Glycobiology and schizophrenia: a biological hypothesis emerging from genomic research

Autor: Sarah E. Williams, Edward M. Scolnick, Richard D. Cummings, Jordan W. Smoller, Robert G. Mealer, Mark J. Daly
Rok vydání: 2020
Předmět:
Zdroj: Mol Psychiatry
ISSN: 1476-5578
1359-4184
DOI: 10.1038/s41380-020-0753-1
Popis: Advances in genomics are opening new windows into the biology of schizophrenia. Though common variants individually have small effects on disease risk, GWAS provide a powerful opportunity to explore pathways and mechanisms contributing to pathophysiology. Here, we highlight an underappreciated biological theme emerging from GWAS: the role of glycosylation in schizophrenia. The strongest coding variant in schizophrenia GWAS is a missense mutation in the manganese transporter SLC39A8, which is associated with altered glycosylation patterns in humans. Furthermore, variants near several genes encoding glycosylation enzymes are unambiguously associated with schizophrenia: FUT9, MAN2A1, TMTC1, GALNT10, and B3GAT1. Here, we summarize the known biological functions, target substrates, and expression patterns of these enzymes as a primer for future studies. We also highlight a subset of schizophrenia-associated proteins critically modified by glycosylation including glutamate receptors, voltage-gated calcium channels, the dopamine D2 receptor, and complement glycoproteins. We hypothesize that common genetic variants alter brain glycosylation and play a fundamental role in the development of schizophrenia. Leveraging these findings will advance our mechanistic understanding of disease and may provide novel avenues for treatment development.
Databáze: OpenAIRE
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