Identification of genes underlying nigrostriatal iron accumulation: transcriptome-wide association study of iron-sensitive brain MRI.

BackgroundNigrostriatal iron accumulation is a hallmark of ageing and neurodegenerative diseases, but the molecular mechanisms regulating iron deposition in the human brain remain unclear. Identifying genes linked to iron accumulation could reveal new pathways for neuroprotection and therapeutic targeting.MethodsWe performed a discovery-replication transcriptome-wide association study (TWAS), integrating GWAS data for quantitative susceptibility mapping and T2∗ MRI measures (n = 29,579) with expression quantitative trait locus data for the substantia nigra, putamen, and caudate. Single-tissue analyses were complemented by multi-tissue TWAS, colocalisation, and summary Mendelian randomisation (SMR + HEIDI) to evaluate biological plausibility and causal evidence. Functional enrichment and comparison with ageing and Parkinson's disease transcriptomic datasets were conducted.FindingsWe identified 230 genes associated with nigrostriatal iron, of which 40 were replicable. Of these, 32 had no previous reported links to brain iron. Replicated genes converged on metal ion transport and inflammatory pathways, with notable associations involving calcium channel (CACNB2), zinc transporter (SLC39A12/ZIP12), and sorting nexin (SNX31) genes. SMR + HEIDI and colocalisation highlighted several putatively causal genes, including SNX31 and TMEM206. Overlap with Parkinson's disease substantia nigra differential expression data highlighted a subset of genes (5.22%), particularly SLC39A12.InterpretationOur data implicate a role of coordinated interactions among iron, zinc, and calcium homoeostasis pathways in nigrostriatal iron accumulation in the general population, with region-specific regulation differing between substantia nigra and dorsal striatum. These findings nominate new mechanistic targets for experimental validation in neurodegeneration.FundingSupported by the Singapore National Medical Research Council and SingHealth/Duke-NUS Academic Medical Centre.