Mendelian Randomization and Multi-Omics in Drug Target Discovery: From Gut to Brain and Skin

The translation of genetic discoveries into therapeutic targets remains a major challenge in precision medicine. Traditional drug development pipelines suffer from high attrition rates, partly due to limited understanding of causal relationships between molecular targets and diseases. Mendelian randomization (MR), which uses genetic variants as instrumental variables, offers a powerful framework to infer causality between modifiable exposures — including gene expression (eQTL), circulating protein levels (pQTL), and metabolites — and disease outcomes. When integrated with multi-omics data and colocalization analyses (e.g., SMR/HEIDI, coloc), MR can prioritize drug targets with human genetic support, an approach shown to more than double late-stage clinical trial success rates.While recent efforts have applied MR methodology within single disease domains — most notably oncology — systematic, cross-disease applications integrating drug-target MR with multi-omics colocalization across gastrointestinal, inflammatory, neuropsychiatric, and skin conditions remain scarce. Yet emerging epidemiological and genetic evidence points to substantial shared causal architecture along the gut-brain, gut-skin, gut-immune, and gut-metabolic axes. For example, inflammatory bowel disease (IBD) shares pleiotropic loci with depression; atopic dermatitis, psoriasis, and acne have been causally linked to gut dysbiosis and systemic inflammation; and the gut-skin-brain axis has been proposed as a unifying framework for comorbid gastrointestinal, dermatological, and mental health conditions. Disentangling these shared mechanisms through pleiotropic and multi-trait MR offers a unique opportunity to identify drug targets with broad therapeutic potential across multiple organ systems and to anticipate on-target side effects before clinical development.This Research Topic aims to advance Mendelian randomization-based drug target discovery, with a deliberate cross-disease focus on gastrointestinal diseases and their inflammatory, neuropsychiatric, and dermatological comorbidities. By integrating two-sample and drug-target MR with eQTL, pQTL, GWAS, and colocalization analyses, we seek to identify causal effects of circulating proteins, gene expression, and metabolites on disease risk, and to prioritize actionable therapeutic targets supported by human genetic evidence. A central ambition is to disentangle shared causal mechanisms along the gut-brain, gut-skin, gut-immune, and gut-metabolic axes through pleiotropic and multi-trait MR, thereby uncovering targets with broad therapeutic potential across multiple conditions — including inflammatory bowel disease, depression, anxiety, atopic dermatitis, psoriasis, acne, and metabolic dysfunction-associated steatotic liver disease (MASLD). We further aim to evaluate drug repurposing opportunities by re-interrogating marketed drug targets for new indications, anticipate on-target side effects through phenome-wide MR, and validate prioritized targets using in vitro, in vivo, or independent clinical datasets. By bridging genetics, multi-omics, and pharmacology, this collection will accelerate the translation of genetic insights into safe, broadly applicable therapeutics across traditionally separated medical specialties.We welcome original research, review articles, and method papers. Submissions may cover, but are not limited to, the following topics:• Two-sample and drug-target Mendelian randomization for causal target identification across gastrointestinal, inflammatory, neuropsychiatric, and skin diseases;• Integration of eQTL, pQTL, and GWAS data with colocalization (SMR/HEIDI, coloc, SuSiE) for target prioritization and pleiotropy assessment;• Cross-disease and pleiotropic MR for shared mechanisms along the gut-brain, gut-skin, gut-immune, and gut-metabolic axes, with emphasis on comorbid conditions (e.g., IBD-depression, IBD-anxiety, psoriasis-depression, atopic dermatitis-anxiety, acne-gut dysbiosis);• Drug-target MR for drug repurposing and phenome-wide MR for anticipating on-target side effects across multiple therapeutic areas;• Functional validation of MR-prioritized targets using in vitro assays, in vivo models, organoids, patient-derived samples, or independent clinical cohorts;• Methodological advances addressing horizontal pleiotropy, weak instruments, sample overlap, and multi-ancestry generalizability in drug-target MR.Cross-disease, multi-ancestry, and multi-cohort studies that combine MR with orthogonal multi-omics, experimental validation, or clinical translation are particularly encouraged. Studies focusing on the gut-skin-brain axis as a unifying framework for drug target discovery are also welcome. Submissions based on re-analysis of pre-existing data collections will be considered if they include appropriate experimental validation or novel data analysis methodologies with verification through independent datasets. Topic editors: Erbao Chen, Junhui Chen, Zhongqiu Xie Source: https://www.frontiersin.org/research-topics/82860/mendelian-randomization-and-multi-omics-in-drug-target-discovery-from-gut-to-brain-and-skin