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Risk factors and long-term consequences of COVID-19 infection are unclear but can be investigated with large-scale genomic data. To distinguish correlation from causation, we performed in-silico analyses of three COVID-19 outcomes (N > 1,000,000). We show genetic correlation and putative causality with depressive symptoms, metformin use (genetic causality proportion (gĉp) with severe respiratory COVID-19 = 0.576, p = 1.07 × 10−5 and hospitalized COVID-19 = 0.713, p = 0.003), and alcohol drinking status (gĉp with severe respiratory COVID-19 = 0.633, p = 7.04 × 10−5 and hospitalized COVID-19 = 0.848, p = 4.13 × 10−13). COVID-19 risk loci associated with several hematologic biomarkers. Comprehensive findings inform genetic contributions to COVID-19 epidemiology, molecular mechanisms, and risk factors and potential long-term health effects of severe response to infection. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme-2 (ACE2) receptor has been identified as the key adhesion molecule for the transmission of the SARS-CoV-2. However, there is no evidence that human genetic variation in ACE2 is singularly responsible for COVID-19 susceptibility. Therefore, we performed an integrative multi-level characterization of genes that interact with ACE2 (ACE2-gene network) for their statistically enriched biological properties in the context of COVID-19. The phenome-wide association of 51 genes including ACE2 with 4,756 traits categorized into 26 phenotype categories, showed enrichment of immunological, respiratory, environmental, skeletal, dermatological, and metabolic domains (p < 4e-4). Transcriptomic regulation of ACE2-gene network was enriched for tissue-specificity in kidney, small intestine, and colon (p < 4.7e-4). Leveraging the drug-gene interaction database we identified 47 drugs, including dexamethasone and spironolactone, among others. Considering genetic variants within ± 10 kb of ACE2-network genes we identified miRNAs whose binding sites may be altered as a consequence of genetic variation. The identified miRNAs revealed statistical over-representation of inflammation, aging, diabetes, and heart conditions. The genetic variant associations in RORA , SLC12A6 , and SLC6A19 genes were observed in genome-wide association study (GWAS) of COVID-19 susceptibility. We also report the GWAS-identified variant in 3p21.31 locus, serves as trans-QTL for RORA and RORC genes. Overall, functional characterization of ACE2-gene network highlights several potential mechanisms in COVID-19 susceptibility. The data can also be accessed at https://gpwhiz.github.io/ACE2Netlas/. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic stress disorder (PTSD) often co‐occurs with alcohol consumption (AC) and alcohol use disorder (AUD). However, it is unknown whether the same etiologic influences that underlie PTSD co‐occurring with AUD are those that underlie PTSD and AC individually. Methods: This study used large‐scale genome‐wide association study (GWAS) data to test whether PTSD and drinks per week [DPW]/AUD are causally related to one another, and, if so, whether PTSD precedes DPW/AUD and/or vice versa. We used Mendelian Randomization methods to analyze European ancestry GWAS summary statistics from the Psychiatric Genomics Consortium (PGC; PTSD), GWAS & Sequencing Consortium of Alcohol and Nicotine Use (GSCAN; DPW), and the Million Veteran Program (MVP; AUD). Results: PTSD exerted a potentially causal effect on AUD (β = 0.039, SE = 0.014, p = 0.005), but not on DPW (β = 0.002, SE = 0.003, p = 0.414). Additionally, neither DPW (β = 0.019, SE = 0.041, p = 0.637) nor AUD (β = 8.87 × 10−4, SE = 0.001, p = 0.441) exerted a causal effect on PTSD. Conclusions: These findings are consistent with the self‐medication model, in which individuals misuse alcohol to cope with aversive trauma‐related symptoms. These findings extend latent analysis and molecular findings of shared and correlated risk between PTSD and alcohol phenotypes. Given the health behaviors associated with these phenotypes, these findings are important in that they suggest groups to prioritize for prevention efforts. Further, they provide a rationale for future preclinical and clinical studies examining the biological mechanisms by which PTSD may impact AUD. [ABSTRACT FROM AUTHOR]

Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of genes and pathways that contribute to COVID-19. Here, we integrate a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n = 18,502). We identify 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. We functionally characterize the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (n = 85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicate these findings across trans-ethnic studies and observed consistent effects in individuals of diverse ancestral backgrounds in Vanderbilt Biobank, pan-UK Biobank, and Biobank Japan. Our study highlights and reconfirms putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response. Genome-wide association studies of COVID-19 have identified genetic loci affecting disease severity, but the mechanisms remain to be fully described. Here, the authors use genetically predicted transcriptome, splicing and proteome data to identify potential genes and pathways underlying COVID- 19 severity. [ABSTRACT FROM AUTHOR]

A polygenic risk score (PRS) derived from genome-wide association studies of posttraumatic stress disorder (PTSD) may inform risk for this disorder. To date, however, no known study has examined whether social environmental factors such as attachment style may moderate the relation between PRS and PTSD. We evaluated main and interactive effects of PRS and attachment style on PTSD symptoms in a nationally representative sample of trauma-exposed European-American U.S. military veterans (N = 2030). PRS was derived from a genome-wide association study of PTSD re-experiencing symptoms (N = 146,660) in the Million Veteran Program cohort. Using one-sample Mendelian randomization with data from the UK Biobank (N = 115,099), we evaluated the effects of re-experiencing PRS and attachment style on PTSD symptoms. Higher re-experiencing PRS and secure attachment style were independently associated with PTSD symptoms. A significant PRS-by-attachment style interaction was also observed (β = −.11, p =. 006), with a positive association between re-experiencing PRS and PTSD symptoms observed only among veterans with an insecure attachment style. One-sample Mendelian randomization analyses suggested that the association between PTSD symptoms and attachment style is bidirectional. PRS enrichment analyses revealed a significant interaction between attachment style and a variant mapping to the IGSF11 gene (rs151177743, p = 2.1 × 10−7), which is implicated in regulating excitatory synaptic transmission and plasticity. Attachment style may moderate polygenic risk for PTSD symptoms, and a novel locus implicated in synaptic transmission and plasticity may serve as a possible biological mediator of this association. These findings may help inform interpersonally oriented treatments for PTSD for individuals with high polygenic risk for this disorder. [ABSTRACT FROM AUTHOR]

Background: Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity.Methods: We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n = 222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n = 132) and whole-blood tissue (n = 369).Results: In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.Conclusions: We report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual's susceptibility to developing radiotoxicity. [ABSTRACT FROM AUTHOR]

There are three possible outcomes from drug therapy: the drug performs as intended; the drug has no effect; or the drug causes an adverse reaction. Variation in drug and endogenous toxin metabolism among individuals in part can be due to genetic makeup. The goal of pharmacogenetics is to elucidate the genetic variation contributing to absorption, distribution, metabolism, excretion, and response (ADME‐R) so that adverse drug reactions can be avoided, and to characterize differential enzyme activity informing appropriate drug dosage on the individual and population levels. The postmortem molecular autopsy may use pharmacogenetic information from a decedent to make conclusions about cause (CoD) and/or manner of death (MoD) when traditional medico‐legal autopsies are negative. The cytochrome p450 family is a group of pharmacogenetically relevant targets with demonstrable utility in the postmortem setting and several key historical applications. ATP‐binding cassettes and opioid receptors are additional critical drug response proteins with essential rolls in additive and suicidal behaviors and drug overdose. Historically, the discipline relied on genetic variation with large effects on a broad spectrum of endogenous and foreign compounds. However, recent advances in pharmacogenomics highlight rare variants and noncoding variation as strong contributing factors to the accuracy of drug response prediction. Furthermore, there is a push to develop more comprehensive predictive models incorporating both rare and common variants contributing to drug response. These advanced genetic capabilities will enable more accurate predictions of drug‐related CoD and/or MoD determinations and contribute to the growing overlap between medical and forensic genetics. This article is categorized under: Forensic Biology > Forensic DNA TechnologiesToxicology > OpioidsForensic Medicine > Methods for Certification of Cause and Manner of Death [ABSTRACT FROM AUTHOR]

To investigate the causal relationship between blood metabolites and traits related to trauma-response, we combined genome-wide and metabolome-wide datasets generated from large-scale cohorts. Five trauma-response traits ascertained in the UK Biobank (52,816 < N < 117,900 individuals) were considered: (i) "Avoided activities/situations because of previous stressful experience" (Avoidance); (ii) "Felt distant from other people" (Distant); (iii) "Felt irritable/had angry outbursts" (Irritable); (iv) "Felt very upset when reminded of stressful experience" (Upset); (v) "Repeated disturbing thoughts of stressful experience". These were investigated with respect to 52 blood metabolites tested in a previous genome-wide-association study (N = 24,925 European-ancestry individuals). Linkage disequilibrium score regression, polygenic risk scoring (PRS), and Mendelian randomization were applied to the datasets. We observed that 14 metabolites were genetically correlated with trauma-response traits (p < 0.05). High-resolution PRS of 4 metabolites (citrate; glycoprotein acetyls; concentration of large very-low-density lipoproteins (VLDL) particles (LVLDLP); total cholesterol in medium particles of VLDL (MVLDLC)) were associated with trauma-response traits (false discovery rate Q < 10%). These genetic associations were partially due to causal relationships (Citrate→Upset β = − 0.058, p = 9.1 × 10-4; Glycoproteins→Avoidance β = 0.008, p = 0.003; LVLDLP→Distant β = 0.008, p = 0.022; MVLDLC→Avoidance β = 0.019, p = 3 × 10-4). No reverse associations were observed. In conclusion, our study supports causal relationships between certain blood metabolites and emotional and behavioral responses to traumatic experiences. [ABSTRACT FROM AUTHOR]

The microFLOQ® Direct Swab was tested by sampling diluted blood, semen, and saliva stains deposited on cotton cloth. DNA typing was performed using the PowerPlex® Fusion 6C System by direct PCR or a modified direct PCR. Direct PCR of swabs sampled the center of a stain, compared to their respective edge samplings, and had higher profile completeness and total relative fluorescent units (RFU) for all dilutions of blood and semen stains tested. The modified direct PCR used template DNA eluted from the swab head using the Casework Direct Kit, Custom and washes either contained 1-thioglycerol (TG) additive or no TG. Modified direct PCR had mixed results for blood, saliva, and semen stains, with semen stains showing significant differences in profile completeness (5% and 1%) and total RFU (neat, 5% and 1%) with the addition of TG to the Casework Direct Reagent. No significant difference was seen in any dilution of blood or saliva stains processed with the modified direct PCR, but profile completeness and total RFU were improved overall compared to stains swabbed with cotton swabs or 4N6FLOQSwabs™. This study supports the hypothesis that the microFLOQ® Direct Swab is able to collect minute amounts of DNA from cotton cloth and may be considered as an alternate pre-screening methodology in forensic biology casework. [ABSTRACT FROM AUTHOR]