Identification of new schizophrenia susceptibility loci in an ethnically homogeneous, family-based, Arab-Israeli sample

FASEB J. 2011 Nov;25(11):4011-23. doi: 10.1096/fj.11-184937. Epub 2011 Jul 27.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Arabs / genetics
  • Case-Control Studies
  • Chromosomes, Human, Pair 2 / genetics
  • Chromosomes, Human, Pair 6 / genetics
  • Family Health
  • Genetic Linkage
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Humans
  • Polymorphism, Single Nucleotide
  • RNA-Binding Proteins / genetics
  • Schizophrenia / ethnology
  • Schizophrenia / genetics*
  • White People / genetics

Substances

  • LRRFIP1 protein, human
  • RNA-Binding Proteins