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.
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 β-1,3-glucuronyltransferase 2 (B3GAT2), were nominally associated with SCZ (.004 ≤ P(empirical) ≤ .05). The rs2460691 was significantly associated in the comparison sample and in the meta-analysis after correction for all 121 SNP/haplotype tests (P(raw) = 1 × 10(-4); P(corrected) = .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 (r(2) = .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.
Kähler
Anna K
AK
Institute of Psychiatry, University of Oslo, Oslo University Hospital-Ulleval, Norway. a.k.kahler@medisin.uio.no
Djurovic
Srdjan
S
Rimol
Lars M
LM
Brown
Andrew Anand
AA
Athanasiu
Lavinia
L
Jönsson
Erik G
EG
Hansen
Thomas
T
Gústafsson
Omar
O
Hall
Håkan
H
Giegling
Ina
I
Muglia
Pierandrea
P
Cichon
Sven
S
Rietschel
Marcella
M
Pietiläinen
Olli P H
OP
Peltonen
Leena
L
Bramon
Elvira
E
Collier
David
D
St Clair
David
D
Sigurdsson
Engilbert
E
Petursson
Hannes
H
Rujescu
Dan
D
Melle
Ingrid
I
Werge
Thomas
T
Steen
Vidar M
VM
Dale
Anders M
AM
Matthews
Russell T
RT
Agartz
Ingrid
I
Andreassen
Ole A
OA
D000483:Alleles; D001284:Atrophy / Q000473:pathology; D018959:CD57 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000166:cytology; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics*
D018959:CD57 Antigens; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; C475472:B3GAT2 protein, human; D014453:Glucuronosyltransferase