Candidate gene analysis of the human natural killer-1 carbohydrate pathway and perineuronal nets in schizophrenia: B3GAT2 is associated with disease risk and cortical surface area

Anna K. Kähler, Srdjan Djurovic, Lars M. Rimol, Andrew A. Brown, Lavinia Athanasiu, Erik G. Jönsson, Thomas Hansen, Ómar Gústafsson, Håkan Hall, Ina Giegling, Pierandrea Muglia, Sven Cichon, Marcella Rietschel, Olli P. H. Pietiläinen, Leena Peltonen, Elvira Bramon, David Collier, David St Clair, Engilbert Sigurdsson, Hannes Petursson & 8 others Dan Rujescu, Ingrid Melle, Thomas Werge, Vidar M. Steen, Anders M Dale, Russell T Matthews, Ingrid Agartz, Ole A. Andreassen

Research output: Contribution to journalArticle

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Abstract

Background
The Human Natural Killer-1 carbohydrate (HNK-1) is involved in neurodevelopment and synaptic plasticity. Extracellular matrix structures called perineuronal nets, condensed around subsets of neurons and proximal dendrites during brain maturation, regulate synaptic transmission and plasticity.

Methods
Ten genes of importance for HNK-1 biosynthesis (B3GAT1, B3GAT2, and CHST10) or for the formation of perineuronal nets (TNR, BCAN, NCAN, HAPLN1, HAPLN2, HAPLN3, and HAPLN4) were investigated for potential involvement in schizophrenia (SCZ) susceptibility, by genotyping 104 tagSNPs in the Scandinavian Collaboration on Psychiatric Etiology sample (849 cases; 1602 control subjects). Genome-wide association study imputation data from the European SGENE-plus sample (2663 cases; 13,498 control subjects) were used for comparison. The effect of SCZ risk alleles on brain structure was investigated in a Norwegian subset (98 cases; 177 control subjects) with structural magnetic resonance imaging data.

Results
Five single nucleotide polymorphisms (SNPs), located in two adjacent estimated linkage disequilibrium blocks in the first intron of ß-1,3-glucuronyltransferase 2 (B3GAT2), were nominally associated with SCZ (.004 = Pempirical = .05). The rs2460691 was significantly associated in the comparison sample and in the meta-analysis after correction for all 121 SNP/haplotype tests (Praw = 1 × 10-4; Pcorrected = .018). Increased dosage of the rs2460691 SCZ risk allele was associated with decreased cortical area (p = .002) but not thickness or hippocampal volume. A second SNP (r2 = .24 with rs10945275), which conferred the highest SCZ risk effect in the Norwegian subset, was also associated with cortical area.

Conclusions
The present results suggest that effects on biosynthesis of the neuronal epitope HNK-1, through common B3GAT2 variation, could increase the risk of SCZ, possibly by decreasing cortical area.
Original languageEnglish
Pages (from-to)90-96
Number of pages7
JournalBiological Psychiatry
Volume69
Issue number1
Early online date15 Oct 2010
DOIs
Publication statusPublished - 1 Jan 2011

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Genetic Association Studies
Schizophrenia
Carbohydrates
Single Nucleotide Polymorphism
Neuronal Plasticity
Alleles
Glucuronosyltransferase
Genome-Wide Association Study
Linkage Disequilibrium
Brain
Dendrites
Synaptic Transmission
Introns
Haplotypes
Extracellular Matrix
Psychiatry
Meta-Analysis
Epitopes
Magnetic Resonance Imaging
Neurons

Keywords

  • association study
  • B3GAT1
  • GlcAT-P
  • GlcAT-S
  • MRI
  • psychosis

Cite this

Candidate gene analysis of the human natural killer-1 carbohydrate pathway and perineuronal nets in schizophrenia : B3GAT2 is associated with disease risk and cortical surface area. / Kähler, Anna K.; Djurovic, Srdjan; Rimol, Lars M.; Brown, Andrew A.; Athanasiu, Lavinia; Jönsson, Erik G.; Hansen, Thomas; Gústafsson, Ómar; Hall, Håkan; Giegling, Ina; Muglia, Pierandrea; Cichon, Sven; Rietschel, Marcella; Pietiläinen, Olli P. H.; Peltonen, Leena; Bramon, Elvira; Collier, David; St Clair, David; Sigurdsson, Engilbert; Petursson, Hannes; Rujescu, Dan; Melle, Ingrid; Werge, Thomas; Steen, Vidar M.; Dale, Anders M; Matthews, Russell T; Agartz, Ingrid; Andreassen, Ole A.

In: Biological Psychiatry, Vol. 69, No. 1, 01.01.2011, p. 90-96.

Research output: Contribution to journalArticle

Kähler, AK, Djurovic, S, Rimol, LM, Brown, AA, Athanasiu, L, Jönsson, EG, Hansen, T, Gústafsson, Ó, Hall, H, Giegling, I, Muglia, P, Cichon, S, Rietschel, M, Pietiläinen, OPH, Peltonen, L, Bramon, E, Collier, D, St Clair, D, Sigurdsson, E, Petursson, H, Rujescu, D, Melle, I, Werge, T, Steen, VM, Dale, AM, Matthews, RT, Agartz, I & Andreassen, OA 2011, 'Candidate gene analysis of the human natural killer-1 carbohydrate pathway and perineuronal nets in schizophrenia: B3GAT2 is associated with disease risk and cortical surface area' Biological Psychiatry, vol. 69, no. 1, pp. 90-96. https://doi.org/10.1016/j.biopsych.2010.07.035
Kähler, Anna K. ; Djurovic, Srdjan ; Rimol, Lars M. ; Brown, Andrew A. ; Athanasiu, Lavinia ; Jönsson, Erik G. ; Hansen, Thomas ; Gústafsson, Ómar ; Hall, Håkan ; Giegling, Ina ; Muglia, Pierandrea ; Cichon, Sven ; Rietschel, Marcella ; Pietiläinen, Olli P. H. ; Peltonen, Leena ; Bramon, Elvira ; Collier, David ; St Clair, David ; Sigurdsson, Engilbert ; Petursson, Hannes ; Rujescu, Dan ; Melle, Ingrid ; Werge, Thomas ; Steen, Vidar M. ; Dale, Anders M ; Matthews, Russell T ; Agartz, Ingrid ; Andreassen, Ole A. / Candidate gene analysis of the human natural killer-1 carbohydrate pathway and perineuronal nets in schizophrenia : B3GAT2 is associated with disease risk and cortical surface area. In: Biological Psychiatry. 2011 ; Vol. 69, No. 1. pp. 90-96.
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abstract = "Background The Human Natural Killer-1 carbohydrate (HNK-1) is involved in neurodevelopment and synaptic plasticity. Extracellular matrix structures called perineuronal nets, condensed around subsets of neurons and proximal dendrites during brain maturation, regulate synaptic transmission and plasticity. Methods Ten genes of importance for HNK-1 biosynthesis (B3GAT1, B3GAT2, and CHST10) or for the formation of perineuronal nets (TNR, BCAN, NCAN, HAPLN1, HAPLN2, HAPLN3, and HAPLN4) were investigated for potential involvement in schizophrenia (SCZ) susceptibility, by genotyping 104 tagSNPs in the Scandinavian Collaboration on Psychiatric Etiology sample (849 cases; 1602 control subjects). Genome-wide association study imputation data from the European SGENE-plus sample (2663 cases; 13,498 control subjects) were used for comparison. The effect of SCZ risk alleles on brain structure was investigated in a Norwegian subset (98 cases; 177 control subjects) with structural magnetic resonance imaging data. Results Five single nucleotide polymorphisms (SNPs), located in two adjacent estimated linkage disequilibrium blocks in the first intron of {\ss}-1,3-glucuronyltransferase 2 (B3GAT2), were nominally associated with SCZ (.004 = Pempirical = .05). The rs2460691 was significantly associated in the comparison sample and in the meta-analysis after correction for all 121 SNP/haplotype tests (Praw = 1 × 10-4; Pcorrected = .018). Increased dosage of the rs2460691 SCZ risk allele was associated with decreased cortical area (p = .002) but not thickness or hippocampal volume. A second SNP (r2 = .24 with rs10945275), which conferred the highest SCZ risk effect in the Norwegian subset, was also associated with cortical area. Conclusions The present results suggest that effects on biosynthesis of the neuronal epitope HNK-1, through common B3GAT2 variation, could increase the risk of SCZ, possibly by decreasing cortical area.",
keywords = "association study, B3GAT1, GlcAT-P, GlcAT-S, MRI, psychosis",
author = "K{\"a}hler, {Anna K.} and Srdjan Djurovic and Rimol, {Lars M.} and Brown, {Andrew A.} and Lavinia Athanasiu and J{\"o}nsson, {Erik G.} and Thomas Hansen and {\'O}mar G{\'u}stafsson and H{\aa}kan Hall and Ina Giegling and Pierandrea Muglia and Sven Cichon and Marcella Rietschel and Pietil{\"a}inen, {Olli P. H.} and Leena Peltonen and Elvira Bramon and David Collier and {St Clair}, David and Engilbert Sigurdsson and Hannes Petursson and Dan Rujescu and Ingrid Melle and Thomas Werge and Steen, {Vidar M.} and Dale, {Anders M} and Matthews, {Russell T} and Ingrid Agartz and Andreassen, {Ole A.}",
note = "Copyright {\circledC} 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.",
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TY - JOUR

T1 - Candidate gene analysis of the human natural killer-1 carbohydrate pathway and perineuronal nets in schizophrenia

T2 - B3GAT2 is associated with disease risk and cortical surface area

AU - Kähler, Anna K.

AU - Djurovic, Srdjan

AU - Rimol, Lars M.

AU - Brown, Andrew A.

AU - Athanasiu, Lavinia

AU - Jönsson, Erik G.

AU - Hansen, Thomas

AU - Gústafsson, Ómar

AU - Hall, Håkan

AU - Giegling, Ina

AU - Muglia, Pierandrea

AU - Cichon, Sven

AU - Rietschel, Marcella

AU - Pietiläinen, Olli P. H.

AU - Peltonen, Leena

AU - Bramon, Elvira

AU - Collier, David

AU - St Clair, David

AU - Sigurdsson, Engilbert

AU - Petursson, Hannes

AU - Rujescu, Dan

AU - Melle, Ingrid

AU - Werge, Thomas

AU - Steen, Vidar M.

AU - Dale, Anders M

AU - Matthews, Russell T

AU - Agartz, Ingrid

AU - Andreassen, Ole A.

N1 - Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PY - 2011/1/1

Y1 - 2011/1/1

N2 - Background The Human Natural Killer-1 carbohydrate (HNK-1) is involved in neurodevelopment and synaptic plasticity. Extracellular matrix structures called perineuronal nets, condensed around subsets of neurons and proximal dendrites during brain maturation, regulate synaptic transmission and plasticity. Methods Ten genes of importance for HNK-1 biosynthesis (B3GAT1, B3GAT2, and CHST10) or for the formation of perineuronal nets (TNR, BCAN, NCAN, HAPLN1, HAPLN2, HAPLN3, and HAPLN4) were investigated for potential involvement in schizophrenia (SCZ) susceptibility, by genotyping 104 tagSNPs in the Scandinavian Collaboration on Psychiatric Etiology sample (849 cases; 1602 control subjects). Genome-wide association study imputation data from the European SGENE-plus sample (2663 cases; 13,498 control subjects) were used for comparison. The effect of SCZ risk alleles on brain structure was investigated in a Norwegian subset (98 cases; 177 control subjects) with structural magnetic resonance imaging data. Results Five single nucleotide polymorphisms (SNPs), located in two adjacent estimated linkage disequilibrium blocks in the first intron of ß-1,3-glucuronyltransferase 2 (B3GAT2), were nominally associated with SCZ (.004 = Pempirical = .05). The rs2460691 was significantly associated in the comparison sample and in the meta-analysis after correction for all 121 SNP/haplotype tests (Praw = 1 × 10-4; Pcorrected = .018). Increased dosage of the rs2460691 SCZ risk allele was associated with decreased cortical area (p = .002) but not thickness or hippocampal volume. A second SNP (r2 = .24 with rs10945275), which conferred the highest SCZ risk effect in the Norwegian subset, was also associated with cortical area. Conclusions The present results suggest that effects on biosynthesis of the neuronal epitope HNK-1, through common B3GAT2 variation, could increase the risk of SCZ, possibly by decreasing cortical area.

AB - Background The Human Natural Killer-1 carbohydrate (HNK-1) is involved in neurodevelopment and synaptic plasticity. Extracellular matrix structures called perineuronal nets, condensed around subsets of neurons and proximal dendrites during brain maturation, regulate synaptic transmission and plasticity. Methods Ten genes of importance for HNK-1 biosynthesis (B3GAT1, B3GAT2, and CHST10) or for the formation of perineuronal nets (TNR, BCAN, NCAN, HAPLN1, HAPLN2, HAPLN3, and HAPLN4) were investigated for potential involvement in schizophrenia (SCZ) susceptibility, by genotyping 104 tagSNPs in the Scandinavian Collaboration on Psychiatric Etiology sample (849 cases; 1602 control subjects). Genome-wide association study imputation data from the European SGENE-plus sample (2663 cases; 13,498 control subjects) were used for comparison. The effect of SCZ risk alleles on brain structure was investigated in a Norwegian subset (98 cases; 177 control subjects) with structural magnetic resonance imaging data. Results Five single nucleotide polymorphisms (SNPs), located in two adjacent estimated linkage disequilibrium blocks in the first intron of ß-1,3-glucuronyltransferase 2 (B3GAT2), were nominally associated with SCZ (.004 = Pempirical = .05). The rs2460691 was significantly associated in the comparison sample and in the meta-analysis after correction for all 121 SNP/haplotype tests (Praw = 1 × 10-4; Pcorrected = .018). Increased dosage of the rs2460691 SCZ risk allele was associated with decreased cortical area (p = .002) but not thickness or hippocampal volume. A second SNP (r2 = .24 with rs10945275), which conferred the highest SCZ risk effect in the Norwegian subset, was also associated with cortical area. Conclusions The present results suggest that effects on biosynthesis of the neuronal epitope HNK-1, through common B3GAT2 variation, could increase the risk of SCZ, possibly by decreasing cortical area.

KW - association study

KW - B3GAT1

KW - GlcAT-P

KW - GlcAT-S

KW - MRI

KW - psychosis

U2 - 10.1016/j.biopsych.2010.07.035

DO - 10.1016/j.biopsych.2010.07.035

M3 - Article

VL - 69

SP - 90

EP - 96

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 1

ER -