Using phenome-wide association to investigate the function of a schizophrenia risk locus at SLC39A8

McCoy, Thomas H.; Pellegrini, Amelia M.; Perlis, Roy H.

doi:10.1038/s41398-019-0386-9

Cited by 19 publications

(18 citation statements)

References 27 publications

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“…Given the association of p.A391T with a broad range of phenotypes, determining how "subclinical" dysglycosylation contributes to disease pathogenesis may elucidate novel mechanisms in schizophrenia, scoliosis, and Crohn's disease. [3][4][5]25 Dysglycosylation in heterozygous SLC39A8-CDG-mutation carriers has not been previously reported. Given that the less severe p.A391T mutation is associated with multiple diseases through GWAS and does not cause a CDG in homozygous carriers, we hypothesize that heterozygous carriers of CDGcausing SLC39A8 mutations may have previously unappreciated health consequences due to their hypofunctioning allele and subsequent dysglycosylation.…”

Section: Discussionmentioning

confidence: 91%

N‐glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency

Park

Mealer

Elias

et al. 2020

J of Inher Metab Disea

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Congenital disorders of glycosylation (CDG) are a growing group of inborn metabolic disorders with multiorgan presentation. SLC39A8-CDG is a severe subtype caused by biallelic mutations in the manganese transporter SLC39A8, reducing levels of this essential cofactor for many enzymes including glycosyltransferases. The current diagnostic standard for disorders of Nglycosylation is the analysis of serum transferrin. Exome and Sanger sequencing were performed in two patients with severe neurodevelopmental phenotypes suggestive of CDG. Transferrin glycosylation was analyzed by highperformance liquid chromatography (HPLC) and isoelectric focusing in addition to comprehensive N-glycome analysis using matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry (MS). Atomic absorption spectroscopy was used to quantify whole blood manganese levels. Both patients presented with a severe, multisystem disorder, and a

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Section: Discussionmentioning

confidence: 91%

N‐glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency

Park

Mealer

Elias

et al. 2020

J of Inher Metab Disea

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“…Moreover, an “unbiased phenome-wide approach” was used in an attempt to understand phenotypic implications of the association of the SLC39A8 p.Ala391Thr variant with schizophrenia. In a large genomic biobank, 50 traits were generated—based on diagnostic codes using latent Dirichlet allocation, and these were examined for correlation with the risk variant; subsequently, any significant phenotypes were further characterized by examining any association with individual diagnostic codes contributing to the trait [63]. Among the 50 phenotypes, one was associated at an experiment-wide significance threshold (beta = 0.003; uncorrected P = 4.9 × 10 −4 ), comprising predominantly brain-related codes—including “intracranial hemorrhage,” “cerebrovascular disease,” and “delirium/dementia” [63].…”

Section: Slc39a8 Clinical Studiesmentioning

confidence: 99%

“…In a large genomic biobank, 50 traits were generated—based on diagnostic codes using latent Dirichlet allocation, and these were examined for correlation with the risk variant; subsequently, any significant phenotypes were further characterized by examining any association with individual diagnostic codes contributing to the trait [63]. Among the 50 phenotypes, one was associated at an experiment-wide significance threshold (beta = 0.003; uncorrected P = 4.9 × 10 −4 ), comprising predominantly brain-related codes—including “intracranial hemorrhage,” “cerebrovascular disease,” and “delirium/dementia” [63]. These findings suggest that the functional SLC39A8 variant, previously associated with schizophrenia risk, is also correlated with increased liability to cerebrovascular disease.…”

Section: Slc39a8 Clinical Studiesmentioning

confidence: 99%

SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside

Nebert

Liu

2019

Hum Genomics

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SLC39A8 is an evolutionarily highly conserved gene that encodes the ZIP8 metal cation transporter in all vertebrates. SLC39A8 is ubiquitously expressed, including pluripotent embryonic stem cells; SLC39A8 expression occurs in every cell type examined. Uptake of ZIP8-mediated Mn2+, Zn2+, Fe2+, Se4+, and Co2+ represents endogenous functions—moving these cations into the cell. By way of mouse genetic differences, the phenotype of “subcutaneous cadmium-induced testicular necrosis” was assigned to the Cdm locus in the 1970s. This led to identification of the mouse Slc39a8 gene, its most closely related Slc39a14 gene, and creation of Slc39a8-overexpressing, Slc39a8(neo/neo) knockdown, and cell type-specific conditional knockout mouse lines; the Slc39a8(−/−) global knockout mouse is early-embryolethal. Slc39a8(neo/neo) hypomorphs die between gestational day 16.5 and postnatal day 1—exhibiting severe anemia, dysregulated hematopoiesis, hypoplastic spleen, dysorganogenesis, stunted growth, and hypomorphic limbs. Not surprisingly, genome-wide association studies subsequently revealed human SLC39A8-deficiency variants exhibiting striking pleiotropy—defects correlated with clinical disorders in virtually every organ, tissue, and cell-type: numerous developmental and congenital disorders, the immune system, cardiovascular system, kidney, lung, liver, coagulation system, central nervous system, musculoskeletal system, eye, and gastrointestinal tract. Traits with which SLC39A8-deficiency variants are currently associated include Mn2+-deficient hypoglycosylation; numerous birth defects; Leigh syndrome-like mitochondrial redox deficiency; decreased serum high-density lipoprotein-cholesterol levels; increased body mass index; greater risk of coronary artery disease, hypotension, cardiovascular death, allergy, ischemic stroke, schizophrenia, Parkinson disease, inflammatory bowel disease, Crohn disease, myopia, and adolescent idiopathic scoliosis; systemic lupus erythematosus with primary Sjögren syndrome; decreased height; and inadvertent participation in the inflammatory progression of osteoarthritis.

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“… 19 ). Recent evidence from a PheWAS study indicates that the ZIP8 A391T missense variant is associated with intracranial hemorrhage and cerebrovascular disease 20 , suggesting that ZIP8 may play a role in the BBB.…”

Section: Introductionmentioning

confidence: 99%

Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling

et al. 2021

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Schizophrenia is a complex and heterogenous disease that presents with abnormalities in glutamate signaling and altered immune and inflammatory signals. Genome-wide association studies have indicated specific genes and pathways that may contribute to schizophrenia. We assessed the impact of the functional missense variant SLC39A8 (ZIP8)-A391T (ZIP8A391T) on zinc transport, glutamate signaling, and the neuroinflammatory response. The ZIP8A391T mutation resulted in reduced zinc transport into the cell, suggesting a loss in the tight control of zinc in the synaptic cleft. Electrophysiological recordings from perturbed neurons revealed a significant reduction in NMDA- and AMPA-mediated spontaneous EPSCs (sEPSCs) and a reduction in GluN2A and GluA1/2/3 receptor surface expression. All phenotypes were rescued by re-expression of wild-type ZIP8 (ZIP8WT) or application of the membrane-impermeable zinc chelator ZX1. ZIP8 reduction also resulted in decreased BBB integrity, increased IL-6/IL-1β protein expression, and increased NFκB following TNFα stimulation, indicating that ZIP8 loss-of-function may exacerbate immune and inflammatory signals. Together, our findings demonstrate that the A391T missense mutation results in alterations in glutamate and immune function and provide novel therapeutic targets relevant to schizophrenia.

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Using phenome-wide association to investigate the function of a schizophrenia risk locus at SLC39A8

Cited by 19 publications

References 27 publications

N‐glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency

N‐glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency

SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside

Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling

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