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 (∼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.
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Acknowledgements
We are grateful to all the patients and their families who participated in this study. This study was supported by RIKEN BSI Funds, Grant-in-aid for scientific studies from the MEXT of Japan to NS and EH, NARSAD Young Investigator Award to EH, and CREST funds from the Japan Science and Technology Agency, Japan to TY. We wish to thank the members of the Research Resource Center at the RIKEN Brain Science Institute for sequencing and genotyping services.
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Hattori, E., Nakajima, M., Yamada, K. et al. Variable number of tandem repeat polymorphisms of DRD4: re-evaluation of selection hypothesis and analysis of association with schizophrenia. Eur J Hum Genet 17, 793–801 (2009). https://doi.org/10.1038/ejhg.2008.247
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DOI: https://doi.org/10.1038/ejhg.2008.247
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