Fine mapping of AHI1 as a schizophrenia susceptibility gene: from association to evolutionary evidence.
Détails
ID Serval
serval:BIB_BBFEE310C2C7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Fine mapping of AHI1 as a schizophrenia susceptibility gene: from association to evolutionary evidence.
Périodique
FASEB journal
ISSN
1530-6860 (Electronic)
ISSN-L
0892-6638
Statut éditorial
Publié
Date de publication
08/2010
Peer-reviewed
Oui
Volume
24
Numéro
8
Pages
3066-3082
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Mots-clé
Adaptor Proteins, Signal Transducing/genetics, Adaptor Proteins, Vesicular Transport, Biological Evolution, Cyclic Nucleotide Phosphodiesterases, Type 7/genetics, Genetic Association Studies, Genetic Predisposition to Disease, Haplotypes, Humans, Microtubule-Associated Proteins/genetics, Polymorphism, Single Nucleotide, Schizophrenia/genetics, Selection, Genetic
Pubmed
Web of science
Création de la notice
12/05/2010 16:44
Dernière modification de la notice
25/02/2023 6:46