MAP3K19 regulatory variation in populations with African ancestry may increase COVID-19 severity

To identify ancestry-linked genetic risk variants associated with COVID-19 hospitalization, we performed an integrative analysis of two genome-wide association studies and resolved four single nucleotide polymorphisms more frequent in COVID-19-hospitalized patients with non-European ancestry. Among them, the COVID-19 risk SNP rs16831827 shows the largest difference in minor allele frequency (MAF) between populations with African and European ancestry and also shows higher MAF in hospitalized COVID-19 patients among cohorts of mixed ancestry (odds ratio [OR] = 1.20, 95% CI: 1.10-1.30) and entirely African ancestry (OR = 1.30, 95% CI: 1.02-1.67). rs16831827 is an expression quantitative trait locus of MAP3K19. MAP3K19 expression is induced during ciliogenesis and most abundant in ciliated tissues including lungs. Single-cell RNA sequencing analyses revealed that MAP3K19 is highly expressed in multiple ciliated cell types. As rs16831827∗T is associated with reduced MAP3K19 expression, it may increase the risk of severe COVID-19 by reducing MAP3K19 expression

A regulatory variant of CHRM3 is associated with cannabis-induced hallucinations in European Americans

Cannabis, the most widely used illicit drug, can induce hallucinations. Our understanding of the biology of cannabis-induced hallucinations (Ca-HL) is limited. We used the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to identify cannabis-induced hallucinations (Ca-HL) among long-term cannabis users (used cannabis ≥1 year and ≥100 times). A genome-wide association study (GWAS) was conducted by analyzing European Americans (EAs) and African Americans (AAs) in Yale-Penn 1 and 2 cohorts individually, then meta-analyzing the two cohorts within population. In the meta-analysis of Yale-Penn EAs (n = 1917), one genome-wide significant (GWS) signal emerged at the CHRM3 locus, represented by rs115455482 (P = 1.66 × 10-10), rs74722579 (P = 2.81 × 10-9), and rs1938228 (P = 1.57 × 10-8); signals were GWS in Yale-Penn 1 EAs (n = 1092) and nominally significant in Yale-Penn 2 EAs (n = 825). Two SNPs, rs115455482 and rs74722579, were available from the Collaborative Study on the Genetics of Alcoholism data (COGA; 3630 long-term cannabis users). The signals did not replicate, but when meta-analyzing Yale-Penn and COGA EAs, the two SNPs' association signals were increased (meta-P-values 1.32 × 10-10 and 2.60 × 10-9, respectively; n = 4291). There were no significant findings in AAs, but in the AA meta-analysis (n = 3624), nominal significance was seen for rs74722579. The rs115455482*T risk allele was associated with lower CHRM3 expression in the thalamus. CHRM3 was co-expressed with three psychosis risk genes (GABAG2, CHRNA4, and HRH3) in the thalamus and other human brain tissues and mouse GABAergic neurons. This work provides strong evidence for the association of CHRM3 with Ca-HL and provides insight into the potential involvement of thalamus for this trait

Association of OPRM1 Functional Coding Variant With Opioid Use Disorder: A Genome-Wide Association Study.

Importance: With the current opioid crisis, it is important to improve understanding of the biological mechanisms of opioid use disorder (OUD). Objectives: To detect genetic risk variants for OUD and determine genetic correlations and causal association with OUD and other traits. Design, Setting, and Participants: A genome-wide association study of electronic health record-defined OUD in the Million Veteran Program sample was conducted, comprising 8529 affected European American individuals and 71 200 opioid-exposed European American controls (defined by electronic health record trajectory analysis) and 4032 affected African American individuals and 26 029 opioid-exposed African American controls. Participants were enrolled from January 10, 2011, to May 21, 2018, with electronic health record data for OUD diagnosis from October 1, 1999, to February 7, 2018. Million Veteran Program results and additional OUD case-control genome-wide association study results from the Yale-Penn and Study of Addiction: Genetics and Environment samples were meta-analyzed (total numbers: European American individuals, 10 544 OUD cases and 72 163 opioid-exposed controls; African American individuals, 5212 cases and 26 876 controls). Data on Yale-Penn participants were collected from February 14, 1999, to April 1, 2017, and data on Study of Addiction: Genetics and Environment participants were collected from 1990 to 2007. The key result was replicated in 2 independent cohorts: proxy-phenotype buprenorphine treatment in the UK Biobank and newly genotyped Yale-Penn participants. Genetic correlations between OUD and other traits were tested, and mendelian randomization analysis was conducted to identify potential causal associations. Main Outcomes and Measures: Main outcomes were International Classification of Diseases, Ninth Revision-diagnosed OUD or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision-diagnosed OUD (Million Veteran Program), and DSM-IV-defined opioid dependence (Yale-Penn and Study of Addiction: Genetics and Environment). Results: A total of 114 759 individuals (101 016 men [88%]; mean [SD] age, 60.1 [12.8] years) were included. In 82 707 European American individuals, a functional coding variant (rs1799971, encoding Asn40Asp) in OPRM1 (μ-opioid receptor gene, the main biological target for opioid drugs; OMIM 600018) reached genome-wide significance (G allele: β = -0.066 [SE = 0.012]; P = 1.51 × 10-8). The finding was replicated in 2 independent samples. Single-nucleotide polymorphism-based heritability of OUD was 11.3% (SE = 1.8%). Opioid use disorder was genetically correlated with 83 traits, including multiple substance use traits, psychiatric illnesses, cognitive performance, and others. Mendelian randomization analysis revealed the following associations with OUD: risk of tobacco smoking, depression, neuroticism, worry neuroticism subcluster, and cognitive performance. No genome-wide significant association was detected for African American individuals or in transpopulation meta-analysis. Conclusions and Relevance: This genome-wide meta-analysis identified a significant association of OUD with an OPRM1 variant, which was replicated in 2 independent samples. Post-genome-wide association study analysis revealed associated pleiotropic characteristics. Recruitment of additional individuals with OUD for future studies-especially those of non-European ancestry-is a crucial next step in identifying additional significant risk loci

Functional variants regulating LGALS1 (Galectin 1) expression affect human susceptibility to influenza A(H7N9)

The fatality of avian influenza A(H7N9) infection in humans was over 30%. To identify human genetic susceptibility to A(H7N9) infection, we performed a genome-wide association study (GWAS) involving 102 A(H7N9) patients and 106 heavily-exposed healthy poultry workers, a sample size critically restricted by the small number of human A(H7N9) cases. To tackle the stringent significance cutoff of GWAS, we utilized an artificial imputation program SnipSnip to improve the association signals. In single-SNP analysis, one of the top SNPs was rs13057866 of LGALS1. The artificial imputation (AI) identified three non-genotyped causal variants, which can be represented by three anchor/partner SNP pairs rs13057866/rs9622682 (AI P = 1.81 × 10-7), rs4820294/rs2899292 (2.13 × 10-7) and rs62236673/rs2899292 (4.25 × 10-7) respectively. Haplotype analysis of rs4820294 and rs2899292 could simulate the signal of a causal variant. The rs4820294/rs2899292 haplotype GG, in association with protection from A(H7N9) infection (OR = 0.26, P = 5.92 × 10-7) correlated to significantly higher levels of LGALS1 mRNA (P = 0.050) and protein expression (P = 0.025) in lymphoblast cell lines. Additionally, rs4820294 was mapped as an eQTL in human primary monocytes and lung tissues. In conclusion, functional variants of LGALS1 causing the expression variations are contributable to the differential susceptibility to influenza A(H7N9).link_to_OA_fulltex

Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits

Identification of susceptibility gene to severe influenza in humans : an integrated study of genetics, molecular biology and bioinformatics

The 2009 influenza A(H1N1) virus (A(H1N1)pdm09) caused the first influenza pandemic in the 21st century. In 2013, a novel avian influenza virus A(H7N9) was identified to cause human infection with case-fatality rate of over 30%. The possible host genetic determinants predisposing to human A(H7N9) influenza and severe A(H1N1)pdm09 influenza have been speculated. We performed two genome-wide association studies (GWAS) to investigate the genetic susceptibility to A(H7N9) influenza and severe A(H1N1)pdm09 influenza. A bioinformatics pipeline, IndelLDplot, has been created to integrate genetic variants with expression quantitative trait loci (eQTLs) data and publicly available genome-wide functional annotation data. IndelLDplot can be utilized to identify potentially functional variants in high linkage disequilibrium (LD) with GWAS SNPs for further validation. Firstly, we demonstrated that four JAK2 SNPs including rs1887429, rs17425819, rs7850484 and rs7034539 were associated with the susceptibility to severe A(H1N1)pdm09 influenza in 436 patients. Two potential functional variants rs59384377 and rs59679286, located in a putative enhancer can tag the two association SNPs rs17425819 and rs7850484. In reporter gene luciferase assay, these two variants could encode regulatory polymorphisms for the enhancer activity. Additionally, the involvement of JAK2 in the pathogenesis of A(H1N1)pdm09 influenza was evidenced with the observation that JAK2 inhibition can attenuate the exuberant immune activation triggered by A(H1N1)pdm09 virus. Thus, JAK2 is a novel host factor whose genetic variations may cause the diversified outcome in A(H1N1)pdm09 patients. Secondly, we conducted a GWAS to investigate the genetic susceptibility to human A(H7N9) influenza in 102 patients and 106 healthy controls. We applied an artificial imputation program to improve the association signals. We identified three variants of LGALS1 represented by three anchor SNPs rs13057866, rs4820294 and rs62236673 coupled with their partner SNPs. A previous study indicated that LGALS1 can bind to various subtypes of influenza A viruses, inhibiting viral infectivity and production. Our in-depth analysis indicated that the protective variants against A(H7N9) infection correlated to the significantly higher levels of LGALS1 expression in lymphoblastoid cell lines, human primary monocytes and lung tissues. Therefore, we conclude that functional variants of LGALS1 causing the expression variations contribute to the differential susceptibility to human A(H7N9) influenza. We further integrated the results of A(H1N1)pdm09 GWAS with a lung eQTL dataset. We demonstrated that the G allele of rs2070788, a higher-expression variant of TMPRSS2, was a risk variant to severe A(H1N1)pdm09 influenza in 409 patients. A potentially functional SNP rs383510 in a putative regulatory region can tag rs2070788. Luciferase assay results showed that rs383510 may dictate the activity of the regulatory element. Due to the shared usage of TMPRSS2 for the activation of A(H1N1)pdm09 and A(H7N9) viruses, we validated the genetic predispositions of rs2070788 and rs383510 to A(H7N9) influenza. Therefore, we demonstrate that genetic variants with higher TMPRSS2 expression confer higher risk to severe A(H1N1)pdm09 influenza and human A(H7N9) influenza. In summary, integrating the genetic association studies, molecular and cell biology studies and bioinformatics analysis, we identified and characterized a number of susceptibility genes for human A(H7N9) influenza and severe A(H1N1)pdm09 influenza.published_or_final_versionMicrobiologyDoctoralDoctor of Philosoph