Liam Gaziano

Safety-related issues account for approximately 25% of failures in new drug discovery programs. On top of that, many are discovered during post-marketing surveillance, significantly limiting drug utility and application. To proactively address these concerns, we developed a genetics-led strategy leveraging Mendelian Randomization (MR) across large-scale genetic datasets from the Million Veteran Program, FinnGen, and UK Biobank. By mapping genetic variants associated with gene expression and protein abundance to 1,449 harmonized human phenotypes, we systematically identified potential adverse drug reactions (ADR). Our extensive MR analysis, encompassing 16,915 protein-coding genes, demonstrated the capacity to predict hundreds of known ADR for approved medications, with approximately 40% corroborated by FDA Adverse Event Reporting System (FAERS) data. Additionally, we found significant enrichment of identified gene-mechanism pairs in clinical trials terminated early due to safety concerns, highlighting the clinical utility of genetics-informed safety prediction. Notably, immune-related pathways were prominently associated with ADR, indicating particular sensitivity within immune modulation targets. Our comprehensive atlas, integrating genetic evidence with pharmacological mechanisms, provides a robust predictive framework for anticipating drug safety, potentially enhancing decision-making in drug development and pharmacovigilance. An interactive web interface allowing filtering by gene, phenotype, drug phase, and mechanism of action is available at https://shiny.parse-health.org/safety/.

Background: Interventions to prevent type 1 diabetes (T1D), an immune-mediated disease requiring lifelong treatment, remain limited. We sought to identify novel therapeutic targets for T1D through Mendelian randomization and colocalization using immune cell-derived instruments. Methods: We selected locally acting genetic variants from 14 transcriptomic studies to instrument expression of 8998 genes measured in immune cell types. Outcome associations were obtained from a T1D genome-wide association study that included 18,942 cases and 501,638 controls. Follow-up analyses included assessments of horizontal pleiotropy and novelty, as well as phenome-wide scans with colocalization (PheWAS-coloc) of instrumental variants. Results: We prioritized 21 genes ( CLNK , EED , LZTFL1 , MGAT4A , NAA38 , NFKB1 , PHACTR4 , PHLPP2 , PLEKHA1 , P2RY12 , REST , RGS14 , SERPINB6 , SESN3 , SLC25A29 , SPAG1 , STIM2 , THEMIS , TMEM80 , VSIR , ZNF217 ) that have not been identified in previous T1D genome-wide association studies. Notably, higher genetically predicted VSIR (encoding the immune checkpoint protein VISTA) was associated with decreased risk of T1D, providing human genetic support that complements existing animal-model evidence for VISTA’s protective role in autoimmune diseases. We also prioritized P2RY12 , which is targeted by several approved drugs, revealing a possible repurposing opportunity. PheWAS-coloc analyses further linked P2RY12 expression to Epstein-Barr virus EBNA-1 antibody levels, implicating a pathway relevant to autoimmunity. Conclusions: Our findings provide novel avenues for drug development and repurposing to prevent or delay T1D onset.

Background: Interventions to prevent type 1 diabetes (T1D), a disease requiring lifelong treatment, remain limited. We sought to identify novel therapeutic targets for T1D through Mendelian randomization and colocalization using immune cell-derived instruments. Methods: We selected locally-acting genetic variants from 14 transcriptomic studies to instrument expression of 8,998 genes measured in immune cell types. Outcome associations were obtained from a T1D genome-wide association study that included 18,942 cases and 501,638 controls. Follow-up analyses included assessments of horizontal pleiotropy and novelty, as well as phenome-wide scans with colocalization (PheWAS-coloc) of instrumental variants. Results: We prioritized 21 genes ( CLNK , EED , LZTFL1 , MGAT4A , NAA38 , NFKB1 , PHACTR4 , PHLPP2 , PLEKHA1 , P2RY12 , REST , RGS14 , SERPINB6 , SESN3 , SLC25A29 , SPAG1 , STIM2 , THEMIS , TMEM80 , VSIR , ZNF217 ) that have not been identified in previous T1D genome-wide association studies. Notably, higher genetically-predicted VSIR (encoding the immune checkpoint protein VISTA) was associated with decreased risk of T1D, providing human genetic support that complements existing animal-model evidence for VISTA’s protective role in autoimmune diseases. We also prioritized P2RY12 , which is targeted by several approved drugs, revealing a possible repurposing opportunity. PheWAS-coloc analyses further linked P2RY12 expression to Epstein-Barr virus EBNA-1 antibody levels, implicating a pathway relevant to autoimmunity. Conclusions: Our findings provide novel avenues for drug development and repurposing to prevent or delay T1D onset.

Schizophrenia is a neurodevelopmental psychiatric disorder characterized by symptoms of psychosis, thought disorder, and flattened affect. Immune mechanisms are associated with schizophrenia, though the precise nature of this relationship (causal, correlated, consequential) and the mechanisms involved are not fully understood. To elucidate these mechanisms, we conducted a transcriptome‐wide Mendelian randomization study using gene expression exposures from 29 human cis‐eQTL data sets encompassing 11 unique immune cell types, available from the eQTL catalog. These analyses highlighted 196 genes, including 67 located within the human leukocyte antigen (HLA) region. Enrichment analyses indicated an overrepresentation of immune genes, which was driven by the HLA genes. Stringent validation and replication steps retained 61 candidate genes, 27 of which were the sole causal signals at their respective loci, thereby representing strong candidate effector genes at known risk loci. We highlighted L3HYPDH as a potential novel schizophrenia risk gene and DPYD and MAPK3 as candidate drug repurposing targets. Furthermore, we performed follow‐up analyses focused on one of the candidate effectors, interferon regulatory transcription factor 3 (IRF3), which coordinates interferon responses to viral infections. We found evidence of shared genetic etiology between schizophrenia and autoimmune diseases at the IRF3 locus, and a significant enrichment of IRF3 chromatin binding at known schizophrenia risk loci. Our findings highlight a novel schizophrenia risk gene, potential drug repurposing opportunities, and provide support for IRF3 as a schizophrenia hub gene, which may play critical roles in mediating schizophrenia‐autoimmune comorbidities and the impact of infections on schizophrenia risk.

Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression, erythropoiesis, immune response and cellular trafficking. Mendelian randomisation of 292 disease outcomes in 1,492,717 participants revealed associations of iron-related loci and iron status with selected health outcomes across multiple domains. These associations were largely driven by HFE, which was associated with the largest iron variation. Our findings enhance understanding of iron homoeostasis and its biomedical consequences, suggesting that lifelong exposure to higher iron levels is likely associated with lower risk of anaemia-related disorders and higher risk of genitourinary, musculoskeletal, infectious and neoplastic diseases.

Background: Schizophrenia is a neurodevelopmental psychiatric disorder characterised by symptoms of psychosis, thought disorder, and flattened affect. Immune mechanisms are associated with schizophrenia, though the precise nature of this relationship (i.e., causal, correlated, consequential) and the mechanisms involved are not fully understood. Methods: To elucidate these mechanisms, we conducted a transcriptome-wide Mendelian randomization study using gene expression exposures from 29 human cis -eQTL datasets encompassing 11 unique immune cell types, all publicly available from the eQTL catalogue. Results: These analyses highlighted 196 genes, including 67 located within the human leukocyte antigen (HLA) region. Enrichment analyses indicated an over-representation of immune genes, which was driven by the HLA genes. Stringent validation and replication steps retained 61 candidate genes, 27 of which were the sole causal signals at their respective loci, thereby representing strong candidate effector genes at known risk loci. We highlighted L3HYPDH as a potential novel schizophrenia risk gene and DPYD and MAPK3 as candidate drug repurposing targets. Futhermore, we performed follow-up analyses focused on one of the candidate effectors, interferon regulatory transcription factor 3 ( IRF3 ), which coordinates interferon responses to viral infections. We found evidence of shared genetic aetiology between schizophrenia and autoimmune diseases at the IRF3 locus, and a significant enrichment of IRF3 chromatin binding at known schizophrenia risk loci. Conclusions: Our findings highlight a novel schizophrenia risk gene, potential drug repurposing opportunities, and provide support for IRF3 as a schizophrenia hub gene, which may play critical roles in mediating schizophrenia-autoimmune comorbidities and the impact of viral infections on schizophrenia risk.