Hermann Evan R, Chambers Emily, Davis Danielle N, Montgomery McKale R, Lin Dingbo, Chowanadisai Winyoo
Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, United States.
Front Genet. 2021 Mar 15;12:647946. doi: 10.3389/fgene.2021.647946. eCollection 2021.
The gene encodes a divalent metal transporter, ZIP8. is associated with pleiotropic effects across multiple tissues, including the brain. We determine the different brain magnetic resonance imaging (MRI) phenotypes associated with 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 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 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 , a trace mineral transport gene, is linked to brain structure differences and may affect brain development and nervous system function.
该基因编码一种二价金属转运蛋白ZIP8。它与包括大脑在内的多个组织的多效性效应相关。我们确定了与ZIP8相关的不同脑磁共振成像（MRI）表型。我们采用全表型关联研究方法，随后进行联合和条件关联分析。利用来自针对成年英国生物银行参与者的脑MRI全基因组关联研究的汇总统计数据集，我们系统地选择了与ZIP8基因座500 kb内单核苷酸多态性（SNP）相关的所有脑MRI表型。对于所有显著的脑MRI表型，我们使用GCTA-COJO来确定独立关联信号的数量，并为每种脑MRI表型识别索引SNP。通过LDpair证实了具有多个独立信号的脑表型的连锁平衡。我们鉴定出24种脑MRI表型，它们因MRI类型和脑区而异，并且包含一个与ZIP8基因座相关的SNP。错义ZIP8多态性rs13107325与22种脑MRI表型相关。在已发表的英国生物银行数据集中存在的罕见ZIP8变体与6种也与rs13107325相关的脑MRI表型相关。在这24个数据集中，GCTA-COJO识别出另外4个关联信号，并使用LDpair证实它们与rs13107325处于连锁平衡。除rs13107325外，这些额外的关联信号代表了新的可能致病SNP。这项研究为一种微量矿物质转运基因ZIP8的遗传变异如何与脑结构差异相关联以及可能如何影响脑发育和神经系统功能提供了线索。
