Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

Area of Science:

• Neurogenetics
• Psychiatric Genetics
• Molecular Psychiatry

Background:

• Catechol-O-methyltransferase (COMT) is implicated in schizophrenia due to its role in neurotransmitter metabolism and prefrontal cognition.
• Genetic linkage and cytogenetic studies support COMT's involvement in schizophrenia pathogenesis.
• Previous family-based association studies have highlighted the COMT Val(108/158)Met variant.

Purpose of the Study:

• To investigate the association of genetic markers spanning COMT and adjacent genes with schizophrenia.
• To examine the potential contribution of the armadillo repeat deleted in velocardiofacial syndrome (ARVCF) gene to schizophrenia risk.

Main Methods:

• Association testing was performed on eight genetic markers across COMT, thioredoxin reductase 2, and ARVCF in 136 schizophrenia families.
• Haplotype analysis was conducted to assess the combined effect of linked markers.
• Linkage disequilibrium between COMT and ARVCF markers was evaluated.

Main Results:

• A nominal association was found between schizophrenia and rs165849 in the ARVCF gene (P=0.051).
• Three-marker haplotypes spanning the 3' regions of COMT and ARVCF, including the Val(108/158)Met variant, showed a significant association with schizophrenia (global P=0.0019-0.0036).
• The Val(108/158) allele was consistently overtransmitted, and Val(108/158)Met was in linkage disequilibrium with ARVCF markers.

Conclusions:

• Findings support previous associations between COMT markers and schizophrenia.
• The ARVCF gene may contribute to the observed genetic association signal for schizophrenia.
• ARVCF's potential role in neurodevelopment suggests a functional link to schizophrenia pathogenesis.