Neurological Sciences

, Volume 35, Issue 1, pp 41–47 | Cite as

Common functional polymorphisms in SLC6A4 and COMT genes are associated with circadian phenotypes in a South American sample

  • Diego A. Ojeda
  • Claudia S. Perea
  • Annjy Suárez
  • Carmen L. Niño
  • Rafael M. Gutiérrez
  • Sandra López-León
  • Ana Adan
  • Humberto Arboleda
  • Andrés Camargo
  • Diego A. ForeroEmail author
Original Article


The molecular study of circadian rhythms in humans could be an excellent approach to understand the relation between genes and behavior. It is possible that variations in genes involved in neurotransmission and/or synaptic plasticity, such as catechol-O-methyltransferase (COMT) and serotonin transporter (SLC6A4) could be of particular interest in understanding human circadian phenotypes. The aim of this study is to analyze the possible and novel associations of the functional polymorphisms in COMT and SLC6A4 genes (Val158Met and 5-HTTLPR) and circadian phenotypes in healthy Colombian subjects. 191 university students were genotyped for two functional polymorphisms in COMT and SLC6A4 genes (rs4680 and rs4795541). We applied two scales to measure phenotypic patterns of human circadian rhythms: Composite Scale of Morningness (CSM) and Epworth Sleepiness Scale (ESS). We found a significant association between 5-HTTLPR polymorphism and morning preference score (CSM) (p = 0.027) using an overdominant genotypic model and association of COMT Val158Met with daytime sleepiness (ESS scores) (p = 0.038) in a genotypic recessive model. These results were supported by differences in genotype frequencies between circadian typologies for SLC6A4 gene (p = 0.007) and categories of diurnal sleepiness for COMT gene (p = 0.032). Our results suggest, for the first time, a significant relationship between functional SLC6A4 and COMT polymorphisms with specific human circadian phenotypes: morning preference and diurnal sleepiness. These results need to be replicated in other populations. Further study of functional polymorphisms in other synaptic genes could be of relevance for the identification of novel candidate genes for circadian phenotypes, and related endophenotypes of neuropsychiatric importance, in healthy humans.


Endophenotypes Molecular genetics Morningness–eveningness Neurogenetics Neuropsychiatric genetics Synaptic genes 



This study was supported by Grants from Colciencias (Contract # 765-2011), Universidad Antonio Nariño (VCTI-UAN) and Universidad de Ciencias Aplicadas y Ambientales (UDCA). The authors thank all those who assisted with recruitment of subjects.

Conflict of interest

S. L-L is employee of Novartis Farmacéutica. All authors have read the journal’s policy and they declare that there is no conflict of interest.


  1. 1.
    Danilenko KV, Cajochen C, Wirz-Justice A (2003) Is sleep per se a zeitgeber in humans? J Biol Rhythms 18:170–178PubMedCrossRefGoogle Scholar
  2. 2.
    Adan A, Archer SN, Hidalgo MP, Di Milia L, Natale V, Randler C (2012) Circadian typology: a comprehensive review. Chronobiol Int 29:1153–1175PubMedCrossRefGoogle Scholar
  3. 3.
    von Schantz M (2008) Phenotypic effects of genetic variability in human clock genes on circadian and sleep parameters. J Genet 87:513–519CrossRefGoogle Scholar
  4. 4.
    Forero DA, Benitez B, Arboleda G, Yunis JJ, Pardo R, Arboleda H (2006) Analysis of functional polymorphisms in three synaptic plasticity-related genes (BDNF, COMT AND UCHL1) in Alzheimer’s disease in Colombia. Neurosci Res 55:334–341PubMedCrossRefGoogle Scholar
  5. 5.
    Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD (1993) Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci USA 90:2542–2546PubMedCrossRefGoogle Scholar
  6. 6.
    Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL, Riederer P (1994) Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 95:157–162PubMedCrossRefGoogle Scholar
  7. 7.
    Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66:2621–2624PubMedCrossRefGoogle Scholar
  8. 8.
    Collier DA, Stober G, Li T, Heils A, Catalano M, Di Bella D, Arranz MJ, Murray RM, Vallada HP, Bengel D, Muller CR, Roberts GW, Smeraldi E, Kirov G, Sham P, Lesch KP (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1:453–460PubMedGoogle Scholar
  9. 9.
    Canli T, Lesch KP (2007) Long story short: the serotonin transporter in emotion regulation and social cognition. Nat Neurosci 10:1103–1109PubMedCrossRefGoogle Scholar
  10. 10.
    Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389PubMedCrossRefGoogle Scholar
  11. 11.
    Shield AJ, Thomae BA, Eckloff BW, Wieben ED, Weinshilboum RM (2004) Human catechol O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes. Mol Psychiatry 9:151–160PubMedCrossRefGoogle Scholar
  12. 12.
    Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR (2001) Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98:6917–6922PubMedCrossRefGoogle Scholar
  13. 13.
    Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6:243–250PubMedCrossRefGoogle Scholar
  14. 14.
    Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR (2004) Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75:807–821PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Rojas W, Parra MV, Campo O, Caro MA, Lopera JG, Arias W, Duque C, Naranjo A, Garcia J, Vergara C, Lopera J, Hernandez E, Valencia A, Caicedo Y, Cuartas M, Gutierrez J, Lopez S, Ruiz-Linares A, Bedoya G (2010) Genetic make up and structure of Colombian populations by means of uniparental and biparental DNA markers. Am J Phys Anthropol 143:13–20PubMedCrossRefGoogle Scholar
  16. 16.
    Beskow LM, Burke W, Merz JF, Barr PA, Terry S, Penchaszadeh VB, Gostin LO, Gwinn M, Khoury MJ (2001) Informed consent for population-based research involving genetics. JAMA 286:2315–2321PubMedCrossRefGoogle Scholar
  17. 17.
    Portaluppi F, Smolensky MH, Touitou Y (2010) Ethics and methods for biological rhythm research on animals and human beings. Chronobiol Int 27:1911–1929PubMedCrossRefGoogle Scholar
  18. 18.
    Smith CS, Reilly C, Midkiff K (1989) Evaluation of three circadian rhythm questionnaires with suggestions for an improved measure of morningness. J Appl Psychol 74:728–738PubMedCrossRefGoogle Scholar
  19. 19.
    Adan A, Caci H, Prat G (2005) Reliability of the Spanish version of the composite scale of morningness. Eur Psychiatry 20:503–509PubMedCrossRefGoogle Scholar
  20. 20.
    Smith CS, Folkard S, Schmieder RA, Parra LF, Spelten E, Almiral H, Sen RN, Sahu S, Perez LM, Tisak J (2002) Investigation of morning–evening orientation in six countries using the preferences scale. Pers Indl Differ 32:949–968CrossRefGoogle Scholar
  21. 21.
    Caci H, Adan A, Bohle P, Natale V, Pornpitakpan C, Tilley A (2005) Transcultural properties of the composite scale of morningness: the relevance of the “morning affect” factor. Chronobiol Int 22:523–540PubMedCrossRefGoogle Scholar
  22. 22.
    Johns MW (1991) A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 14:540–545PubMedGoogle Scholar
  23. 23.
    Chica-Urzola HL, Escobar-Cordoba F, Eslava-Schmalbach J (2007) Validating the Epworth sleepiness scale. Rev Salud Publica (Bogota) 9:558–567CrossRefGoogle Scholar
  24. 24.
    Lahiri DK, Nurnberger JI Jr (1991) A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 19:5444PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Liu Q, Thorland EC, Heit JA, Sommer SS (1997) Overlapping PCR for bidirectional PCR amplification of specific alleles: a rapid one-tube method for simultaneously differentiating homozygotes and heterozygotes. Genome Res 7:389–398PubMedGoogle Scholar
  26. 26.
    Sole X, Guino E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22:1928–1929PubMedCrossRefGoogle Scholar
  27. 27.
    Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69:138–147PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Chang AM, Buch AM, Bradstreet DS, Klements DJ, Duffy JF (2011) Human diurnal preference and circadian rhythmicity are not associated with the CLOCK 3111C/T gene polymorphism. J Biol Rhythms 26:276–279PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Osland TM, Bjorvatn BR, Steen VM, Pallesen S (2011) Association study of a variable-number tandem repeat polymorphism in the clock gene PERIOD3 and chronotype in Norwegian university students. Chronobiol Int 28:764–770PubMedCrossRefGoogle Scholar
  31. 31.
    Pedrazzoli M, Louzada FM, Pereira DS, Benedito-Silva AA, Lopez AR, Martynhak BJ, Korczak AL, Koike Bdel V, Barbosa AA, D’Almeida V, Tufik S (2007) Clock polymorphisms and circadian rhythms phenotypes in a sample of the Brazilian population. Chronobiol Int 24:1–8Google Scholar
  32. 32.
    Barclay NL, Eley TC, Mill J, Wong CC, Zavos HM, Archer SN, Gregory AM (2011) Sleep quality and diurnal preference in a sample of young adults: associations with 5HTTLPR, PER3, and CLOCK 3111. Am J Med Genet B Neuropsychiatr Genet 156B:681–690PubMedCrossRefGoogle Scholar
  33. 33.
    Deuschle M, Schredl M, Schilling C, Wust S, Frank J, Witt SH, Rietschel M, Buckert M, Meyer-Lindenberg A, Schulze TG (2010) Association between a serotonin transporter length polymorphism and primary insomnia. Sleep 33:343–347PubMedGoogle Scholar
  34. 34.
    Fiedorowicz JG, Moser DJ, Hynes SM, Beglinger LJ, Schultz SK, Ellingrod VL (2007) LA allelic heterozygosity of the 5HTTLPR polymorphism is associated with higher cognitive function and lower interpersonal sensitivity. Psychiatr Genet 17:3–4PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Sonuga-Barke EJ, Kumsta R, Schlotz W, Lasky-Su J, Marco R, Miranda A, Mulas F, Oades RD, Banaschewski T, Mueller U, Andreou P, Christiansen H, Gabriels I, Uebel H, Kuntsi J, Franke B, Buitelaar J, Ebstein R, Gill M, Anney R, Roeyers H, Rothenberger A, Sergeant J, Steinhausen HC, Asherson P, Faraone SV (2011) A functional variant of the serotonin transporter gene (SLC6A4) moderates impulsive choice in attention-deficit/hyperactivity disorder boys and siblings. Biol Psychiatry 70:230–236PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Steffens DC, Taylor WD, McQuoid DR, Krishnan KR (2008) Short/long heterozygotes at 5HTTLPR and white matter lesions in geriatric depression. Int J Geriatr Psychiatry 23:244–248PubMedCrossRefGoogle Scholar
  37. 37.
    Dzirasa K, Ribeiro S, Costa R, Santos LM, Lin SC, Grosmark A, Sotnikova TD, Gainetdinov RR, Caron MG, Nicolelis MA (2006) Dopaminergic control of sleep-wake states. J Neurosci 26:10577–10589PubMedCrossRefGoogle Scholar
  38. 38.
    Dauvilliers Y, Neidhart E, Lecendreux M, Billiard M, Tafti M (2001) MAO-A and COMT polymorphisms and gene effects in narcolepsy. Mol Psychiatry 6:367–372PubMedCrossRefGoogle Scholar
  39. 39.
    Ciarleglio CM, Ryckman KK, Servick SV, Hida A, Robbins S, Wells N, Hicks J, Larson SA, Wiedermann JP, Carver K, Hamilton N, Kidd KK, Kidd JR, Smith JR, Friedlaender J, McMahon DG, Williams SM, Summar ML, Johnson CH (2008) Genetic differences in human circadian clock genes among worldwide populations. J Biol Rhythms 23:330–340PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Pereira DS, Tufik S, Louzada FM, Benedito-Silva AA, Lopez AR, Lemos NA, Korczak AL, D’Almeida V, Pedrazzoli M (2005) Association of the length polymorphism in the human Per3 gene with the delayed sleep-phase syndrome: does latitude have an influence upon it? Sleep 28:29–32PubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 2013

Authors and Affiliations

  • Diego A. Ojeda
    • 1
  • Claudia S. Perea
    • 1
  • Annjy Suárez
    • 1
    • 2
  • Carmen L. Niño
    • 2
  • Rafael M. Gutiérrez
    • 3
  • Sandra López-León
    • 4
  • Ana Adan
    • 5
  • Humberto Arboleda
    • 6
  • Andrés Camargo
    • 2
  • Diego A. Forero
    • 1
  1. 1.Laboratory of Neuropsychiatric Genetics, School of MedicineUniversidad Antonio NariñoBogotáColombia
  2. 2.School of NursingUniversidad de Ciencias Aplicadas y Ambientales UDCABogotáColombia
  3. 3.Complex Systems Group, Research Center for Basic and Applied SciencesUniversidad Antonio NariñoBogotáColombia
  4. 4.Global Clinical Epidemiology, Novartis Farmacéutica SABarcelonaSpain
  5. 5.Department of Psychiatry and Clinical Psychobiology, School of PsychologyUniversity of BarcelonaBarcelonaSpain
  6. 6.Neurosciences Research Group, School of Medicine and Institute of GeneticsUniversidad Nacional de ColombiaBogotáColombia

Personalised recommendations