Family-based association study of common variants, rare mutation study and epistatic interaction detection in HDAC genes in schizophrenia

Abstract

Background: Histone deacetylases (HDACs) are key enzymes of histone acetylation, and abnormalities in histone modifications and in the level of HDAC proteins have been reported in schizophrenia. The objective of the present study was to systematically test the HDAC genes for its association with schizophrenia.

Methods: A family-based genetic association study (951 Caucasian subjects in 313 nuclear families) using 601 tag-single nucleotide polymorphisms in HDAC genes was conducted followed by a replication study of top-ranked markers in a sample of 1427 Caucasian subjects from 241 multiplex families and 176 trios. Epistasis interaction was tested by using the pedigree-based generalized multifactor dimensionality reduction (GMDR). Furthermore, we analyzed exome sequencing data of 1134 subjects for detection of rare mutations in HDAC genomic regions.

Results: In the exploratory study, ten markers were in significant association with schizophrenia (P<0.01). One maker rs14251 (HDAC3) was replicated (P=0.04) and remained significant in the whole sample (P=0.004). GMDR identified that a significant three-locus interaction model was detected involving rs17265596 (HDAC9), rs7290710 (HDAC10) and rs7634112 (HDAC11) with a good testing accuracy (0.58). No rare mutations were found associated with schizophrenia.

Conclusion: This first exploratory systematic study of the HDAC genes provides consistent support for the involvement of the HDAC3 gene in the etiology of schizophrenia. A statistical epistatic interaction between HDAC9, HDAC10, and HDAC11 was detected and seems biologically plausible.

Keywords: Epigenetics; Epistasis; Histone acetylation; Pedigree-based generalized multifactor dimensionality; Psychosis; Tag-SNP.