Fine mapping of AHI1 as a schizophrenia susceptibility gene: from association to evolutionary evidence.
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.
Torri
Federica
F
Genomics and Bioinformatics Unit, University of Milan-Fondazione Filarete, University of Milan, Milan, Italy.
Akelai
Anna
A
Lupoli
Sara
S
Sironi
Manuela
M
Amann-Zalcenstein
Daniela
D
Fumagalli
Matteo
M
Dal Fiume
Chiara
C
Ben-Asher
Edna
E
Kanyas
Kyra
K
Cagliani
Rachele
R
Cozzi
Paolo
P
Trombetti
Gabriele
G
Strik Lievers
Luisa
L
Salvi
Erika
E
Orro
Alessandro
A
Beckmann
Jacques S
JS
Lancet
Doron
D
Kohn
Yoav
Y
Milanesi
Luciano
L
Ebstein
Richard B
RB
Lerer
Bernard
B
Macciardi
Fabio
F
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
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