Human Molecular Genetics Advance Access published online on September 9, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn291
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Association of common variants in the Joubert syndrome gene (AHI1) with autism
1 Department of Psychiatry, UCLA Neuropsychiatric Research Institute, Los Angeles, CA, 90095, USA 2 Department of Human Genetics, UCLA School of Medicine, Los Angeles, CA, 90095. USA 3 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0691, USA 4 U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598 USA 5 Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 USA 6 Department of Neurology, UCLA School of Medicine, Los Angeles, CA, 90095, USA
* To whom correspondence should be addressed: DH Geschwind, MD, PhD, Department of Neurology, UCLA School of Medicine, 695 Charles E Young Drive South, Los Angeles, CA 90095-1761, USA. Ph: 310 206-6814. Fax (310) 267-2401. E-mail: dhg{at}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, have been shown to contribute to disease susceptibility in an allied common condition. Joubert syndrome 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 Joubert syndrome, 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 3-stage analysis of AHI1 as an a priori candidate gene for autism. Re-sequencing was first used to screen AHI1, followed by 2 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.