Genetic Association Analysis of ITGB3 Polymorphisms with Age at Onset of Schizophrenia

Abstract

Schizophrenia (SCZ) is a debilitating disorder with a prevalence of approximately 1 % worldwide. SCZ is known to have a high degree of genetic and clinical heterogeneity and is a major health problem worldwide. The integrin-β 3 subunit gene (ITGB3) gene at 17q21.32 has been implicated in psychiatric disorders. We therefore hypothesized that ITGB3 gene polymorphisms might also play a role in SCZ and age at onset (AAO) of SCZ. We investigated the genetic associations of 23 single-nucleotide polymorphisms (SNPs) of the ITGB3 gene with AAO in SCZ in two Caucasian samples (2,166 cases and 2,525 controls) using linear regression analysis and meta-analysis. We observed four ITGB3-SNPs associated with AAO in SCZ in a non-Genetic Association Information Network (GAIN) sample (p < 10(-3)). Three of these four SNPs were replicated in the GAIN sample. The SNP rs16941771 was most significantly associated with AAO (p = 7.47 × 10(-5)). Meta-analysis showed that 6 of 23 SNPs were associated with AAO. The haplotype analysis also supports the association of ITGB3 with AAO. Three disease-associated SNPs were located at species-conserved regions, indicating functional importance. This is the first report which shows that ITGB3 variants are associated with AAO in SCZ, providing direct evidence of the use of AAO as an intermediate phenotype to dissect the complex genetics of SCZ.

Integrin activity in neuronal connectivity

“…Indeed, mice lacking Itgb3 exhibit behavioural abnormalities with a strong analogy to ASD in humans, including abnormal social interactions and repetitive behaviour (Carter et al, 2011). ITGB3 gene variants in humans are also linked to the age of onset in schizophrenia (Wang et al, 2013). Mechanistically, β3 integrin expression regulates the brain serotonin (5-HT) system, a key neurotransmitter pathway.…”

In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders

“…Integrins, a family of heterodimeric cell adhesion molecules (CAMs) consisting of several different α - and β -subunits, interact with ECM molecules to carry out a multitude of developmental and adult brain functions. Support for the idea that integrins may be implicated in the pathology of schizophrenia comes in part from genetic studies pointing to association of this disorder with a number of integrin gene variants, such as SNPs in the ITGA8 and ITGB3 genes [ 81 , 82 ]. Additional evidence supporting the involvement of integrins in schizophrenia includes increased expression of integrin α (IIb) and β (IIIa) in first episode subjects with schizophrenia and, notably, abnormal cell adhesion in cultures from olfactory mucosa biopsies from patients with this disorder, which was ameliorated by antibodies blocking integrins [ 83 , 84 ].…”

Extracellular matrix proteomics in schizophrenia and Alzheimer’s disease

“…For example, altered expression of ITGA8 and ITGB3 have been observed in Sz [61, 62]. In addition, a flow cytometry study analyzed surface expression of several glycoproteins and found a significant increase in integrin α2 b β3 a expression in first episode Sz patients compared with healthy controls [63].…”