Fine mapping of and genome wide significant evidence for its involvement in schizophrenia and bipolar disorder.

Michael Owen (1) , Hywel John Williams (1) , Nadine Norton (1) , Sarah Dwyer (1) , Valentina Moskvina (1) , Ivan Nikolov (1) , Liam Carroll (1) , Lyudmila Georgieva (1) , Nigel M Williams (1) , Derek Morris (1) , Emma Quinn (1) , Ina Giegling (1) , Masashi Ikeda (1) , Joel Wood (1) , Todd Lencz (1) , Christina Hultman (1) , Paul Lichtenstein (1) , Dawn Thiselton (1) , Brion Maher (1) , Molecular Genetics of Schizophrenia Collaboration (mgs) (1) , International Schizophrenia Consortium (isc) (1) , Sgene -Plus (1) , Group Na (1) , Anil Malhotra (1) , Brien Riley (1) , Kenneth Kendler (1) , Michael Gill (1) , Patrick Sullivan (1) , Pamela Sklar (1) , Shaun M. Purcell (1) , Vishwajit Nimgaonkar (1) , George Kirov (1) , Peter A. Holmans (1) , Aiden Corvin (1) , Dan Rujescu (1) , Nicholas Craddock (1) , Michael C. O'Donovan (1)

1 Division of Psychiatric Genomics

A recent genome wide association study reported evidence for association between rs1344706 within (encoding zinc finger protein 804A) and schizophrenia (P=1.61 x10), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 x10). Here we provide additional evidence for association through meta-analysis of a larger dataset (schizophrenia/schizoaffective disorder = 18945, schizophrenia plus bipolar disorder =21274, controls =38675). We also sought to better localize the association signal using a combination of polymorphism discovery in exons, pooled polymorphism discovery spanning the genomic sequence of the locus and high density LD mapping. Meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 x10, OR=1.10, 95% CI 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 x10, OR=1.11, 95% CI 1.07-1.14). After polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.

Mots clés: ZNF804A; sequencing; association; schizophrenia; bipolar disorder; meta-analysis

Michael Owen, Hywel John Williams, Nadine Norton, Sarah Dwyer, Valentina Moskvina, et al.. Fine mapping of and genome wide significant evidence for its involvement in schizophrenia and bipolar disorder.. Molecular Psychiatry, 2010, ⟨10.1038/mp.2010.36⟩. ⟨hal-00523672⟩