Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Table of Contents Supplementary Note ........................................................................................................................... 1 Author contributions ............................................................................................................................... 1 Additional authors from study groups .............................................................................................. 2 Task Force COVID-19 Humanitas ......................................................................................................................................... 2 TASK FORCE COVID-19 HUMANITAS GAVAZZENI & CASTELLI ............................................................................. 3 COVICAT Study Group ............................................................................................................................................................... 4 Pa COVID-19 Study Group ....................................................................................................................................................... 5 Covid-19 Aachen Study (COVAS) .......................................................................................................................................... 5 Norwegian SARS-CoV-2 Study group .................................................................................................................................. 6 Supplementary Methods ................................................................................................................... 8 DNA extraction and SNP genotyping ................................................................................................... 8 DNA extraction Institute of Clinical Molecular Biology .............................................................................................. 8 DNA extraction for the GCAT cohort ................................................................................................................................... 9 DNA extraction Genomics Department of Life&Brain Center, Bonn ..................................................................... 9 DNA extraction COMRI cohort ............................................................................................................................................... 9 Genotyping at the Institute of Clinical Molecular Biology ......................................................................................... 9 Genotyping at the Life&Brain Center, Bonn, Germany ............................................................................................. 10 Genotyping at the Regeneron Genetics Center ............................................................................................................ 10 Genotyping at the Genotyping laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki ....................................................................................................... 10 Genotype calling, quality control and imputation ...................................................................... 11 Genotype calling ........................................................................................................................................................................ 11 SNP and sample quality control and principal component analysis .................................................................. 11 SNP genotype imputation ..................................................................................................................................................... 12 Imputation of the ~0.9-Mb inversion polymorphism at 17q21.31 .................................................................... 12 Genome-wide and candidate-based association analysis ........................................................ 13 Cohort-specific analyses ........................................................................................................................................................ 13 Meta-analysis of cohort-specific summary statistics. ............................................................................................... 14 Bayesian fine-mapping analysis ......................................................................................................................................... 15 Meta-Analysis Model-based Assessment of replicability ........................................................................................ 15 Association analysis and meta-analyses of candidate loci ...................................................................................... 16 Functional characterization of genome-wide significant lead variants and associated candidate genes ...................................................................................................................................... 18 Phenome-wide association studies (PheWAS) ............................................................................................................ 18 Tissue-specific expression and splicing quantitative trait loci (eQTL, sQTL) ................................................ 18 Selection and definition of candidate genes at 17q21.31 and 19q13.33 .......................................................... 19 Gene expression analysis for candidate genes from genome-wide significant susceptibility loci ........ 19 Mendelian Randomization analysis .................................................................................................................................. 20 17q21.31 inversion-related effects with respect to gene expression in infection-stimulated CD14+ monocytes .................................................................................................................................................................................... 20 HLA locus fine mapping and association analysis ....................................................................... 22 HLA allele, amino acid and SNP imputation .................................................................................................................. 22 Construction of an imputation panel for the Spanish and Italian cohorts ....................................................... 22 SNP- and amino-acid-wide association study .............................................................................................................. 23 Peptidome-wide association study (PepWAS) ............................................................................................................ 23 Analysis of quantitative HLA parameters ...................................................................................................................... 24 HLA-presentation of shared peptides (‘molecular mimicry’) ............................................................................... 25 Association analysis of Y-chromosomal haplogroups ............................................................... 27 Calling of genotypes ................................................................................................................................................................. 27 Y-chromosome haplogroup characterization by genotyping ................................................................................ 27 Y-chromosome association analysis ................................................................................................................................. 29 Supplementary Information, Results and Discussion ......................................................... 30 Functional characterization of genome-wide significant lead variants and associated candidate genes ...................................................................................................................................... 30 Expression analysis ................................................................................................................................................................. 30 HLA locus fine mapping and association analysis ....................................................................... 32 HLA typing and imputation .................................................................................................................................................. 32 HLA fine mapping of association ....................................................................................................................................... 32 Peptidome-wide association study (PepWAS) ............................................................................................................ 33 Analysis of quantitative HLA parameters ...................................................................................................................... 33 HLA-presentation of shared peptides (‘molecular mimicry’) ............................................................................... 33 Introduction ................................................................................................................................................................................ 34 Methods ........................................................................................................................................................................................ 35 Results ..........................................................................................................................................................................................