Genetic associations and candidate functional genes linking depression and obesity: a multi-omics integrative study

Exploratory Genome and Transcriptome-Wide Association Analyses of Addiction-Related Phenotypes in a Twin Cohort

Background/Objectives: Substance use behaviors share a complex, overlapping polygenic architecture, yet translating genome-wide association study (GWAS) findings into actionable biological mechanisms remains challenging. This study aimed to characterize the genetic architecture of five substance use traits (alcohol consumption, alcohol dependence, nicotine use, illicit drug use, and behavioral disinhibition) and identify shared and distinct gene expression signatures within the neural circuits governing addiction. Methods: We reanalyzed 7188 individuals from the Minnesota Center for Twin and Family Research (MCTFR) cohort utilizing longitudinal composite phenotypes spanning five substance-use domains and general behavioral disinhibition. Post-QC, 6874 individuals were retained for downstream analysis. Following genomic imputation and linear mixed model GWAS (GEMMA), we utilized the SNipar framework to partition polygenic risk scores (PRS) into direct and indirect genetic effects, investigating intergenerational shifts in genetic penetrance and effects of assortative mating. Finally, we integrated our summary statistics with brain tissue reference panels to perform a transcriptome-wide association study (TWAS) modeling genetically regulated gene expression within neural circuits relevant to addiction. Results: Partitioning of polygenic risk revealed that while surface-level parental DNA correlations were modest (r = 0.08), underlying latent genetic correlations approached unity (Rδ ≈ 0.99), indicating that addiction risk clustering in families is driven by intense assortive mating and concentrated biological inheritance. Multi-phenotype TWAS identified several significant gene–phenotype associations—notably ADAM32 and SLC9A3, which demonstrated pleiotropic effects across multiple substance use categories. Crucially, these significant TWAS signals were enriched in striatal structures (caudate, putamen, substantia nigra) and frontal cortical regions. Conclusions: Our findings support a model of shared genetic liability across diverse substance use behaviors, mediated by specific gene expression patterns in the mesolimbic dopamine system and frontal cortex. By integrating multi-phenotype GWAS and TWAS, this study highlights pleiotropic candidate genes and provides critical insights into the tissue-specific neurobiological pathways underlying addiction vulnerability.

Shared Genetic Architecture Between Epigenetic Aging and Musculoskeletal Diseases

Background: The directional relationship between epigenetic age acceleration (EAA) and musculoskeletal disease remains unresolved. This study integrated bidirectional Mendelian randomization (MR) with multi-layer genomic evidence to evaluate directionality, shared genetic architecture, and robustness to instrument definition. Methods: Four EAA clocks (IEAA, PhenoAA, HannumAA, and GrimAA) and ten musculoskeletal phenotypes were analyzed in a 10 × 4 bidirectional two-sample MR design. EAA instruments underwent GRCh37 functional annotation, genome-wide-significant external-association screening for the index variants and European linkage-disequilibrium proxies, pair-specific Steiger filtering, and conservative Set A/B/C sensitivity analyses. The juvenile-arthritis reverse models underwent instrument-flow reconstruction, strength assessment, liability-scale directionality testing, and minimum-detectable-effect analysis. Additional analyses comprised LD score regression (LDSC), PLACO+ cross-trait locus mapping, Bayesian colocalization, multivariable MR (MVMR) with exact-SNP matched univariable comparators, and integrated evidence synthesis. Results: Forward MR yielded two nominal HannumAA associations. The inverse HannumAA–spondyloarthritis estimate remained directionally consistent across the original, Steiger-filtered, and conservative external-association-filtered sets, whereas the HannumAA–pain-in-thoracic-spine estimate lost nominal significance in the conservative set; no forward result survived correction across 40 tests. GrimAA forward estimates were sensitive to use of the fallback instrument threshold. Reverse MR identified ten nominal associations. For juvenile arthritis, three harmonized instruments had F statistics of 51.25–102.35; liability-scale Steiger comparisons supported the tested direction under all 16 outcome-by-prevalence combinations, although the 788-case discovery GWAS and possible winner’s curse remained important limitations. LDSC identified FDR-significant positive genetic correlations of GrimAA with hip osteoarthritis (r_g = 0.267, p = 8.49 × 10−5, q = 0.0019) and knee osteoarthritis (r_g = 0.269, p = 9.52 × 10−5, q = 0.0019). PLACO+ identified 738 genome-wide-significant cross-trait variants and 65 independent loci; six of 37 evaluable loci showed strong colocalization. Of 96 MVMR models, 43 had primary-exposure conditional F ≥ 10, and 32 also had candidate-trait conditional F ≥ 10. After exact-SNP matching, the 43 primary-strength models were operationally classified as 35 partially attenuated and eight independent-signal models, with no fully attenuated model; no adjusted association survived multiplicity correction. Conclusions: The results support a prioritized genomic map with substantial instrument- and model-specific uncertainty. Disease-to-clock signals were richer than clock-to-disease signals, GrimAA shared polygenic architecture with osteoarthritis, and selected loci showed strong shared-variant evidence, while the MR and MVMR findings remained unsuitable for definitive causal or mediation claims.

Mapping the Heterogeneity of Major Depressive Disorder: A Systematic Review of Multi-Omics Integration Studies

Results indicate that multi-omics integration, in addition to explaining the molecular architecture of MDD, also characterizes patient subgroups with pathophysiological mechanisms, dimensions of symptoms, and disease treatment, which demonstrates that there is a shift in psychiatry toward a more mechanistic approach.

Genetic clusters of BMI reveal symptom-specific causal effects on depression.

It is indicated that the causal effect of BMI on depression detected in typical non-clustered Mendelian randomization is driven to an extent by appetite, with no or inconsistent evidence for effects on core psychological symptoms such as anhedonia and depressed mood.

Cross-definition GWAS of IBS in 2.8 million individuals reveals cardiometabolic and triglyceride-linked mechanisms

This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance and linking IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.

Genetic evidence links hypertension to accelerated brain aging