While the use of population-based samples is a common strategy in genome-wide association studies (GWASs), family-based samples have considerable advantages, such as robustness against population stratification and false-positive associations, better quality control, and the possibility to check for both linkage and association. In a genome-wide linkage study of schizophrenia in Arab-Israeli families with multiple affected individuals, we previously reported significant evidence for a susceptibility locus at chromosome 6q23.2-q24.1 and suggestive evidence at chromosomes 10q22.3-26.3, 2q36.1-37.3 and 7p21.1-22.3. To identify schizophrenia susceptibility genes, we applied a family-based GWAS strategy in an enlarged, ethnically homogeneous, Arab-Israeli family sample. We performed genome-wide single nucleotide polymorphism (SNP) genotyping and single SNP transmission disequilibrium test association analysis and found genome-wide significant association (best value of P=1.22×10(-11)) for 8 SNPs within or near highly reasonable functional candidate genes for schizophrenia. Of particular interest are a group of SNPs within and flanking the transcriptional factor LRRFIP1 gene. To determine replicability of the significant associations beyond the Arab-Israeli population, we studied the association of the significant SNPs in a German case-control validation sample and found replication of associations near the UGT1 subfamily and EFHD1 genes. Applying an exploratory homozygosity mapping approach as a complementary strategy to identify schizophrenia susceptibility genes in our Arab Israeli sample, we identified 8 putative disease loci. Overall, this GWAS, which emphasizes the important contribution of family based studies, identifies promising candidate genes for schizophrenia.
Identification of new schizophrenia susceptibility loci in an ethnically homogeneous, family-based, Arab-Israeli sample / A. Alkelai, S. Lupoli, L. Greenbaum, I. Giegling, Y. Kohn, K. Sarner-Kanyas, E. Ben-Asher, D. Lancet, D. Rujescu, F. Macciardi, B. Lerer. - In: THE FASEB JOURNAL. - ISSN 0892-6638. - 25:11(2011 Nov), pp. 4011-4023.
|Titolo:||Identification of new schizophrenia susceptibility loci in an ethnically homogeneous, family-based, Arab-Israeli sample|
|Parole Chiave:||Genetic Linkage ; Polymorphism, Single Nucleotide ; Humans ; Chromosomes, Human, Pair 6 ; Genome-Wide Association Study ; Schizophrenia ; Chromosomes, Human, Pair 2 ; European Continental Ancestry Group ; RNA-Binding Proteins ; Arabs; Case-Control Studies ; Genetic Predisposition to Disease ; Family Health|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
|Data di pubblicazione:||nov-2011|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1096/fj.11-184937|
|Appare nelle tipologie:||01 - Articolo su periodico|