title: A primate-specific functional GTTT-repeat in the core promoter of CYTH4 is linked to bipolar disorder in human.
abstract: Evidence of primate-specific genes and gene regulatory mechanisms linked to bipolar disorder (BD) lend support to evolutionary/adaptive processes in the pathogenesis of this disorder. Following a genome-scale analysis of the entire protein coding genes annotated in the GeneCards database, we have recently reported that cytohesin-4 (CYTH4) contains the longest tetra-nucleotide short tandem repeat (STR) identified in a human protein-coding gene core promoter, which may be of adaptive advantage to this species. In the current study, we analyzed the evolutionary trend of this STR across evolution. We also analyzed the functional implication and distribution of this STR in a group of patients with type 1 BD (n=233) and controls (n=262). We found that this STR is exceptionally expanded in primates (Fisher exact p<0.00003). Association was observed between type I BD and the 6-repeat allele of this STR, (GTTT)₆ (Yates corrected Χ(2)=12.68, p<0.0001, OR: 1.68). This allele is the shortest length of the GTTT-repeat identified in the human subjects studied. Consistent with that finding, excess homozygosity was observed for the shorter alleles, (GTTT)₆ and (GTTT)₇, vs. the longer alleles, (GTTT)₈ and (GTTT)₉ in the BD group (Yates corrected Χ(2)=5.18, p<0.01, 1 df, OR: 1.96). Using Dual Glo luciferase system in HEK-293 cells, a trend for gene expression repression was observed from the 6- to the 9-repeat allele (p<0.003), and the GTTT-repeat significantly down-regulated gene expression, per se (p<0.0006). This is the first evidence of a link between a primate-specific STR and a major psychiatric disorder in human. It may be speculated that the CYTH4 GTTT-repeat in primates may have conferred selective advantage to this order, reflected in neural function and neurophenotypes. The role of the CYTH4 gene in the pathogenesis of type I BD remains to be clarified in the future studies.
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: M
authors.initials: M
authors.lastname: Rezazadeh
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: J
authors.initials: J
authors.lastname: Gharesouran
authors.affiliation: Department of Psychiatry, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: A
authors.initials: A
authors.lastname: Mirabzadeh
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: H R
authors.initials: HR
authors.lastname: Khorram Khorshid
authors.affiliation: Department of Biostatistics, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: A
authors.initials: A
authors.lastname: Biglarian
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. Electronic address: ohadi.mina@yahoo.com.
authors.forename: M
authors.initials: M
authors.lastname: Ohadi
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D019295:Computational Biology; D019143:Evolution, Molecular; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007492:Iran; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014162:Transfection
chemical_list: C404511:CYTH4 protein, human; D015815:Cell Adhesion Molecules; D020662:Guanine Nucleotide Exchange Factors
keywords: Bipolar disorder; CYTH4; GTTT-repeat; Primate-specific