Identification of Schizophrenia Susceptibility Genes in an Ethnically Homogeneous,
Family-Based, Arab Israeli Sample
Bernard Lerer, Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center,
Jerusalem, 91120, Israel
There is strong evidence supporting a heritable basis for schizophrenia, a severe neuropsychiatric
disorder that has its onset in adolescence and early adulthood and has a lifetime prevalence of ~1%.
Concerted efforts are being mounted to identify the specific genes that confer susceptibility to
schizophrenia. These efforts have had limited success. We have taken the approach that the
likelihood of finding schizophrenia susceptibility genes should be increased in ethnically homogeneous
samples. 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 (1). To focus on the linkage peak and to identify susceptibility genes within the 6q23
region, fine-mapping was performed in the linkage sample (2) and extensive SNP genotyping was
done in an expanded sample of Arab-Israeli nuclear families from the same geographical region of
Israel (3, 4). The most significant genetic association with schizophrenia was detected within a
genomic region that contains the AHI1 gene and the nearby C6orf217 gene (3, 4). The top SNP
associations were further replicated in an independent case-control sample of Icelandic ancestry (5)
and recently in large European and Spanish/German case-control samples (6, 7) and also in patients
with autism. Translational studies from our laboratory provided convergent support for association of
AHI1 with schizophrenia by demonstrating increased AHI1 expression in lymphoblast cell lines from
schizophrenia patients in the Arab Israeli family sample and association of increased AHI1 expression
with homozygosity for the over-expressed A allele of SNP rs932150, in brain samples from the Stanley
Collection (8). Notwithstanding our replicated identification of schizophrenia susceptibility genes in the
6q region, additional associated variants could have been missed in our genome wide linkage study.
With finer microsatellite mapping of the 10q23-q26 region we demonstrated stronger evidence for
linkage with schizophrenia and identified a possible genetic interaction with the 6q23 region (9). To
identify additional schizophrenia susceptibility genes, we applied a family-based GWAS strategy in an
enlarged Arab Israeli family sample and found genome-wide significant association (best pvalue=1.22x10-11) 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
repressor LRRFIP1 gene. To determine replicability of the significant associations beyond the ArabIsraeli population, we genotyped the SNPs in Jewish Israeli and German case-control samples and
found replication of associations near the ACSL3, UGT1 subfamily and EFHD1 genes. Overall, this
GWAS, which emphasizes the important contribution of family based studies, identifies promising
candidate genes for schizophrenia.
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