AHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia

Abstract

Schizophrenia, a severe neuropsychiatric disorder, is believed to involve multiple genetic factors. A significant body of evidence supports a pivotal role for abnormalities of brain development in the disorder. Linkage signals for schizophrenia map to human chromosome 6q. To obtain a finer localization, we genotyped 180 single nucleotide polymorphisms (SNPs) in a young, inbred Arab-Israeli family sample with a limited number of founders. The SNPs were mostly within a B7 Mb region around the strong linkage peak at 136.2 Mb that we had previously mapped. The most significant genetic association with schizophrenia for single SNPs and haplotypes was within a 500 kb genomic region of high linkage disequilibrium (LD) at 135.85 Mb. In a different, outbred, nuclear family sample that was not appropriate for linkage analysis, under-transmitted haplotypes incorporating the same SNPs (but not the individual SNPs) were significantly associated with schizophrenia. The implicated genomic region harbors the Abelson Helper Integration Site 1 (AHI1) gene, which showed the strongest association signal, and an adjacent, primate-specific gene, C6orf217. Mutations in human AHI1 underlie the autosomal recessive Joubert Syndrome with brain malformation and mental retardation. Previous comparative genomic analysis has suggested accelerated evolution of AHI1 in the human lineage. C6orf217 has multiple splice isoforms and is expressed in brain but does not seem to encode a functional protein. The two genes appear in opposite orientations and their regulatory upstream regions overlap, which might affect their expression. Both, AHI1 and C6orf217 appear to be highly relevant candidate genes for schizophrenia.

Support for involvement of the AHI1 locus in schizophrenia

“…In summary, we have presented results from a casecontrol association analysis that are in line with data presented by Amann-Zalcenstein et al, 8 showing that the AHI1 locus contributes to schizophrenia. Still, three neighbouring genes, AHI1, BC040979 and PDE7B can be affected by variants in this region and none of these genes can be excluded.…”

“…For the overtransmitted alleles in the study of AmannZalcenstein et al, 8 odds ratios (ORs) ranged from 1.15 to 1.29 in the Icelandic sample. For all seven markers, Pvalues were o0.05, and for two markers, the difference was significant after Bonferroni correction for seven tests.…”

“…Figure 1 LD around the AHI1 locus. All seven markers from the Amann-Zalcenstein study 8 are within the same LD block, although substructures can be detected. Two genes, AHI1 and BC040979, are found within the boundaries of the LD block.…”

“…8 The association was found in an LD block, spanning Mb 135.667 -136.179 (NCBI Build 36) on chromosome 6 harbouring the AHI1 gene. We found all seven significantly overtransmitted alleles from their study in higher frequency in Icelandic schizophrenics than in controls (Table 1).…”

“…6,7 Subsequent familybased association study of the same pedigrees, using SNP markers from the 6q23.3 locus, revealed significant association of markers in a linkage disequilibrium (LD) block harbouring the Abelson Helper Integration Site 1 (AHI1) gene. 8 The AHI1 gene is expressed at high levels in both foetal and adult human brain. 9 Mutations in the gene have been shown to cause Joubert Syndrome, an autosomal recessive brain disorder.…”