Fine mapping of AHI1 as a schizophrenia susceptibility gene: from association to evolutionary evidence
Articolo
Data di Pubblicazione:
2010
Citazione:
Fine mapping of AHI1 as a schizophrenia susceptibility gene: from association to evolutionary evidence / F. Torri, A. Akelai, S. Lupoli, M. Sironi, D. Amann Zalcenstein, M. Fumagalli, C. Dal Fiume, E. Ben Asher, K. Kanyas, R. Cagliani, P. Cozzi, G. Trombetti, L.S. Lievers, E. Salvi, A. Orro, J.S. Beckmann, D. Lancet, Y. Kohn, L. Milanesi, R.B. Ebstein, B. Lerer, F. Macciardi. - In: THE FASEB JOURNAL. - ISSN 0892-6638. - 24:8(2010), pp. 3066-3082. [10.1096/fj.09-152611]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
AHI1 association studies; Positive selection
Elenco autori:
F. Torri, A. Akelai, S. Lupoli, M. Sironi, D. Amann Zalcenstein, M. Fumagalli, C. Dal Fiume, E. Ben Asher, K. Kanyas, R. Cagliani, P. Cozzi, G. Trombetti, L.S. Lievers, E. Salvi, A. Orro, J.S. Beckmann, D. Lancet, Y. Kohn, L. Milanesi, R.B. Ebstein, B. Lerer, F. Macciardi
Link alla scheda completa: