Association of common variants in the Joubert syndrome gene (AHI1) with autism

Abstract

It has been suggested that autism, like other complex genetic disorders, may benefit from the study of rare or Mendelian variants associated with syndromic or non-syndromic forms of the disease. However, there are few examples in which common variation in genes causing a Mendelian neuropsychiatric disorder has been shown to contribute to disease susceptibility in an allied common condition. Joubert syndrome (JS) is a rare recessively inherited disorder, with mutations reported at several loci including the gene Abelson's Helper Integration 1 (AHI1). A significant proportion of patients with JS, in some studies up to 40%, have been diagnosed with autism spectrum disorder (ASD) and several linkage studies in ASD have nominally implicated the region on 6q where AHI1 resides. To evaluate AHI1 in ASD, we performed a three-stage analysis of AHI1 as an a priori candidate gene for autism. Re-sequencing was first used to screen AHI1, followed by two subsequent association studies, one limited and one covering the gene more completely, in Autism Genetic Resource Exchange (AGRE) families. In stage 3, we found evidence of an associated haplotype in AHI1 with ASD after correction for multiple comparisons, in a region of the gene that had been previously associated with schizophrenia. These data suggest a role for AHI1 in common disorders affecting human cognition and behavior.

Figure 1.

Fine-scale depiction of the AHI1 ASD-associated haplotype. The genomic region is shown on top, followed by an exon–intron map and NCBI genome release 35 SNP location. Shown below is an LD plot of the region based on r² (see Materials and Methods). SNPs genotyped in the autism sample in this study are boxed, whereas those genotyped in the published schizophrenia associations (34,45) are circled. The single SNP P-values are shown adjacent to each SNP. Schizophrenia SNPs are marked ‘Scza 1’ or ‘Scza 2’ depending on whether they were typed in the Arab-Israeli (34) or in the Icelandic population (45). Associated SNPs in our study are marked as ‘Auts’. The two schizophrenia haplotypes in the Arab-Israeli study are depicted with discontinuous lines. One can see the ∼30 kb area of overlap of these two haplotypes in the center of this region, which occurs in a region of strong LD within the gene. The region also harbors the two most highly associated SNPs in our current autism study (rs4896144 and rs17707754), which are in the center of this block of low LD.