Human Molecular Genetics Advance Access originally published online on September 9, 2008
Human Molecular Genetics 2008 17(24):3887-3896; doi:10.1093/hmg/ddn291


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Association of common variants in the Joubert syndrome gene (AHI1) with autism
Ana I. Alvarez Retuerto1, Rita M. Cantor2, Joseph G. Gleeson4, Anna Ustaszewska5, Wendy S. Schackwitz5,6, Len A. Pennacchio5,6 and Daniel H. Geschwind1,2,3,*
1 Center for Autism Research and Treatment Semel Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA 2 Department of Human Genetics 3 Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA 4 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0691, USA 5 US Department of Energy, Joint Genome Institute, Walnut Creek, CA 94598, USA 6 Genomics Division, MS 84–171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

* To whom correspondence should be addressed at: Department of Neurology, UCLA School of Medicine, 695 Charles E. Young Drive South, Los Angeles, CA 90095-1761, USA. Tel: +1 3102066814; Fax: +1 3102672401; Email: dhg@ucla.edu

Received March 18, 2008; Revised June 25, 2008; Accepted September 8, 2008

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.