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Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531

Molecular Psychiatry volume 11, pages 224–226 (2006)Cite this article

The human serotonin transporter gene (SLC6A4, 5-HTT) possesses several polymorphic loci that affect its expression or function. Rare gain-of-function coding mutations such as Ile425Val and Gly56Ala have recently been discovered,1, 2 while common noncoding polymorphisms that impact transcription include an intron 2 VNTR and the 5-HTT-linked polymorphic region (5-HTTLPR).3, 4 The latter polymorphism is commonly subdivided into S (short, lesser expressing) and L (long, greater expressing) alleles based on the presence of a 43 bp indel (initially described as 44 bp)3, 5, 6 and has been extensively analyzed in over 300 behavioral, psychiatric, pharmacogenetic and other medical genetics papers over the past 10 years.7, 8

Recent reports have raised the possibility that the established subdivision of 5-HTTLPR into S and L alleles requires reconsideration. Several variants of S and L were originally described by Nakamura, Sakai and colleagues, although they were found to not be functionally significant in reporter gene assays; these studies also did not replicate the original differential activities of S vs L.3, 5, 9 Hu et al.,10 however, recently noted an A/G SNP within the 5-HTTLPR insertion that renders only the A variant of the L allele (designated LA, corresponding to allele 16-A,5 GenBank accession number AB031251) as yielding high 5-HTT mRNA levels, while the G variant (LG, 16-D, AB031254) did not. Thus, LG apparently behaves equivalent to the low-expressing S allele. Another report, in turn, presented data on a potentially functional SNP (rs25531) located immediately upstream of the indel in an AP-2 binding region.6

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Acknowledgements

This work was supported by the Intramural Research Program of the NIMH, NIH.

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Authors and Affiliations

  1. Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD, USA

    J R Wendland, B J Martin, M R Kruse & D L Murphy

  2. Department of Psychiatry and Psychotherapy, Clinical and Molecular Psychobiology, University of Würzburg, Würzburg, Germany

    K-P Lesch

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  1. J R Wendland
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Correspondence to J R Wendland.

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Wendland, J., Martin, B., Kruse, M. et al. Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Mol Psychiatry 11, 224–226 (2006). https://doi.org/10.1038/sj.mp.4001789

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