Abstract
Non-coding regulatory elements can transduce the human genome's response to environmental stimuli. Thus, there is a possibility that variation in non-coding regulatory elements may underlie some of the diversity in human behavior. However, this idea has remained largely untested due to the difficulty in accurately identifying regulatory elements in the 98% of the human genome that does not encode protein. The recent recognition that small trans-acting RNAs anneal to mRNA and regulate gene expression provides a means to identify and test such variants. Here, we show that microRNA-directed silencing of mRNA can be attenuated by a common human polymorphism. We have identified an element (A-element) within serotonin receptor 1B (HTR1B) mRNA that confers repression by miR-96. The repressive activity of this element is attenuated by a common human variant (G-element) that disrupts a nucleotide critical for its interaction with miR-96. Because deletion of the HTR1B gene leads to an aggressive phenotype in mice, we hypothesized an association between the A/G polymorphism and aggressive phenotypes in a sample of 359 college students. As predicted, individuals homozygous for the ancestral A-element reported more conduct-disorder behaviors than individuals with the G-element. Our studies suggest that such functional variants may be common and may help to refine the search for genes involved in complex behavioral disorders.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
King MC, Wilson AC . Evolution at two levels in humans and chimpanzees. Science 1975; 188: 107–116.
Hellmann I, Zollner S, Enard W, Ebersberger I, Nickel B, Paabo S . Selection on human genes as revealed by comparisons to chimpanzee cDNA. Genome Res 2003; 13: 831–837.
Hammock EA, Young LJ . Microsatellite instability generates diversity in brain and sociobehavioral traits. Science 2005; 308: 1630–1634.
Lee RC, Ambros V . An extensive class of small RNAs in Caenorhabditis elegans. Science 2001; 294: 862–864.
Lau NC, Lim LP, Weinstein EG, Bartel DP . An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 2001; 294: 858–862.
Hutvagner G, Zamore PD . A microRNA in a multiple-turnover RNAi enzyme complex. Science 2002; 297: 2056–2060.
Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T . Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell 2004; 15: 185–197.
Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T . Identification of novel genes coding for small expressed RNAs. Science 2001; 294: 853–858.
Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 2000; 408: 86–89.
Lewis BP, Burge CB, Bartel DP . Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120: 15–20.
Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB . Prediction of mammalian microRNA targets. Cell 2003; 115: 787–798.
Doench JG, Sharp PA . Specificity of microRNA target selection in translational repression. Genes Dev 2004; 18: 504–511.
Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X, Bibe B et al. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet 2006; 38: 813–818.
Chen K, Rajewsky N . Natural selection on human microRNA binding sites inferred from SNP data. Nat Genet 2006; 38: 1452–1456.
Saunders MA, Liang H, Li WH . Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci USA 2007; 104: 3300–3305.
Adams BD, Furneaux H, White BA . The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines. Mol Endocrinol 2007; 21: 1132–1147.
Saudou F, Amara DA, Dierich A, LeMeur M, Ramboz S, Segu L et al. Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science 1994; 265: 1875–1878.
Covault J, Tennen H, Armeli S, Conner TS, Herman AI, Cillessen AH et al. Interactive effects of the serotonin transporter 5-HTTLPR polymorphism and stressful life events on college student drinking and drug use. Biol Psychiatry 2006; 61: 609–619.
John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS . Human microRNA targets. PLoS Biol 2004; 2: e363.
Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ et al. Combinatorial microRNA target predictions. Nat Genet 2005; 37: 495–500.
Rehmsmeier M, Steffen P, Hochsmann M, Giegerich R . Fast and effective prediction of microRNA/target duplexes. RNA 2004; 10: 1507–1517.
International HapMap Consortium. A haplotype map of the human genome. Nature 2005; 437: 1299–1320.
Cohen J . Statistical Power Analysis for the Behavioral Sciences, 2nd edn. Lawrence Erlbaum Associates: Hillsdale, NJ, 1988.
Sethupathy P, Borel C, Gagnebin M, Grant GR, Deutsch S, Elton TS et al. Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3′ untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. Am J Hum Genet 2007; 81: 405–413.
Martin MM, Buckenberger JA, Jiang J, Malana GE, Nuovo GJ, Chotani M et al. The human angiotensin II type 1 receptor +1166 A/C polymorphism attenuates microRNA-155 binding. J Biol Chem 2007; 282: 24262–24269.
Mishra PJ, Humeniuk R, Longo-Sorbello GS, Banerjee D, Bertino JR . A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Natl Acad Sci USA 2007; 104: 13513–13518.
Abelson JF, Kwan KY, O'Roak BJ, Baek DY, Stillman AA, Morgan TM et al. Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science 2005; 310: 317–320.
Quist JF, Barr CL, Schachar R, Roberts W, Malone M, Tannock R et al. The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder. Mol Psychiatry 2003; 8: 98–102.
Hawi Z, Dring M, Kirley A, Foley D, Kent L, Craddock N et al. Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample. Mol Psychiatry 2002; 7: 718–725.
Smoller JW, Biederman J, Arbeitman L, Doyle AE, Fagerness J, Perlis RH et al. Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD. Biol Psychiatry 2006; 59: 460–467.
Mundo E, Richter MA, Zai G, Sam F, McBride J, Macciardi F et al. 5HT1Dbeta receptor gene implicated in the pathogenesis of obsessive-compulsive disorder: further evidence from a family-based association study. Mol Psychiatry 2002; 7: 805–809.
Lappalainen J, Long JC, Eggert M, Ozaki N, Robin RW, Brown GL et al. Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch Gen Psychiatry 1998; 55: 989–994.
Huang YY, Oquendo MA, Friedman JM, Greenhill LL, Brodsky B, Malone KM et al. Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism. Neuropsychopharmacology 2003; 28: 163–169.
Ickowicz A, Feng Y, Wigg K, Quist J, Pathare T, Roberts W et al. The serotonin receptor HTR1B: gene polymorphisms in attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2007; 144: 121–125.
Kranzler HR, Hernandez-Avila CA, Gelernter J . Polymorphism of the 5-HT1B receptor gene (HTR1B): strong within-locus linkage disequilibrium without association to antisocial substance dependence. Neuropsychopharmacology 2002; 26: 115–122.
Proudnikov D, LaForge KS, Hofflich H, Levenstien M, Gordon D, Barral S et al. Association analysis of polymorphisms in serotonin 1B receptor (HTR1B) gene with heroin addiction: a comparison of molecular and statistically estimated haplotypes. Pharmacogenet Genomics 2006; 16: 25–36.
Conner TS, Jensen KP, Tennen H, Covault J, Furneaux HM, Kranzler HR . Broadening the genetic basis of emotionality: a polymorphism in the serotonin 1B receptor gene is associated with feelings of anger and hostility in daily life among young men (manuscript under review).
Lautenberger JA, Stephens JC, O'Brien SJ, Smith MW . Significant admixture linkage disequilibrium across 30 cM around the FY locus in African Americans. Am J Hum Genet 2000; 66: 969–978.
Barad O, Meiri E, Avniel A, Aharonov R, Barzilai A, Bentwich I et al. MicroRNA expression detected by oligonucleotide microarrays: system establishment and expression profiling in human tissues. Genome Res 2004; 14: 2486–2494.
Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V . Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 2004; 5: R13.
Voight BF, Kudaravalli S, Wen X, Pritchard JK . A map of recent positive selection in the human genome. PLoS Biol 2006; 4: e72.
Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC, Silverman JS et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet 2007; 39: 31–40.
Martianov I, Ramadass A, Serra Barros A, Chow N, Akoulitchev A . Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 2007; 445: 666–670.
Loeber R, Burke JD, Lahey BB, Winters A, Zera M . Oppositional defiant and conduct disorder: a review of the past 10 years, part I. J Am Acad Child Adolesc Psychiatry 2000; 39: 1468–1484.
Acknowledgements
This study was supported by NIH Grants P50 AA03510, M01 RR06192 (University of Connecticut GCRC), K24 AA13736, T32 AA07290 and DA 022226. We gratefully acknowledge the assistance of Nicholas Maltby for web programming and the technical assistance of Linda Burian.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jensen, K., Covault, J., Conner, T. et al. A common polymorphism in serotonin receptor 1B mRNA moderates regulation by miR-96 and associates with aggressive human behaviors. Mol Psychiatry 14, 381–389 (2009). https://doi.org/10.1038/mp.2008.15
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2008.15
Keywords
This article is cited by
-
Effects of miR-143 and its target receptor 5-HT2B on agonistic behavior in the Chinese mitten crab (Eriocheir sinensis)
Scientific Reports (2021)
-
Functional polymorphisms and transcriptional analysis in the 5′ region of the human serotonin receptor 1B gene (HTR1B) and their associations with psychiatric disorders
BMC Psychiatry (2020)
-
Effects of HTR1B 3′ region polymorphisms and functional regions on gene expression regulation
BMC Genetics (2020)
-
Polymorphisms in the human serotonin receptor 1B (HTR1B) gene are associated with schizophrenia: a case control study
BMC Psychiatry (2018)
-
Alcohol Intoxication Moderates the Association between a Polygenic Risk Score and Unprovoked Intimate Partner Aggression
Journal of Family Violence (2018)