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5HTTLPR: White Knight or Dark Blight?
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Laboratory of Clinical Science, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland, United States
*Mailing address: Laboratory of Clinical Science, National Institute of Mental Health, 10/3D41, 10 Center Dr, Bethesda, MD 20892. Telephone: 301-496-2757. Fax: 301-402-0188. E-mail: [email protected]
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ACS Chemical Neuroscience

Cite this: ACS Chem. Neurosci. 2013, 4, 1, 13–15
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https://doi.org/10.1021/cn3002224
Published January 16, 2013

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Abstract

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In over 100 neuroscience genetics reports on SLC6A4 published in the first part of 2012, >40% reported data from genotyping only the serotonin transporter-linked promoter region [5HTTLPR] indel, omitting genotyping of two nearby SNPs that substantially alter 5HTTLPR allele frequencies and functionality. And 25% of these papers did not report ethnicity of the subjects genotyped, another factor that alters allele frequencies. This field thus seems stultified. Improved science for the present and future will be better served by attention to more complete methods for genotyping and subject sample reporting.

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SPECIAL ISSUE

This article is part of the Celebrating 25 Years of the Serotonin Club special issue.

The purpose of this Viewpoint is to alert neuroscience authors, readers, reviewers, and editors to the fact that, in scientific publications that include genotyping of the serotonin transporter gene [SLC6A4], substantial oversights and omissions have been present since 2006, and are continuing to be published.

Based on a recent search of publications from 2012 catalogued in PubMed that included SLC6A4 genotyping (see below), 44% reported only the promoter polymorphism 5HTTLPR (simple long “L” versus short “S” allele classifications), neglecting other promoter region variants that alter the functional effects of the “L” versus “S” variants. This lack of detailed analysis leads to errors in interactive variant consequences and thus statistical inaccuracy in overstating or understating the conclusions presented.

The history of this story is as follows:

1.

In our 1996 publication in Science, we reported differences in anxiety-related personality traits in normal individuals that seemed relatable to the SLC6A4 5HTTLPR. (1) Despite calculations in this publication that the results from 505 individuals only contributed “a modest but replicable 3 to 4% of total variance and 7 to 9% of the genetic variance,” today’s PubMed lists >2100 publications (since 2000) on the serotonin transporter gene and its variants.

2.

In 2006, an important advance in SLC6A4 variant consequences was reported: the discovery of the rs25531 variant (Figure 1). (2) Now consistently confirmed, this variant is located in close proximity to the 5HTTLPR. It comprises a single base substitution (A > G) that yields a “LG” allele, which is functionally equivalent to the 5HTTLPR “S” allele. (2, 3) Importantly, up to 15% of individuals previously considered in all studies of 5HTTLPR to be “L” carriers should instead be functionally classified with “S” carriers. This error rate of ±15% might have influenced study results, leading to false positives or false negatives.

Figure 1

Figure 1. Human SERT gene (SLC6A4) organization showing multiple functional variants. [Adapted from ref 4.]

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Of note, there are large ethnic differences in the presence of different variants: Caucasians have ∼22% “S”/“LG” alleles while Asians have ∼60% “S”/“LG” alleles, with other populations having intermediate values (Figure 2). (2) These differences have been found to be of particular importance in association studies of drug treatment responses and drug side effects. (4, 5)

Figure 2

Figure 2. Distributions (%) of SLC6A4 alleles in different global populations. [Adapted from ref 2.]

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3.

Most recently in 2008, a promoter region SLC6A4 variant, rs25532, was reported (Figure 1). (6) Located close to the much-studied 5HTTLPR, this variant showed an allele-dependent effect on serotonin transporter expression of up to 7-fold when tested in a serotonergic, raphe-derived cell line. (6) Since this report 4 years ago, not a single publication has included genotyping of this variant or evaluations of its relationship to disease, drug response, or to other phenotypes.

4.

We thought we might have reached a watershed in 2006, with the discovery of rs25531 regulating the 5HTTLPR and thus comprising a triallele. (2) However, further reports by other groups have identified additional SNPs, some involving amino acid changes across the gene that affect transporter function and regulation such as G56A and I425 V. (7, 8) In addition, the STin2 VNTR (9) and 3′ untranslated region gene variants (10, 11) have been identified as functional SLC6A4 elements. The latter are of increasing interest since they affect microRNA-mediated translational regulation; therefore, it is likely that variants located within or near such microRNA sites will have a marked impact on SLC6A4 expression. (10, 11)

However, despite concerns expressed to editors and reviewers, papers continue to be published that not only neglect all but the 5HTTLPR, but also ignore the use of now accessible methods to more fully evaluate the multiple known functional elements in this gene. (3, 4, 12, 13) For example, when we surveyed the papers catalogued in PubMed for January 2012 to November 2012 using the search terms “serotonin transporter gene”, “SLC6A4”, “serotonin transporter genotype”, “5HTTLPR”, and “5-HTTLPR” (conducted separately, omitting duplicates), we identified 102 relevant papers. In 27/102 of these, we could find no mention of “ethnicity” (or “white” or “Caucasian” or “Asian”). In 45/102 papers, we could find no mention of any other SLC6A4 variant other than 5HTTLPR. Perhaps, in these postmedieval times, 72/102 papers missing one or both of these elements might be considered analogous to sending Don Quixote into battle with an arm tied behind his back (due to inattention to genotyping other now-known functional variants) and a hobbled horse (due to inattention to ethnicity).

Basing research on finely tuned and available methods of genotyping SLC6A4 only stands to have a positive impact in the field. By including more detailed analyses, positive and negative findings alike will be more accurate and will serve to move the field forward.

Author Information

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  • Corresponding Author
    • Dennis L. Murphy,  Laboratory of Clinical Science, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland, United States,  Email: [email protected]
  • Authors
    • Michelle S. Maile,  Laboratory of Clinical Science, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland, United States
    • Nicholas M. Vogt,  Laboratory of Clinical Science, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland, United States
  • Funding

    Funding from the National Institute of Mental Health Intramural Research Program is acknowledged

  • Notes
    The authors declare no competing financial interest.

Acknowledgment

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A database containing all references identified from PubMed searches used for the analyses herein are available by request to the authors.

References

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This article references 13 other publications.

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  • Abstract

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    Figure 1

    Figure 1. Human SERT gene (SLC6A4) organization showing multiple functional variants. [Adapted from ref 4.]

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    Figure 2

    Figure 2. Distributions (%) of SLC6A4 alleles in different global populations. [Adapted from ref 2.]

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  • References

    This article references 13 other publications.

    1. 1
      Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., Benjamin, J., Muller, C. R., Hamer, D. H., and Murphy, D. L. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region Science 274, 1527– 1531
      1
      Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region
      Lesch, Klaus-Peter; Bengel, Dietmar; Heils, Armin; Sabol, Sue Z.; Greenberg, Benjamin D.; Petri, Susanne; Benjamin, Jonathan; Mueller, Clemens R.; Hamer, Dean H.; Murphy, Dennis L.
      Science (Washington, D. C.) (1996), 274 (5292), 1527-1531CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Transporter-facilitated uptake of serotonin (5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Assocn. studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3-4% of total variation and 7-9% of inherited variance in anxiety-related personality traits in individuals as well as sibships.
    2. 2
      Hu, X. Z., Lipsky, R. H., Zhu, G., Akhtar, L. A., Taubman, J., Greenberg, B. D., Xu, K., Arnold, P. D., Richter, M. A., Kennedy, J. L., Murphy, D. L., and Goldman, D. (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder Am. J. Hum. Genet. 78, 815– 826
      2
      Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder
      Hu, Xian-Zhang; Lipsky, Robert H.; Zhu, Guanshan; Akhtar, Longina A.; Taubman, Julie; Greenberg, Benjamin D.; Xu, Ke; Arnold, Paul D.; Richter, Margaret A.; Kennedy, James L.; Murphy, Dennis L.; Goldman, David
      American Journal of Human Genetics (2006), 78 (5), 815-826CODEN: AJHGAG; ISSN:0002-9297. (University of Chicago Press)
      A functional serotonin transporter promoter polymorphism, HTTLPR, alters the risk of disease as well as brain morphometry and function. Here, we show that HTTLPR is functionally triallelic. The LG allele, which is the L allele with a common G substitution, creates a functional AP2 transcription-factor binding site. Expression assays in 62 lymphoblastoid cell lines representing the six genotypes and in transfected raphe-derived cells showed co-dominant allele action and low, nearly equiv. expression for the S and LG alleles, accounting for more variation in HTT expression than previously recognized. The gain-of-function LALA genotype was approx. twice as common in 169 whites with obsessive-compulsive disorder (OCD) than in 253 ethnically matched controls. We performed a replication study in 175 trios consisting of probands with OCD and their parents. The LA allele was twofold over-transmitted to the patients with OCD. The HTTLPR LALA genotype exerts a moderate (1.8-fold) effect on risk of OCD, which crystallizes the evidence that the HTT gene has a role in OCD.
    3. 3
      Wendland, J. R., Martin, B. J., Kruse, M. R., Lesch, K. P., and Murphy, D. L. (2006) Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531 Mol. Psychiatry 11, 224– 226
      3
      Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531
      Wendland, J. R.; Martin, B. J.; Kruse, M. R.; Lesch, K-P.; Murphy, D. L.
      Molecular Psychiatry (2006), 11 (3), 224-226CODEN: MOPSFQ; ISSN:1359-4184. (Nature Publishing Group)
      A triplex PCR protocol followed by double restriction endonuclease digestion allows rapid, cost-effective and detailed detn. of common functional polymorphisms at the 5-HTTLPR, rs25531 and intron 2 loci of the human serotonin transporter gene (SLC6A4, 5-HTT). This method simultaneously screens for rare mutations at the Ile425 codon. All genotyping was performed in duplicate, with an overall completion rate of 99%. Sequenced controls and no template controls consistently yielded expected results.
    4. 4
      Murphy, D. L. and Moya, P. R. (2011) Human serotonin transporter gene (SLC6A4) variants: their contributions to understanding pharmacogenomic and other functional GxG and GxE differences in health and disease Curr. Opin. Pharmacol. 11, 3– 10
      4
      Human serotonin transporter gene (SLC6A4) variants: their contributions to understanding pharmacogenomic and other functional G × G and G × E differences in health and disease
      Murphy, Dennis L.; Moya, Pablo R.
      Current Opinion in Pharmacology (2011), 11 (1), 3-10CODEN: COPUBK; ISSN:1471-4892. (Elsevier Ltd.)
      A review. Recent major findings from studies of SLC6A4 and its corresponding protein, the serotonin (5-HT) transporter (SERT) in humans, rodents and non-human primates indicate that combinations of SLC6A4 non-coding 5', 3' UTRs and intronic regions plus coding variants acting together can change 5HT transport as much as 40-fold in vitro. In vivo, SLC6A4 variants in humans and other species lead to marked physiol. changes, despite mitigating neurodevelopmental adaptations in 5-HT receptors plus compensatory alterations in 5-HT synthesis and metab. Polymorphisms in SLC6A4 are assocd. with differences in emotional, endocrine, and personality characteristics as well as many diseases. This gene, in combinations with gene × gene (G × G) and gene × environment (G × E) interactions nonetheless remains incompletely understood, with some assocn. findings remaining controversial. Considering its primary importance in the regulation and function of the entire serotonergic system (as evidenced by the consequences of SERT-mediated reuptake inhibition by SRIs like fluoxetine in humans and of genetically engineered changes in mice and rats), it seems likely that SLC6A4 and SERT will remain areas of high interest in our field's attempts to better understand and treat 5-HT-related disorders.
    5. 5
      Murphy, D. L., Fox, M. A., Timpano, K. R., Moya, P. R., Ren-Patterson, R., Andrews, A. M., Holmes, A., Lesch, K. P., and Wendland, J. R. (2008) How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems Neuropharmacology 55, 932– 960
      There is no corresponding record for this reference.
    6. 6
      Wendland, J. R., Moya, P. R., Kruse, M. R., Ren-Patterson, R. F., Jensen, C. L., Timpano, K. R., and Murphy, D. L. (2008) A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder Hum. Mol. Genet. 17, 717– 723
      6
      A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder
      Wendland, Jens R.; Moya, Pablo R.; Kruse, Matthew R.; Ren-Patterson, Renee F.; Jensen, Catherine L.; Timpano, Kiara R.; Murphy, Dennis L.
      Human Molecular Genetics (2008), 17 (5), 717-723CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
      Obsessive-compulsive disorder (OCD) is a disabling neuropsychiatric illness with strong segregation data indicative of major genetic contributions. Assocn. analyses of common functional variants of the serotonin transporter gene (SLC6A4), a long-standing OCD candidate, have so far been inconsistent. Here, we set out to investigate the role of addnl. functional SLC6A4 loci in OCD. We describe a common, functional C > T single nucleotide polymorphism, rs25532, located less than 150 nucleotides centromeric of the serotonin transporter-linked polymorphic region indel known as 5-HTTLPR. The minor allele of rs25532 significantly decreased luciferase reporter gene expression levels by 15-80%, depending on 5-HTTLPR allele background and cell type. Haplotype-based testing of rs25532 and all other known non-coding functional SLC6A4 variants revealed a highly significant omnibus assocn. with OCD in a large case-control sample. Remarkably, the haplotype significantly overrepresented in probands contained the higher-expressing allele at each locus, supporting the notion of increased serotonin transporter functioning being pathogenetically involved in OCD. Conditional haplotype analyses with the software WHAP revealed that this assocn. is primarily driven by 5-HTTLPR, rs25532 and rs16965628. Our results contribute to a better understanding of SLC6A4 expression genetics and provide a functional haplotype framework for future serotonin-related studies.
    7. 7
      Ozaki, N., Goldman, D., Kaye, W. H., Plotnicov, K., Greenberg, B. D., Lappalainen, J., Rudnick, G., and Murphy, D. L. (2003) Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype Mol. Psychiatry 8, 933– 936
      7
      Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype
      Ozaki, N.; Goldman, D.; Kaye, W. H.; Plotnicov, K.; Greenberg, B. D.; Lappalainen, J.; Rudnick, G.; Murphy, D. L.
      Molecular Psychiatry (2003), 8 (11), 933-936CODEN: MOPSFQ; ISSN:1359-4184. (Nature Publishing Group)
      Two common serotonin transporter (SERT) untranslated region gene variants have been intensively studied, but remain inconclusively linked to depression and other neuropsychiatric disorders. We now report an uncommon coding region SERT mutation, Ile425Val, in two unrelated families with OCD and other serotonin-related disorders. Six of the seven family members with this mutation had OCD (n=5) or obsessive-compulsive personality disorder (n=1) and some also met diagnostic criteria for multiple other disorders (Asperger's syndrome, social phobia, anorexia nervosa, tic disorder and alc. and other substance abuse/dependence). The four most clin. affected individuals-the two probands and their two sibs-had the I425V SERT gene gain-of-function mutation and were also homozygous for 5'-UTR SERT gene variant with greater transcriptional efficacy.
    8. 8
      Veenstra-VanderWeele, J., Muller, C. L., Iwamoto, H., Sauer, J. E., Owens, W. A., Shah, C. R., Cohen, J., Mannangatti, P., Jessen, T., Thompson, B. J., Ye, R., Kerr, T. M., Carneiro, A. M., Crawley, J. N., Sanders-Bush, E., McMahon, D. G., Ramamoorthy, S., Daws, L. C., Sutcliffe, J. S., and Blakely, R. D. (2012) Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior Proc. Natl. Acad. Sci. U.S.A. 109, 5469– 5474
      8
      Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior
      Veenstra-Vanderweele, Jeremy; Muller, Christopher L.; Iwamoto, Hideki; Sauer, Jennifer E.; Owens, W. Anthony; Shah, Charisma R.; Cohen, Jordan; Mannangatti, Padmanabhan; Jessen, Tammy; Thompson, Brent J.; Ye, Ran; Kerr, Travis M.; Carneiro, Ana M.; Crawley, Jacqueline N.; Sanders-Bush, Elaine; McMahon, Douglas G.; Ramamoorthy, Sammanda; Daws, Lynette C.; Sutcliffe, James S.; Blakely, Randy D.
      Proceedings of the National Academy of Sciences of the United States of America (2012), 109 (14), 5469-5474, S5469/1-S5469/9CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) was assocd. with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT1A and 5HT2A receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further anal. of ASD mechanisms and potentially novel treatments.
    9. 9
      MacKenzie, A. and Quinn, J. (1999) A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo Proc. Natl. Acad. Sci. U.S.A. 96, 15251– 15255
      There is no corresponding record for this reference.
    10. 10
      Baudry, A., Mouillet-Richard, S., Schneider, B., Launay, J. M., and Kellermann, O. (2010) miR-16 targets the serotonin transporter: A new facet for adaptive responses to antidepressants Science 329, 1537– 1541
      There is no corresponding record for this reference.
    11. 11
      Moya, P. R., Wendland, J. R., Salemme, J., Fried, R. L., and Murphy, D. L. (2012) miR-15a and miR-16 regulate serotonin transporter expression in human placental and rat brain raphe cells Int. J. Neuropsychopharmacol. 1– 9
      11
      miR-15a and miR-16 regulate serotonin transporter expression in human placental and rat brain raphe cells
      Moya Pablo R; Wendland Jens R; Salemme Jennifer; Fried Ruby L; Murphy Dennis L
      The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) (2012), (), 1-9 ISSN:.
      The serotonin transporter (SERT) is a key regulatory molecule in serotonergic transmission implicated in numerous biological processes relevant to human disorders. Recently, it was shown that SERT expression is controlled by miR-16 in mouse brain. Here, we show that SERT expression is regulated additionally by miR-15a as well as miR-16 in human and rat tissues. This post-transcriptional regulation was observed and characterized in reporter assays and likewise when endogenous SERT expression was evaluated in human placental choriocarcinoma JAR cells and rat brain raphe RN46A cells - two cell lines that endogenously express SERT. Similar effects for miR-16 to those of miR-15a were found in both human and rat cell lines. The effects of miR-15a and miR-16 were comparable in extent to those originally reported for miR-16 in mice. These findings represent a novel layer of complexity for SERT expression regulation exerted by the mir-15a/16 cluster, whose genes are adjacently located at human chromosome 13q14.3.
    12. 12
      Wray, N. R., James, M. R., Gordon, S. D., Dumenil, T., Ryan, L., Coventry, W. L., Statham, D. J., Pergadia, M. L., Madden, P. A., Heath, A. C., Montgomery, G. W., and Martin, N. G. (2009) Accurate, large-scale genotyping of 5HTTLPR and flanking single nucleotide polymorphisms in an association study of depression, anxiety, and personality measures Biol. Psychiatry 66, 468– 476
      12
      Accurate, Large-Scale Genotyping of 5HTTLPR and Flanking Single Nucleotide Polymorphisms in an Association Study of Depression, Anxiety, and Personality Measures
      Wray, Naomi R.; James, Michael R.; Gordon, Scott D.; Dumenil, Troy; Ryan, Leanne; Coventry, William L.; Statham, Dixie J.; Pergadia, Michele L.; Madden, Pamela A. F.; Heath, Andrew C.; Montgomery, Grant W.; Martin, Nicholas G.
      Biological Psychiatry (2009), 66 (5), 468-476CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)
      The length polymorphism repeat in the promoter region of the serotonin transporter gene (5HTTLPR) is one of the most studied polymorphisms for assocn. with a range of psychiatric and personality phenotypes. However, the original 5HTTLPR assay is prone to bias toward short allele calling. We designed new assays for the 5HTTLPR suitable for large-scale genotyping projects and we genotyped 13 single nucleotide polymorphisms (SNPs) in a 38-kilobase region around the 5HTTLPR, including SNP rs25531, a polymorphism of the 5HTTLPR long allele. Assocn. anal. was conducted for major depression and/or anxiety disorder in unrelated cases (n = 1161) and control subjects (n = 1051) identified through psychiatric interviews administered to a large population sample of Australian twin families. Participants had been scored for personality traits several years earlier (n ≥ 2643 unrelated individuals). We identified a two-SNP haplotype proxy for 5HTTLPR; the CA haplotype of SNPs rs4251417 and rs2020934 is coupled with the short allele of 5HTTLPR (r 2 = .72). We found evidence for assocn. (p = .0062, after accounting for multiple testing) for SLC6A4 SNPs rs6354 and rs2020936 (positioned in a different linkage disequil. [LD] block about 15.5 kb from 5HTTLPR) with anxiety and/or depression and neuroticism, with the strongest assocn. for recurrent depression with onset in young adulthood (odds ratio = 1.55, 95% confidence interval = 1.16-2.06). The assocd. SNPs are in the same LD block as the variable no. of tandem repeats serotonin transporter intron 2 marker, for which assocn. has previously been reported.
    13. 13
      Avula, R., Rand, A., Black, J. L., and O’Kane, D. J. (2011) Simultaneous genotyping of multiple polymorphisms in human serotonin transporter gene and detection of novel allelic variants Transl. Psychiatry 1, e32
      There is no corresponding record for this reference.