title: Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia.
abstract: Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 x 10(-5)), we performed a peakwide association fine mapping study by using 1414 SNPs across approximately 12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 x 10(-7). We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 x 10(-2)), with a combined p value of 2.30 x 10(-7). After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 x 10(-3). NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Pei-Lung
authors.initials: PL
authors.lastname: Chen
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Avramopoulos
authors.forename: Virginia K
authors.initials: VK
authors.lastname: Lasseter
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.forename: M Daniele
authors.initials: MD
authors.lastname: Fallin
authors.forename: Kung-Yee
authors.initials: KY
authors.lastname: Liang
authors.forename: Gerald
authors.initials: G
authors.lastname: Nestadt
authors.forename: Ningping
authors.initials: N
authors.lastname: Feng
authors.forename: Gary
authors.initials: G
authors.lastname: Steel
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cutting
authors.forename: Paula
authors.initials: P
authors.lastname: Wolyniec
authors.forename: Ann E
authors.initials: AE
authors.lastname: Pulver
authors.forename: David
authors.initials: D
authors.lastname: Valle
mesh_terms: D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D020880:Neuregulins; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C486357:NRG3 protein, human; D020880:Neuregulins