title: Identification and functional studies of regulatory variants responsible for the association ofNRG3with a delusion phenotype in schizophrenia.
abstract: We previously reported genetic linkage for Schizophrenia (SZ) (NPL of 4.7) at 10q22 in the Ashkenazi Jewish (AJ) population. In follow up fine mapping we found strong evidence of association between three intronic single nucleotide variants (SNVs) in the 5' end of Neuregulin 3 (NRG3)and the delusion factor score of our phenotypic principal component analysis. Two independent groups replicated these findings, indicating that variants inNRG3confer risk for a delusion-rich SZ subtype. To identify the causative variants, we sequenced the 162 kb linkage disequilibrium (LD) block covering theNRG35' end in 47 AJ SZ patients at the extremes of the delusion factor quantitative trait distribution. Among the identified variants we found 5 noncoding SNVs present on the high delusion factor haplotype and significantly overrepresented in high delusion factor subjects. We tested these for regulatory effects and found that risk alleles of rs10883866 and rs60827755 decreased and increased, respectively, the expression of a reporter gene as compared to the reference allele. In post-mortem brain RNA quantification experiments we found the same variants also perturb relative expression of alternativeNRG3isoforms. In summary, we have identified regulatory SNVs contributing to the association ofNRG3with delusion symptoms in SZ.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD ; Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD ; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Mariela
authors.initials: M
authors.lastname: Zeledón
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD ; Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Nicole
authors.initials: N
authors.lastname: Eckart
authors.affiliation: Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
authors.forename: Margaret
authors.initials: M
authors.lastname: Taub
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Hilary
authors.initials: H
authors.lastname: Vernon
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD ; Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Megan
authors.initials: M
authors.lastname: Szymanksi
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei City, Taiwan.
authors.forename: Pei-Lung
authors.initials: PL
authors.lastname: Chen
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Gerry
authors.initials: G
authors.lastname: Nestadt
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD ; Epidemiology-Genetics Program, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD ; Epidemiology-Genetics Program, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Pulver
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD ; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Avramopoulos
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: David
authors.initials: D
authors.lastname: Valle
keywords: Ashkenazi; NRG3; delusion; functional studies; neuregulin-3; psychiatric disease