@article{653c18d871c747d1beb75a1670611c9e,
title = "Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease",
abstract = "ZIP8 is a metal transporter with a role in manganese (Mn) homeostasis. A common genetic variant in ZIP8 (rs13107325; A391T) ranks in the top 10 of pleiotropic SNPs identified in GWAS; A391T has associations with an increased risk of schizophrenia, obesity, Crohn{\textquoteright}s disease, and reduced blood Mn. Here, we used CRISPR/Cas9-mediated knockin (KI) to generate a mouse model of ZIP8 A391T (Zip8 393T-KI mice). Recapitulating the SNP association with blood Mn, blood Mn was reduced in Zip8 393T-KI mice. There was restricted abnormal tissue Mn homeostasis, with decreases in liver and kidney Mn and a reciprocal increase in biliary Mn, providing in vivo evidence of hypomorphic Zip8 function. Upon challenge in a chemically induced colitis model, male Zip8 393T-KI mice exhibited enhanced disease susceptibility. ZIP8 391-Thr associated with reduced triantennary plasma N-glycan species in a population-based cohort to define a genotype-specific glycophenotype hypothesized to be linked to Mn-dependent glycosyltransferase activity. This glycophenotype was maintained in a cohort of patients with Crohn{\textquoteright}s disease. These data and the pleiotropic disease associations with ZIP8 391-Thr suggest underappreciated roles of Mn homeostasis in complex human disease.",
author = "Laxmi Sunuwar and Azra Frkatovi{\'c} and Sodbo Sharapov and Qinchuan Wang and Neu, {Heather M.} and Xinqun Wu and Talin Haritunians and Fengyi Wan and Sarah Michel and Shaoguang Wu and Mark Donowitz and Dermot McGovern and Gordan Lauc and Cynthia Sears and Joanna Melia",
note = "Funding Information: The authors acknowledge the technical assistance of Chip Hawkins in the Transgenic Core Laboratory at Johns Hopkins University School of Medicine, George McNamara in the Imaging Core of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Johns Hopkins Conte Gastrointestinal Core Center (P30 DK-089502), and the Johns Hopkins University School of Medicine Transcriptomics and Deep Sequencing Core. The authors thank Mark Anderson for helpful discussions. Funding was provided by the NIH (DK114478 to JM), National Science Foundation (CHE1708732 to SM), and Russian Science Foundation (19-15-00115 to SS). Internal funding was provided through the Johns Hopkins University School of Medicine Clinician Scientist Award, 2019 Johns Hopkins University School of Medicine Core Coins Program, and the Johns Hopkins Specialized Center for Research Excellence in Sex Differences (U54AG062333 to JM). Publisher Copyright: Copyright: {\textcopyright} 2020, Sunuwar et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",
year = "2020",
month = oct,
day = "15",
doi = "10.1172/jci.insight.140978",
language = "English (US)",
volume = "5",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "20",
}