title: DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population.
abstract: It is well accepted that schizophrenia has a strong genetic component. Several genome-wide association studies (GWASs) of schizophrenia have been published in recent years; most of them population based with a case-control design. Nevertheless, identifying the specific genetic variants which contribute to susceptibility to the disorder remains a challenging task. A family-based GWAS strategy may be helpful in the identification of schizophrenia susceptibility genes since it is protected against population stratification, enables better accounting for genotyping errors and is more sensitive for identification of rare variants which have a very low frequency in the general population. In this project we implemented a family-based GWAS of schizophrenia in a sample of 107 Jewish-Israeli families. We found one genome-wide significant association in the intron of the DOCK4 gene (rs2074127, p value=1.134×10⁻⁷) and six additional nominally significant association signals with p<1×10⁻⁵. One of the top single nucleotide polymorphisms (p<1×10⁻⁵) which is located in the predicted intron of the CEACAM21 gene was significantly replicated in independent family-based sample of Arab-Israeli origin (rs4803480: p value=0.002; combined p value=9.61×10⁻⁸), surviving correction for multiple testing. Both DOCK4 and CEACAM21 are biologically reasonable candidate genes for schizophrenia although generalizability of the association of DOCK4 with schizophrenia should be investigated in further studies. In addition, gene-wide significant associations were found within three schizophrenia candidate genes: PGBD1, RELN and PRODH, replicating previously reported associations. By application of a family-based strategy to GWAS, our study revealed new schizophrenia susceptibility loci in the Jewish-Israeli population.
authors.affiliation: Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Alkelai
authors.forename: Sara
authors.initials: S
authors.lastname: Lupoli
authors.forename: Lior
authors.initials: L
authors.lastname: Greenbaum
authors.forename: Yoav
authors.initials: Y
authors.lastname: Kohn
authors.forename: Kyra
authors.initials: K
authors.lastname: Kanyas-Sarner
authors.forename: Edna
authors.initials: E
authors.lastname: Ben-Asher
authors.forename: Doron
authors.initials: D
authors.lastname: Lancet
authors.forename: Fabio
authors.initials: F
authors.lastname: Macciardi
authors.forename: Bernard
authors.initials: B
authors.lastname: Lerer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D030541:Databases, Genetic; D005192:Family Health; D005326:Fetal Proteins / Q000235:genetics; D000080865:Formins; D020690:GTPase-Activating Proteins / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007585:Jews / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; D012559:Schizophrenia / Q000208:ethnology / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; C510122:DOCK4 protein, human; D005326:Fetal Proteins; D000080865:Formins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; C456602:NETO1 protein, human; D009687:Nuclear Proteins; C509689:PARD3 protein, human; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; C000717127:RELN protein, human