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

Abstract

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.

Impact of Zinc Transport Mechanisms on Embryonic and Brain Development

“…These results have been confirmed by work from Dickinson and colleagues, who showed that ZIP8 homozygous KO embryos have heart morphologic defects at embryonic day 14.5 [217]. Furthermore, and consistent with its detection throughout the CNS, SLC39A8 SNPs and mutations have been associated with specific brain structure alteration phenotypes by MRI [397,398]. Interestingly, over the past decade, SLC39A8 polymorphisms have been largely shown to be associated with higher schizophrenia risk [399][400][401][402][403][404].…”

“…Mutations in SLC39A8 are also associated with congenital disorder of glycosylation, type IIn [218,219], in which patients display normal localization of the mutant ZIP8 protein, but exhibit low blood Zn and Mn levels as well as high levels of these cations in urine, suggesting renal wasting of the cations. SLC39A8 is also expressed in the brain, and SLC39A8 SNPs and mutations have been associated with specific brain structure alteration phenotypes by MRI [397,398]; SLC39A8 polymorphisms have also been shown to be associated with higher schizophrenia risk [399][400][401][402][403][404]. Thus, the phenotypes associated with mutations in SLC39A8 are complex and will require additional study.…”

The schizophrenia-associated missense variant rs13107325 regulates dendritic spine density

“…rs13107325 is a highly pleiotropic missense variant that showed strong association with many complex human traits and diseases, including schizophrenia [ 5 , 15 ], blood lipids [ 36 , 55 ], steatohepatitis [ 56 ], intelligence [ 57 ], Crohn’s disease [ 58 ], severe idiopathic scoliosis [ 59 ], brain structure [ 60 – 62 ], and others. The risk allele of rs13107325 only appears in European (8%) and American (5%) populations, but not in Asian and African populations (Supplementary Figure 2 ).…”

Genetics and Epigenetics of Manganese Toxicity

“…The SLC39A8 rs13107325 variant is one of the most pleiotropic polymorphisms known so far and has been repeatedly associated with neurological and metabolic disorders [ 45 , 46 ]. Interestingly, SLC39A8 polymorphisms, including rs13107325, and polymorphisms in linkage disequilibrium with rs13107325, are associated with different magnetic resonance imaging phenotypes of the brain [ 47 ].…”