Impact of the AHI1 Gene on the Vulnerability to Schizophrenia: A Case-Control Association Study

BackgroundThe Abelson helper integration-1 (AHI1) gene is required for both cerebellar and cortical development in humans. While the accelerated evolution of AHI1 in the human lineage indicates a role in cognitive (dys)function, a linkage scan in large pedigrees identified AHI1 as a positional candidate for schizophrenia. To further investigate the contribution of AHI1 to the susceptibility of schizophrenia, we evaluated the effect of AHI1 variation on the vulnerability to psychosis in two samples from Spain and Germany.Methodology/Principal Findings29 single-nucleotide polymorphisms (SNPs) located in a genomic region including the AHI1 gene were genotyped in two samples from Spain (280 patients with psychotic disorders; 348 controls) and Germany (247 patients with schizophrenic disorders; 360 controls). Allelic, genotypic and haplotype frequencies were compared between cases and controls in both samples separately, as well as in the combined sample. The effect of genotype on several psychopathological measures (BPRS, KGV, PANSS) assessed in a Spanish subsample was also evaluated. We found several significant associations in the Spanish sample. Particularly, rs7750586 and rs911507, both located upstream of the AHI1 coding region, were found to be associated with schizophrenia in the analysis of genotypic (p = 0.0033, and 0.031, respectively) and allelic frequencies (p = 0.001 in both cases). Moreover, several other risk and protective haplotypes were detected (0.006<p<0.036). Joint analysis also supported the association of rs7750586 and rs911507 with the risk for schizophrenia. The analysis of clinical measures also revealed an effect on symptom severity (minimum P value = 0.0037).Conclusions/SignificanceOur data support, in agreement with previous reports, an effect of AHI1 variation on the susceptibility to schizophrenia in central and southern European populations

Linkage disequilibrium (LD) pattern of <i>AHI1</i> gene.

<p>Figures represent pairwise r² values observed in control subjects from German (a) and Spanish (b) origin. Values are represented in a grayscale ranging from white (no LD) to black (high LD).</p

Single alleles and haplotypes of the <i>AHI1</i> region associated with schizophrenia in the present study.

<p>Significant values are marked in bold. The corrected P-values are indicated in brackets.</p>a<p>To avoid redundant information, other significant haplotypes, which are variations of other larger significant haplotypes from this table, have not been included.</p>b<p>SNP27 had significantly different genotypic distributions in the German and the Spanish sample (heterogeneity <i>P</i> value = 0.016 uncorrected).</p><p>Abbreviations: Cont, control; SCZ, schizophrenia; ns, not significant; perm, permutation; ref, reference haplotype.</p

<i>AHI1</i> SNPs significantly associated with clinical traits in the Spanish sample.

<p>Significant <i>P</i> values (P<0.05) are indicated in bold.</p><p><b>^a</b>The corrected <i>P</i> value is indicated in brackets.</p><p>Abbreviations: SE, standard error; CI, confidence interval.</p

List of SNPs included in the present study.

<p>Abbreviations: CEU, CEPH collection - DNA samples of Utah residents with ancestry from northern and western Europe; MAF, minor allele frequency.</p

Genomic region and SNPs analyzed in this study.

<p>The position of each SNP is indicated with an orange arrow.</p