Association Analysis of Inter-Alpha-Trypsin Inhibitor Genes in Schizophrenia

Schizophrenia (SCZ) is a common psychiatric disorder with relatively high morbidity and heritability. Affecting approximately 1% of the global population, SCZ is estimated to have an individual heritability of 60-85%. In recent years, several promising genetic loci have been identified using novel approaches such as genome-wide association studies (GWAS). Multiple GWAS have consistently reported that inter-alpha-trypsin inhibitor heavy chain (ITIH) family genes located on chromosome 3p21 are associated with SCZ in European populations, as demonstrated by the Schizophrenia Working Group of the Psychiatric Genomics Consortium and subsequent studies, as well as with bipolar disorder, another major psychotic disorder.

In the present study, we conducted a case-control association analysis and haplotype analysis of single-nucleotide polymorphisms (SNPs) within the ITIH gene cluster at the 3p21 region to examine whether these variants confer genetic risk for schizophrenia in a Japanese population. In addition, we resequenced the ITIH1 gene to identify single-nucleotide variants (SNVs) and performed protein structural analyses to predict the effects of these variants on protein stability, aiming to clarify the potential contribution of ITIH1 to the pathophysiology of schizophrenia.

A significant difference in haplotype frequencies for the two-SNP window comprising rs2710322 and rs1042779 was observed. Resequencing identified 4 potentially deleterious variants.

This study suggests a possible role of ITIH1 in the pathophysiology of schizophrenia.