Glycobiology and schizophrenia: a biological hypothesis emerging from genomic research


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.

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Fig. 1: Glycosylation enzymes unambiguously associated with schizophrenia through GWAS.
Fig. 2: Select neuronal proteins critically modified through glycosylation and associated with schizophrenia through GWAS.


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We would like to thank Stephan Ripke of MGH and Broad Institute for allowing inclusion of the current estimate of schizophrenia GWAS associations and B3GAT1 as a personal communication. This work was supported by a foundation grant from the Stanley Center for Psychiatric Research at the Broad Institute of Harvard/MIT (awarded to RGM).

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Correspondence to Robert G. Mealer.

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Mealer, R.G., Williams, S.E., Daly, M.J. et al. Glycobiology and schizophrenia: a biological hypothesis emerging from genomic research. Mol Psychiatry 25, 3129–3139 (2020).

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