A role for zinc transporter gene SLC39A12 in the nervous system and beyond.

The SLC39A12 gene encodes the zinc transporter protein ZIP12, which is expressed across many tissues and is highly abundant in the vertebrate nervous system. As a zinc transporter, ZIP12 functions to transport zinc across cellular membranes, including cellular zinc influx across the plasma membrane. Genome-wide association and exome sequencing studies have shown that brain susceptibility-weighted magnetic resonance imaging (MRI) intensity is associated with ZIP12 polymorphisms and rare mutations. ZIP12 is required for neural tube closure and embryonic development in Xenopus tropicalis. Frog embryos depleted of ZIP12 by antisense morpholinos develop an anterior neural tube defect and lack viability. ZIP12 is also necessary for neurite outgrowth and mitochondrial function in mouse neural cells. ZIP12 mRNA is increased in brain regions of schizophrenic patients. Outside of the nervous system, hypoxia induces ZIP12 expression in multiple mammalian species, including humans, which leads to endothelial and smooth muscle thickening in the lung and contributes towards pulmonary hypertension. Other studies have associated ZIP12 with other diseases such as cancer. Given that ZIP12 is highly expressed in the brain and that susceptibility-weighted MRI is associated with brain metal content, ZIP12 may affect neurological diseases and psychiatric illnesses such as Parkinson's disease, Alzheimer's disease, and schizophrenia. Furthermore, the induction of ZIP12 and resultant zinc uptake under pathophysiological conditions may be a critical component of disease pathology, such as in pulmonary hypertension. Drug compounds that bind metals like zinc may be able to treat diseases associated with impaired zinc homeostasis and altered ZIP12 function.

Brain Magnetic Resonance Imaging Phenome-Wide Association Study With Metal Transporter Gene SLC39A8.

The SLC39A8 gene encodes a divalent metal transporter, ZIP8. SLC39A8 is associated with pleiotropic effects across multiple tissues, including the brain. We determine the different brain magnetic resonance imaging (MRI) phenotypes associated with SLC39A8. We used a phenome-wide association study approach followed by joint and conditional association analysis. Using the summary statistics datasets from a brain MRI genome-wide association study on adult United Kingdom (UK) Biobank participants, we systematically selected all brain MRI phenotypes associated with single-nucleotide polymorphisms (SNPs) within 500 kb of the SLC39A8 genetic locus. For all significant brain MRI phenotypes, we used GCTA-COJO to determine the number of independent association signals and identify index SNPs for each brain MRI phenotype. Linkage equilibrium for brain phenotypes with multiple independent signals was confirmed by LDpair. We identified 24 brain MRI phenotypes that vary due to MRI type and brain region and contain a SNP associated with the SLC39A8 locus. Missense ZIP8 polymorphism rs13107325 was associated with 22 brain MRI phenotypes. Rare ZIP8 variants present in a published UK Biobank dataset are associated with 6 brain MRI phenotypes also linked to rs13107325. Among the 24 datasets, an additional 4 association signals were identified by GCTA-COJO and confirmed to be in linkage equilibrium with rs13107325 using LDpair. These additional association signals represent new probable causative SNPs in addition to rs13107325. This study provides leads into how genetic variation in SLC39A8, a trace mineral transport gene, is linked to brain structure differences and may affect brain development and nervous system function.