonsina Tirozzi, Giovanni de Gaetano, Licia Iacoviello, Alessandro Gialluisi, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli 86077, Italy
Federica Santonastaso, Licia Iacoviello, Alessandro Gialluisi, Department of Medicine and Surgery, University of Insubria, Varese 21100, Italy
Author contributions: Tirozzi A and Santonastaso F contributed equally to the present manuscript; Gialluisi A was responsible for conceptualization and analysis plan; Gialluisi A, Tirozzi A and Santonastaso F did the statistical analysis; Gialluisi A and Tirozzi A drafted the first manuscript; Iacoviello L and de Gaetano G were responsible for the manuscript reviewing and editing; Tirozzi A and Santonastaso F were in charge of figures; all co-authors did the data interpretation and literature search.
Supported by Fondazione Umberto Veronesi (to Gialluisi A).
Conflict-of-interest statement: The authors declare no competing financial interests.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Licia Iacoviello, MD, PhD, Professor, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Via Atinense 18, Pozzilli 86077, Italy. licia.iacoviello@moli-sani.org
Received: November 12, 2021
Peer-review started: November 12, 2021
First decision: December 12, 2021
Revised: January 3, 2022
Accepted: February 23, 2022
Article in press: February 23, 2022
Published online: March 19, 2022
Processing time: 125 Days and 22.1 Hours
Abstract

Observational studies based on electronic health records (EHR) report an increased risk of neurological/neuropsychiatric sequelae for patients who have had coronavirus disease 2019 (COVID-19). However, these studies may suffer from biases such as unmeasured confounding, residual reverse causality, or lack of precision in EHR-based diagnoses. To rule out these biases, we tested causal links between COVID-19 and different potential neurological/neuropsychiatric sequelae through a two-sample Mendelian randomization analysis of summary statistics from large Genome-Wide Association Scans of susceptibility to COVID-19 and different neurological and neuropsychiatric disorders, including major depression, anxiety, schizophrenia, stroke, Parkinson’s and Alzheimer’s diseases. We found robust evidence suggesting that COVID-19 – notably the hospitalized and most severe forms – carries an increased risk of neuropsychiatric sequelae, particularly Alzheimer’s disease, and to a lesser extent anxiety disorder. In line with a large longitudinal EHR-based study, this evidence was stronger for more severe COVID-19 forms. These results call for a targeted screening strategy to tackle the post-COVID neuropsychiatric pandemic.

Keywords: COVID-19; Sars-CoV-2; Neurological disorders; Neuropsychiatric disorders; Alzheimer’s disease; Anxiety; Mendelian randomization

Core Tip: Inspired by suggestive findings of an increased incident risk of neurological and neuropsychiatric sequelae in people who have had coronavirus disease 2019 (COVID-19), we carried out a two-sample Mendelian randomization analysis to further investigate causality links and build evidence free of biases such as unmeasured confounding, residual reverse causality or lack of precision in electronic health record-based diagnoses. This analysis – typically applied to genetic associations from large genomic studies on the diseases of interest – indicated that the most severe forms of COVID-19 increased the risk of Alzheimer’s disease and anxiety, further supporting the findings of large observational studies.