title: Variable number of tandem repeat polymorphisms of DRD4: re-evaluation of selection hypothesis and analysis of association with schizophrenia.
abstract: Associations have been reported between the variable number of tandem repeat (VNTR) polymorphisms in the exon 3 of dopamine D4 receptor gene gene and multiple psychiatric illnesses/traits. We examined the distribution of VNTR alleles of different length in a Japanese cohort and found that, as reported earlier, the size of allele '7R' was much rarer (0.5%) in Japanese than in Caucasian populations (approximately 20%). This presents a challenge to an earlier proposed hypothesis that positive selection favoring the allele 7R has contributed to its high frequency. To further address the issue of selection, we carried out sequencing of the VNTR region not only from human but also from chimpanzee samples, and made inference on the ancestral repeat motif and haplotype by use of a phylogenetic analysis program. The most common 4R variant was considered to be the ancestral haplotype as earlier proposed. However, in a gene tree of VNTR constructed on the basis of this inferred ancestral haplotype, the allele 7R had five descendent haplotypes in relatively long lineage, where genetic drift can have major influence. We also tested this length polymorphism for association with schizophrenia, studying two Japanese sample sets (one with 570 cases and 570 controls, and the other with 124 pedigrees). No evidence of association between the allele 7R and schizophrenia was found in any of the two data sets. Collectively, this study suggests that the VNTR variation does not have an effect large enough to cause either selection or a detectable association with schizophrenia in a study of samples of moderate size.
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Hattori
authors.forename: Mizuho
authors.initials: M
authors.lastname: Nakajima
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.forename: Naruya
authors.initials: N
authors.lastname: Saitou
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000483:Alleles; D044466:Asian People; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005828:Genetics, Population; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D020080:Tandem Repeat Sequences / Q000235:genetics*
chemical_list: C493599:DRD4 protein, human; D050638:Receptors, Dopamine D4