title: Fine mapping of AHI1 as a schizophrenia susceptibility gene: from association to evolutionary evidence.
abstract: In previous studies, we identified a locus for schizophrenia on 6q23.3 and proposed the Abelson helper integration site 1 (AHI1) as the candidate gene. AHI1 is expressed in the brain and plays a key role in neurodevelopment, is involved in Joubert syndrome, and has been recently associated with autism. The neurodevelopmental role of AHI1 fits with etiological hypotheses of schizophrenia. To definitively confirm our hypothesis, we searched for associations using a dense map of the region. Our strongest findings lay within the AHI1 gene: single-nucleotide polymorphisms rs11154801 and rs7759971 showed significant associations (P=6.23E-06; P=0.84E-06) and haplotypes gave P values in the 10E-8 to 10E-10 range. The second highest significant region maps close to AHI1 and includes the intergenic region between BC040979 and PDE7B (rs2038549 at P=9.70E-06 and rs1475069 at P=6.97E-06), and PDE7B and MAP7. Using a sample of Palestinian Arab families to confirm these findings, we found isolated signals. While these results did not retain their significance after correction for multiple testing, the joint analysis across the 2 samples supports the role of AHI1, despite the presence of heterogeneity. Given the hypothesis of positive selection of schizophrenia genes, we resequenced a 11 kb region within AHI1 in ethnically defined populations and found evidence for a selective sweep. Network analysis indicates 2 haplotype clades, with schizophrenia-susceptibility haplotypes clustering within the major clade. In conclusion, our data support the role of AHI1 as a susceptibility gene for schizophrenia and confirm it has been subjected to positive selection, also shedding light on new possible candidate genes, MAP7 and PDE7B.
authors.affiliation: Genomics and Bioinformatics Unit, University of Milan-Fondazione Filarete, University of Milan, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Torri
authors.forename: Anna
authors.initials: A
authors.lastname: Akelai
authors.forename: Sara
authors.initials: S
authors.lastname: Lupoli
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
authors.forename: Daniela
authors.initials: D
authors.lastname: Amann-Zalcenstein
authors.forename: Matteo
authors.initials: M
authors.lastname: Fumagalli
authors.forename: Chiara
authors.initials: C
authors.lastname: Dal Fiume
authors.forename: Edna
authors.initials: E
authors.lastname: Ben-Asher
authors.forename: Kyra
authors.initials: K
authors.lastname: Kanyas
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.forename: Paolo
authors.initials: P
authors.lastname: Cozzi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Trombetti
authors.forename: Luisa
authors.initials: L
authors.lastname: Strik Lievers
authors.forename: Erika
authors.initials: E
authors.lastname: Salvi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Orro
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Doron
authors.initials: D
authors.lastname: Lancet
authors.forename: Yoav
authors.initials: Y
authors.lastname: Kohn
authors.forename: Luciano
authors.initials: L
authors.lastname: Milanesi
authors.forename: Richard B
authors.initials: RB
authors.lastname: Ebstein
authors.forename: Bernard
authors.initials: B
authors.lastname: Lerer
authors.forename: Fabio
authors.initials: F
authors.lastname: Macciardi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D033942:Adaptor Proteins, Vesicular Transport; D005075:Biological Evolution; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D012641:Selection, Genetic
chemical_list: C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D008869:Microtubule-Associated Proteins; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517463:PDE7B protein, human