Skip to main content
SpringerLink
Log in

The association of DNA sequence variation at the MAOA genetic locus with quantitative behavioural traits in normal males

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Monoamine oxidase A (MAOA) catalyses the oxidative deamination of biogenic amines including neurotransmitters, mainly norepinephrine and serotonin in the brain and peripheral tissues. A nonsense mutation in the gene was shown to be involved in a rare X-linked behavioural syndrome, which includes impaired impulse control, aggression and borderline mental retardation (Brunner syndrome). Several recent studies have shown the association of genetic variation of a VNTR in the gene promoter with various pathological behavioural traits. In the present study the association of MAOA genetic variation with a large set of quantitative behavioural traits in normal individuals has been examined. DNA samples from 421 unrelated males were genotyped for 14 SNPs and for the promoter VNTR at the MAOA locus. An additional 16 SNPs were genotyped at apparently neutral loci across the X chromosome to serve as a genomic control for possible false positive associations due to population structure. Behavioural traits were measured using the NEO psychometric questionnaire, which is based on a 5-axis model of personality, and consists of 30 different quantitative traits. There was a robust association of the A2 (“straightforwardness”) facet with common allelic variants at the promoter VNTR. Most of the tested traits were not associated with the VNTR despite reasonable power, thus demonstrating that the VNTR influence on quantitative behavioural traits in normal males may be very specific. In contrast, several traits of the C (“conscientiousness”) axis were associated with less common SNP-defined haplotypes. Hence, it appears that common genetic variation at the VNTR contributes to the behavioural attribute of “straightforwardness”, while rare haplotypes defined by SNPs downstream of the transcription start site may contribute to “conscientiousness”. This study is used to address the validation, interpretation and limitation of genetic association studies of quantitative behavioural traits.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Bacanu SA, Devlin B, Roeder K (2002) Association studies for quantitative traits in structured populations. Genet Epidemiol 22:78–93

    Article  PubMed  Google Scholar 

  • Balciuniene J, Jazin E (2001) Human monoamine oxidase: from genetic variation to complex human phenotypes. Gene Funct Dis 1:26–37

    Article  Google Scholar 

  • Boehringer S, Epplen JT, Krawczak M (2000) Genetic association studies of bronchial asthma—a need for Bonferroni correction? Hum Genet 107:197

    Article  PubMed  CAS  Google Scholar 

  • Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA (1993a) Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262:578–580

    Article  PubMed  CAS  Google Scholar 

  • Brunner HG, Nelen MR, van Zandvoort P, Abeling NG, van Gennip AH, Wolters EC, Kuiper MA, Ropers HH, van Oost BA (1993b) X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism. Am J Hum Genet 52:1032–1039

    PubMed  CAS  Google Scholar 

  • Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Muller U, Aguet M, Babinet C, Shih JC et al (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268:1763–1766

    Article  PubMed  CAS  Google Scholar 

  • Cases O, Vitalis T, Seif I, De Maeyer E, Sotelo C, Gaspar P (1996) Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period. Neuron 16:297–307

    Article  PubMed  CAS  Google Scholar 

  • Caspi A, McClay J, Moffitt T, Mill J, Martin J, Craig I, Taylor A, Poulton R (2002) Role of genotype in the cycle of violence in maltreated children. Science 297:851–854

    Article  PubMed  CAS  Google Scholar 

  • Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH (2004) Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305:869–872

    Article  PubMed  CAS  Google Scholar 

  • Cooper DN, Nussbaum RL, Krawczak M (2002) Proposed guidelines for papers describing DNA polymorphism-disease associations. Hum Genet 110:207–208

    Article  PubMed  CAS  Google Scholar 

  • Daiger SP (2005) Genetics. Was the human genome project worth the effort? Science 308:362–364

    Article  PubMed  CAS  Google Scholar 

  • Davidson JR (1998) Pharmacotherapy of social anxiety disorder. J Clin Psychiatry 59:47–53

    CAS  Google Scholar 

  • Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D, Nothen MM, Maffei P, Franke P, Fritze J, Maier W, Propping P, Beckmann H, Bellodi L, Lesch KP (1999) Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 8:621–624

    Article  PubMed  CAS  Google Scholar 

  • Devlin B, Roeder K, Wasserman L (2001) Genomic control, a new approach to genetic-based association studies. Theor Popul Biol 60:155–166

    Article  PubMed  CAS  Google Scholar 

  • Felsenstein J (2004) PHYLIP (Phylogeny Inference Package) version 3.6. Distributed by the author. Department of Genome Sciences, University of Washington, Seattle

  • Freimer N, Sabatti C (2003) The human phenome project. Nat Genet 34:15–21

    Article  PubMed  CAS  Google Scholar 

  • Freimer N, Sabatti C (2004) The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology. Nat Genet 36:1045–1051

    Article  PubMed  CAS  Google Scholar 

  • Gilad Y, Rosenberg S, Przeworski M, Lancet D, Skorecki K (2002) Evidence for positive selection and population structure at the human MAO-A gene. Proc Natl Acad Sci USA 99:862–867

    Article  PubMed  CAS  Google Scholar 

  • Jackson PE, Scholl PF, Groopman JD (2000) Mass spectrometry for genotyping: an emerging tool for molecular medicine. Mol Med Today 6:271–276

    Article  PubMed  CAS  Google Scholar 

  • Jang KL, Livesley WJ, Vernon PA (1996) Heritability of the big five personality dimensions and their facets: a twin study. J Pers 64:577–591

    Article  PubMed  CAS  Google Scholar 

  • Jurinke C, van den Boom D, Cantor CR, Koster H (2002) The use of MassARRAY technology for high throughput genotyping. Adv Biochem Eng Biotechnol 77:57–74

    PubMed  CAS  Google Scholar 

  • Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308:385–389

    Google Scholar 

  • Livingston MG, Livingston HM (1996) Monoamine oxidase inhibitors. An update on drug interactions. Drug Saf 14:219–227

    PubMed  CAS  Google Scholar 

  • Long AD, Langley CH (1999) The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits. Genome Res 9:720–731

    PubMed  CAS  Google Scholar 

  • Mackay TF (2001) The genetic architecture of quantitative traits. Annu Rev Genet 35:303–339

    Article  PubMed  CAS  Google Scholar 

  • Manuck SB, Flory JD, Ferrell RE, Mann JJ, Muldoon MF (2000) A regulatory polymorphism of the monoamine oxidase-A gene may be associated with variability in aggression, impulsivity, and central nervous system serotonergic responsivity. Psychiatry Res 95:9–23

    Article  PubMed  CAS  Google Scholar 

  • Marchini J, Cardon LR, Phillips MS, Donnelly P (2004) The effects of human population structure on large genetic association studies. Nat Genet 36: 512–7. Epub 2004 Mar 28

    Google Scholar 

  • Nei M (1987) Molecular evolutionary genetics. Columbia University Press, New York, p 180

    Google Scholar 

  • Perneger TV (1998) What’s wrong with Bonferroni adjustments. BMJ 316:1236–1238

    PubMed  CAS  Google Scholar 

  • Piedmont RL (1998) The revised NEO personality inventory. Plenum Press, New York

    Google Scholar 

  • Sabol S, Hu S, Hamer D (1998) A functional polymorphism in monoamine oxidase A gene promoter. Hum Genet 103:273–279

    Article  PubMed  CAS  Google Scholar 

  • Salisbury BA, Pungliya M, Choi JY, Jiang R, Sun XJ, Stephens JC (2003) SNP and haplotype variation in the human genome. Mutat Res 526:53–61

    PubMed  CAS  Google Scholar 

  • Sans M (2000) Admixture studies in Latin America: from the 20th to the 21st century. Hum Biol 72:155–177

    PubMed  CAS  Google Scholar 

  • Schneider S, Roessli D, Excoffier L (2000) Arlequin ver. 2000: a software for population genetics data analysis. Genetics and Biometry Laboratory, University of Geneva, Switzerland

  • Shih JC, Chen K, Ridd MJ (1999) Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 22:197–217

    Article  PubMed  CAS  Google Scholar 

  • Shih JC, Thompson RF (1999) Monoamine oxidase in neuropsychiatry and behavior. Am J Hum Genet 65:593–598

    Article  PubMed  CAS  Google Scholar 

  • Templeton AR, Boerwinkle E, Sing CF (1987) A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. I. Basic theory and an analysis of alcohol dehydrogenase activity in Drosophila. Genetics 117:343–351

    PubMed  CAS  Google Scholar 

  • Templeton AR, Crandall KA, Sing CF (1992) A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping and DNA sequence data. III. Cladogram estimation. Genetics 132:619–633

    PubMed  CAS  Google Scholar 

  • Tishkoff SA, Kidd KK (2004) Implications of biogeography of human populations for ‘race’ and medicine. Nat Genet 36:S21–S27

    Article  PubMed  CAS  Google Scholar 

  • Tishkoff SA, Verrelli BC (2003) Patterns of human genetic diversity: implications for human evolutionary history and disease. Annu Rev Genomics Hum Genet 4:293–340

    Article  PubMed  CAS  Google Scholar 

  • Wilson JF, Goldstein DB (2000) Consistent long-range linkage disequilibrium generated by admixture in a Bantu-Semitic hybrid population. Am J Hum Genet 67:926–935 Epub 2000 Aug 28

    Google Scholar 

Download references

Acknowledgments

We would like to thank Edna Ben-Asher and Nili Avidan for lab work assistance and useful discussions. We would like to thank Mike Weale and Katheryn Roeder for useful discussions about Genomic Control. This study was supported by the Israel Academy of Science—FIRST award.

Author information

Authors and Affiliations

  1. Rappaport Faculty of Medicine and Research Institute, Technion–Israel Institute of Technology, 1 Efron Street, Haifa, 31096, Israel

    Shai Rosenberg, Sara Selig & Karl Skorecki

  2. Department of Biology, Washington University, 1 Brookings, Campus Box 1137, St. Louis, MO, 63130, USA

    Alan R. Templeton

  3. William Davidson Faculty of Industrial Engineering and Management, Technion–Israel Institute of Technology, Technion City, Haifa, 32000, Israel

    Paul D. Feigin

  4. Department of Molecular Genetics and the Crown Human Genome Center, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Doron Lancet

  5. Department of Medical Genetics, University of Lausanne, 2 Avenue Pierre Decker, 1011, Lausanne, Switzerland

    Jacques S. Beckmann

  6. Dépt de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    Jacques S. Beckmann

  7. Laboratory of Biochemistry, NCI, NIH, 9000 Rockville Pike, Bethesda, MD, 20892, USA

    Dean H. Hamer

  8. Department of Nephrology and Molecular Medicine, Rambam Medical Center, 1 Efron Street, Haifa, 31096, Israel

    Sara Selig & Karl Skorecki

Authors
  1. Shai Rosenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan R. Templeton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul D. Feigin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Doron Lancet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jacques S. Beckmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sara Selig
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dean H. Hamer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Karl Skorecki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shai Rosenberg or Karl Skorecki.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rosenberg, S., Templeton, A.R., Feigin, P.D. et al. The association of DNA sequence variation at the MAOA genetic locus with quantitative behavioural traits in normal males. Hum Genet 120, 447–459 (2006). https://doi.org/10.1007/s00439-006-0198-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-006-0198-x

Keywords

Search

Navigation