Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium

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1. Version published to 10.1186/s13073-021-00866-2

   Apr 21, 2021
2. 

   ScreenIT

   Oct 4, 2020

   SciScore for 10.1101/2020.10.01.20202820: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   NIH rigor criteria are not applicable to paper type.

   Table 2: Resources

   Experimental Models: Cell Lines
   Sentences	Resources
   To include in our candidate list, we chose genes that 1) have adjusted P-value < 0.05 in the differential expression analysis from primary cells and either cell lines (Calu-3 or ACE2-expressing A549 cells, low-MOI infection; excluded genes with adjusted P = 0) or samples derived from COVID-19 patients, and 2) log2 fold change > 0.5 in absolute scale in primary cells and log2 fold change > 1 in absolute scale in the other experiment.	A549 suggested: None
   Experimental Models: Organisms/Strains
   Sentences	Resources
   pheWAS of lead COVID-19 cis-eQTLs in SPIROMICS: We performed phenome-wide …

   SciScore for 10.1101/2020.10.01.20202820: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   NIH rigor criteria are not applicable to paper type.

   Table 2: Resources

   Experimental Models: Cell Lines
   Sentences	Resources
   To include in our candidate list, we chose genes that 1) have adjusted P-value < 0.05 in the differential expression analysis from primary cells and either cell lines (Calu-3 or ACE2-expressing A549 cells, low-MOI infection; excluded genes with adjusted P = 0) or samples derived from COVID-19 patients, and 2) log2 fold change > 0.5 in absolute scale in primary cells and log2 fold change > 1 in absolute scale in the other experiment.	A549 suggested: None
   Experimental Models: Organisms/Strains
   Sentences	Resources
   pheWAS of lead COVID-19 cis-eQTLs in SPIROMICS: We performed phenome-wide association studies in 1,980 non-Hispanic White (NHW) and 696 individuals from other ethnic and racial groups from SPIROMICS for the 108 lead cis-eQTLs to evaluate for phenotypic associations with spirometric measures, cell count differentials, immunoglobulin concentrations, longitudinal exacerbation risk, self-reported asthma history, cardiovascular diseases, CT scan measures of emphysema (bilateral percentage lung density <-950HFU at total lung capacity), CT scan functional small airways disease (PRM-fSAD), and alpha1-antitrypsin concentrations (subgroup of 1,191 NHW and 396 from other racial/ethnic groups).	non-Hispanic White suggested: None
   Software and Algorithms
   Sentences	Resources
   FASTQ files were quality filtered and aligned to the Ensembl GRCh38 genome build using STAR50.	Ensembl suggested: (Ensembl, RRID:SCR_002344)
   Differential expression analysis of ACE2 in relation to host/environmental factors: Visualization and analyses of single gene and gene signature analyses were done using RLE normalized and COMBAT batch corrected gene expression from the DESeq2 and SVA packages in R.	DESeq2 suggested: (DESeq, RRID:SCR_000154)
   As per the ASpli and EdgeR package recommendations, raw exon counts were adjusted for gene counts to remove the signal from differential gene expression using the formula: (Exon Count in each sample*mean raw ACE2 count)/raw ACE2 gene count in that sample.	EdgeR suggested: (edgeR, RRID:SCR_012802)
   Biological pathway gene sets were built by inputting the genes differentially downregulated between SARS-CoV-2 infection and other viral illness (P < 0.05) into the Ingenuity Pathway Analysis canonical pathway function.	Ingenuity Pathway Analysis suggested: (Ingenuity Pathway Analysis, RRID:SCR_008653)
   Expression quantitative trait mapping: Expression quantitative trait (eQTL) mapping was performed in 144 unrelated individuals from the SPIROMICS bronchoscopy sub-study with WGS genotype data from TOPMed and gene expression from bronchial epithelium profiled with RNA-seq following the analysis pipeline from the Genotype-Tissue Expression (GTEx) Consortium15	WGS suggested: None
   LD pruning was performed using Plink 1.961 based on pairwise genotypic correlation of 200 SNPs at a time, with a step of 100 SNPs, and using LD threshold of > 0.1 to remove one of a pair of SNPs (option --indep-pairwise 200 100 0.1).	Plink suggested: (PLINK, RRID:SCR_001757)
   The top 4 PCs explained > 0.1% of the variance, and were associated with subpopulations inferred from 1000 Genomes Project using k-nearest neighbors clustering (F-test P < 2×10−10	1000 Genomes Project suggested: (1000 Genomes Project and AWS, RRID:SCR_008801)
   Window-size was set to 1 Mb from the transcription start site (TSS) of the gene according to the GENCODE version 33, 10,000 permutations were used to correct for multiple testing, and false discovery rate (FDR) < 0.05 was used to identify genes with statistically significant eQTLs (eGenes).	GENCODE suggested: (GENCODE, RRID:SCR_014966)
   We queried PhenoScanner database based on the rs IDs of the lead cis-eQTLs obtained from dbSNP version 151 (GRCh38p7, including also former rs ID to query).	dbSNP suggested: (dbSNP, RRID:SCR_002338)

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   Results from OddPub: Thank you for sharing your code and data.

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   Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

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   Results from TrialIdentifier: No clinical trial numbers were referenced.

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   Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

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   Results from JetFighter: We did not find any issues relating to colormaps.

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   Results from rtransparent:

   • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
   • No funding statement was detected.
   • No protocol registration statement was detected.

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3. 

   Version published to 10.1101/2020.10.01.20202820v1 on medRxiv

   Oct 4, 2020