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Updated: Jan 8, 2026
Assessing Iron Deposition in the Brains of 5xFAD Mice by Perls'/DAB Staining
Published on: May 23, 2025
Identification of genes underlying nigrostriatal iron accumulation: transcriptome-wide association study of
Thomas Welton1, Wuan Ting Saw2, Zhidong Zhou1
1Department of Research, National Neuroscience Institute, 11 Jln Tan Tock Seng, Singapore, 308433; Neuroscience Academic Clinical Programme, Duke-NUS Medical School, 8 College Rd, Singapore, 169857.
Background:
Nigrostriatal 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.
Methods:
We 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.
Findings:
We 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.
Interpretation:
Our 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.
Funding:
Supported by the Singapore National Medical Research Council and SingHealth/Duke-NUS Academic Medical Centre.
