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.
Highlights
Manganese is an essential mineral for neurodevelopment and brain function, high manganese exposure can lead to neurotoxicity that can manifest as parkinsonism and psychosis (Horning et al, 2015)
We found that singlenucleotide polymorphism (SNP) at or near the SLC39A8 locus were associated with 24 different brain magnetic resonance imaging (MRI) phenotypes
SNPs that are in high linkage disequilibrium (LD) with rs13107325 (Supplementary Figure 1, r2 > 0.85) are linked to 22 brain MRI phenotypes (Table 1, p-value < 5.0 × 10−8)
Summary
Manganese is an essential mineral for neurodevelopment and brain function, high manganese exposure can lead to neurotoxicity that can manifest as parkinsonism and psychosis (Horning et al, 2015). Subjects homozygous for rs13107325 have low whole blood manganese (Ng et al, 2015) and plasma manganese (Haller et al, 2018) concentrations and altered protein glycosylation (Lin et al, 2017) This missense ZIP8 polymorphism is associated with pleiotropic effects including childhood neurodevelopment and behavioral problems (Wahlberg et al, 2018), lower fluid intelligence (Hill et al, 2019), and greater risks for schizophrenia (Carrera et al, 2012; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014; Pickrell et al, 2016) and Crohn’s disease (Li et al, 2016). The significance of associations between the total number of coding or loss of function variants and brain MRI phenotypes for brain region and hemisphere was set at p < 0.05
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