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A latent modeling approach to genotype–phenotype relationships: maternal problem behavior clusters, prenatal smoking, and MAOA genotype

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Abstract

This study illustrates the application of a latent modeling approach to genotype–phenotype relationships and gene × environment interactions, using a novel, multidimensional model of adult female problem behavior, including maternal prenatal smoking. The gene of interest is the monoamine oxidase A (MAOA) gene which has been well studied in relation to antisocial behavior. Participants were adult women (N = 192) who were sampled from a prospective pregnancy cohort of non-Hispanic, white individuals recruited from a neighborhood health clinic. Structural equation modeling was used to model a female problem behavior phenotype, which included conduct problems, substance use, impulsive-sensation seeking, interpersonal aggression, and prenatal smoking. All of the female problem behavior dimensions clustered together strongly, with the exception of prenatal smoking. A main effect of MAOA genotype and a MAOA × physical maltreatment interaction were detected with the Conduct Problems factor. Our phenotypic model showed that prenatal smoking is not simply a marker of other maternal problem behaviors. The risk variant in the MAOA main effect and interaction analyses was the high activity MAOA genotype, which is discrepant from consensus findings in male samples. This result contributes to an emerging literature on sex-specific interaction effects for MAOA.

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References

  • Arbuckle JL (2007a) Amos 16.0 User's Guide. SPSS, Chicago

  • Arbuckle JL (2007b) Amos (version 16.0). SPSS, Chicago

  • Aslund C, Nordquist N, Comasco E, Leppert J, Oreland L, Nilsson KW (2011) Maltreatment, MAOA, and delinquency: sex differences in gene-environment interaction in a large population-based cohort of adolescents. Behav Genet 41(2):262–272

    Article  PubMed  CAS  Google Scholar 

  • Baler RD, Volkow ND, Fowler JS, Benveniste H (2008) Is fetal brain monoamine oxidase inhibition the missing link between maternal smoking and conduct disorders? J Psychiatry Neurosci 33(3):187–195

    PubMed  Google Scholar 

  • Benjamin D, Van Bakel I, Craig IW (2000) A novel expression based approach for assessing the inactivation status of human X-linked genes. Eur J Hum Genet 8(2):103–108

    Article  PubMed  CAS  Google Scholar 

  • Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, Sapareto E, Ruggiero J (1994) Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry 151(8):1132–1136

    PubMed  CAS  Google Scholar 

  • Bloss CS, Schiabor KM, Schork NJ (2010) Human behavioral informatics in genetic studies of neuropsychiatric disease: multivariate profile-based analysis. Brain Res Bull 83(3–4):177–188

    Article  PubMed  CAS  Google Scholar 

  • Buckholtz JW, Meyer-Lindenberg A (2008) MAOA and the neurogenetic architecture of human aggression. Trends Neurosci 31(3):120–129

    Article  PubMed  CAS  Google Scholar 

  • Byrne BM (2004) Testing for multigroup invariance using AMOS graphics: a road less traveled structural equation modeling. A Multidiscip J 11(2):272–300

    Google Scholar 

  • Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434(7031):400–404

    Article  PubMed  CAS  Google Scholar 

  • Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R (2002) Role of genotype in the cycle of violence in maltreated children. Science 297(5582):851–854

    Article  PubMed  CAS  Google Scholar 

  • Caspi A, Hariri AR, Holmes A, Uher R, Moffitt TE (2010) Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry 167(5):509–527

    Article  PubMed  Google Scholar 

  • Chakravorty SG, Halbreich U (1997) The influence of estrogen on monoamine oxidase activity. Psychopharmacol Bull 33(2):229–233

    PubMed  CAS  Google Scholar 

  • Costa PT Jr, McCrae RR (1997) Longitudinal stability of adult personality. In: Hogan R, Johnson JA, Briggs SR (eds) Handbook of personality psychology. Academic Press, San Diego, pp 269–290

    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(4):621–624

    Article  PubMed  CAS  Google Scholar 

  • D'Onofrio BM, Van Hulle CA, Waldman ID, Rodgers JL, Harden KP, Rathouz PJ, Lahey BB (2008) Smoking during pregnancy and offspring externalizing problems: an exploration of genetic and environmental confounds. Dev Psychopathol 20(1):139–164

    Article  PubMed  Google Scholar 

  • D'Onofrio BM, Singh AL, Iliadou A, Lambe M, Hultman CM, Grann M, Neiderhiser JM, Langstrom N, Lichtenstein P (2010) Familial confounding of the association between maternal smoking during pregnancy and offspring criminality: a population-based study in Sweden. Arch Gen Psychiatry 67(5):529–538

    Article  PubMed  Google Scholar 

  • Ducci F, Enoch MA, Hodgkinson C, Xu K, Catena M, Robin RW, Goldman D (2008) Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women. Mol Psychiatry 13(3):334–347

    Article  PubMed  CAS  Google Scholar 

  • Dukic VM, Niessner M, Benowitz N, Hans S, Wakschlag L (2007) Modeling the relationship of cotinine and self-reported measures of maternal smoking during pregnancy: a deterministic approach. Nicotine Tob Res 9(4):453–465

    Article  PubMed  Google Scholar 

  • Duncan LE, Keller MC (2011) A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. Am J Psychiatry 168(10):1041–1049. doi:10.1176/appi.ajp.2011.11020191

    Article  PubMed  Google Scholar 

  • Fergusson DM, Horwood LJ, Ridder EM (2005) Show me the child at seven: the consequences of conduct problems in childhood for psychosocial functioning in adulthood. J Child Psychol Psychiatr 46(8):837–849

    Article  Google Scholar 

  • Ferreira MA, Purcell SM (2009) A multivariate test of association. Bioinformatics 25(1):132–133

    Article  PubMed  CAS  Google Scholar 

  • Fontaine N, Carbonneau R, Vitaro F, Barker ED, Tremblay RE (2009) Research review: a critical review of studies on the developmental trajectories of antisocial behavior in females. J Child Psychol Psychiatry 50(4):363–385

    Article  PubMed  Google Scholar 

  • Frazzetto G, Di Lorenzo G, Carola V, Proietti L, Sokolowska E, Siracusano A, Gross C, Troisi A (2007) Early trauma and increased risk for physical aggression during adulthood: the moderating role of MAOA genotype. PLoS One 2(5):e486

    Article  PubMed  Google Scholar 

  • Gilman SE, Gardener H, Buka SL (2008) Maternal smoking during pregnancy and children's cognitive and physical development: a causal risk factor? Am J Epidemiol 168(5):522–531

    Article  PubMed  Google Scholar 

  • Hall MH, Smoller JW (2010) A new role for endophenotypes in the GWAS era: functional characterization of risk variants. Harv Rev Psychiatry 18(1):67–74

    Article  PubMed  Google Scholar 

  • Hanrahan JP, Tager IB, Segal MR, Tosteson TD, Castile RG, Van Vunakis H, Weiss ST, Speizer FE (1992) The effect of maternal smoking during pregnancy on early infant lung function. Am Rev Respir Dis 145(5):1129–1135

    Article  PubMed  CAS  Google Scholar 

  • Hendriks RW, Chen ZY, Hinds H, Schuurman RK, Craig IW (1992) An X chromosome inactivation assay based on differential methylation of a CpG island coupled to a VNTR polymorphism at the 5' end of the monoamine oxidase A gene. Hum Mol Genet 1(3):187–194

    Article  PubMed  CAS  Google Scholar 

  • Hetherington EM, Clingempeel WG, Anderson ER, Deal JE, Hagan MS, Hollier EA, Lindner MS (1992) Coping with marital transitions: a family systems perspective. Monogr Soc Res Child Dev 57(2/3)

  • Houle D, Govindaraju DR, Omholt S (2010) Phenomics: the next challenge. Nat Rev Genet 11(12):855–866

    Article  PubMed  CAS  Google Scholar 

  • Huang YY, Cate SP, Battistuzzi C, Oquendo MA, Brent D, Mann JJ (2004) An association between a functional polymorphism in the monoamine oxidase a gene promoter, impulsive traits and early abuse experiences. Neuropsychopharmacology 29(8):1498–1505

    Article  PubMed  CAS  Google Scholar 

  • Jaffee SR, Belsky J, Harrington H, Caspi A, Moffitt TE (2006) When parents have a history of conduct disorder: how is the caregiving environment affected? J Abnorm Psychol 115(2):309–319

    Article  PubMed  Google Scholar 

  • Jesor R, Jessor SL (1977) Problem behavior and psychosocial development: a longitudinal study of youth. Academic Press, New York

    Google Scholar 

  • Karg K, Burmeister M, Shedden K, Sen S (2011) The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatry. doi:10.1001/archgenpsychiatry.2010.189

  • Keenan K, Wroblewski K, Hipwell A, Loeber R, Stouthamer-Loeber M (2010) Age of onset, symptom threshold, and expansion of the nosology of conduct disorder for girls. J Abnorm Psychol 119(4):689–698

    Article  PubMed  Google Scholar 

  • Kerig PK (1996) Assessing the links between interparental conflict and child adjustment: the conflicts and problem-solving scales. J Fam Psychol 10(4):454–473

    Article  Google Scholar 

  • Kim-Cohen J, Caspi A, Taylor A, Williams B, Newcombe R, Craig IW, Moffitt TE (2006) MAOA, maltreatment, and gene-environment interaction predicting children's mental health: new evidence and a meta-analysis. Mol Psychiatry 11(10):903–913

    Article  PubMed  CAS  Google Scholar 

  • Kline RB (2005) Principles and practice of structural equation modeling, 2nd edn. Guilford Press, New York

    Google Scholar 

  • Krueger RF, Hicks BM, Patrick CJ, Carlson SR, Iacono WG, McGue M (2002) Etiologic connections among substance dependence, antisocial behavior, and personality: modeling the externalizing spectrum. J Abnorm Psychol 111(3):411–424

    Article  PubMed  Google Scholar 

  • Krueger RF, Markon KE, Patrick CJ, Benning SD, Kramer MD (2007) Linking antisocial behavior, substance use, and personality: an integrative quantitative model of the adult externalizing spectrum. J Abnorm Psychol 116(4):645–666

    Article  PubMed  Google Scholar 

  • Lange C, Silverman EK, Xu X, Weiss ST, Laird NM (2003) A multivariate family-based association test using generalized estimating equations: FBAT-GEE. Biostatistics 4(2):195–206

    Article  PubMed  Google Scholar 

  • Loeber R (1991) Antisocial behavior: more enduring than changeable? J Am Acad Child Adolesc Psychiatry 30(3):393–397

    Article  PubMed  CAS  Google Scholar 

  • Loehlin JC (2004) Latent variable models, 4th edn. Lawrence Erlbaum Associates, Mahwah

    Google Scholar 

  • Maughan B, Taylor A, Caspi A, Moffitt TE (2004) Prenatal smoking and early childhood conduct problems: testing genetic and environmental explanations of the association. Arch Gen Psychiatry 61(8):836–843

    Article  PubMed  Google Scholar 

  • Medland SE, Neale MC (2010) An integrated phenomic approach to multivariate allelic association. Eur J Hum Genet 18(2):233–239

    Article  PubMed  Google Scholar 

  • Middeldorp CM, Landt MC Slof-Op 't, Medland SE, van Beijsterveldt CE, Bartels M, Willemsen G, Hottenga JJ, de Geus EJ, Suchiman E, Dolan CV, Neale MC, Slagboom PE, Boomsma DI (2010) Anxiety and depression in children and adults: influence of serotonergic and neurotrophic genes? Genes Brain Behav 9(7):808–816

    Article  PubMed  CAS  Google Scholar 

  • Moffitt TE, Caspi A, Rutter M, Silva PA (2001) Sex differences in antisocial behavior. Cambridge University Press, Cambridge

    Book  Google Scholar 

  • Munafo MR, Durrant C, Lewis G, Flint J (2009) Gene × environment interactions at the serotonin transporter locus. Biol Psychiatry 65(3):211–219

    Article  PubMed  CAS  Google Scholar 

  • Neale MC, Boker SM, Xie G, Maes HH (2002) Mx: statistical modeling, 6th edn. Departmentt of Psychiatry, Virginia Commonwealth University, Richmond

    Google Scholar 

  • Nilsson KW, Comasco E, Aslund C, Nordquist N, Leppert J, Oreland L (2011) MAOA genotype, family relations and sexual abuse in relation to adolescent alcohol consumption. Addict Biol 16(2):347–355

    Article  PubMed  Google Scholar 

  • Nordquist N, Oreland L (2006) Monoallelic expression of MAOA in skin fibroblasts. Biochem Biophys Res Commun 348(2):763–767

    Article  PubMed  CAS  Google Scholar 

  • Ou XM, Chen K, Shih JC (2006) Glucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1. J Biol Chem 281(30):21512–21525

    Article  PubMed  CAS  Google Scholar 

  • Plomin R, Haworth CM, Davis OS (2009) Common disorders are quantitative traits. Nat Rev Genet 10(12):872–878

    Article  PubMed  CAS  Google Scholar 

  • Prom-Wormley EC, Eaves LJ, Foley DL, Gardner CO, Archer KJ, Wormley BK, Maes HH, Riley BP, Silberg JL (2009) Monoamine oxidase A and childhood adversity as risk factors for conduct disorder in females. Psychol Med 39(4):579–590

    Article  PubMed  CAS  Google Scholar 

  • Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR (2009) Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 301(23):2462–2471

    Article  PubMed  CAS  Google Scholar 

  • Roberts BW, Caspi A, Moffitt TE (2001) The kids are alright: growth and stability in personality development from adolescence to adulthood. J Pers Soc Psychol 81(4):670–683

    Article  PubMed  CAS  Google Scholar 

  • Sabol SZ, Hu S, Hamer D (1998) A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 103(3):273–279

    Article  PubMed  CAS  Google Scholar 

  • Sakai JT, Boardman JD, Gelhorn HL, Smolen A, Corley RP, Huizinga D, Menard S, Hewitt JK, Stallings MC (2010) Using trajectory analyses to refine phenotype for genetic association: conduct problems and the serotonin transporter (5HTTLPR). Psychiatr Genet 20(5):199–206

    Article  PubMed  Google Scholar 

  • Schulze TG, McMahon FJ (2004) Defining the phenotype in human genetic studies: forward genetics and reverse phenotyping. Hum Hered 58(3–4):131–138

    Article  PubMed  Google Scholar 

  • Serbin LA, Stack DM, De Jenna M, Grunzeweig N, Temcheff CE, Schwartzman AE, Ledingham J (2004) When aggressive girls become mothers. In: Putallaz M, Bierman KL (eds) Aggression, antisocial behavior and violence among girls. Guilford Press, New York, pp 262–285

    Google Scholar 

  • Silberg JL, Parr T, Neale MC, Rutter M, Angold A, Eaves LJ (2003) Maternal smoking during pregnancy and risk to boys' conduct disturbance: an examination of the causal hypothesis. Biol Psychiatry 53(2):130–135

    Article  PubMed  Google Scholar 

  • Sjoberg RL, Nilsson KW, Wargelius HL, Leppert J, Lindstrom L, Oreland L (2007) Adolescent girls and criminal activity: role of MAOA-LPR genotype and psychosocial factors. Am J Med Genet B Neuropsychiatr Genet 144B(2):159–164

    Article  PubMed  Google Scholar 

  • Skinner HA (1982) The drug abuse screening test. Addict Behav 7(4):363–371

    Article  PubMed  CAS  Google Scholar 

  • Sörbom D (1974) A general method for studying differences in factor means and factor structure between groups. Br J Mat Stat Psychol 27:229–239

    Article  Google Scholar 

  • Sullivan PF (2007) Spurious genetic associations. Biol Psychiatry 61(10):1121–1126

    Article  PubMed  CAS  Google Scholar 

  • Tager IB, Ngo L, Hanrahan JP (1995) Maternal smoking during pregnancy. Effects on lung function during the first 18 months of life. Am J Respir Crit Care Med 152(3):977–983

    PubMed  CAS  Google Scholar 

  • Thapar A, Rice F, Hay D, Boivin J, Langley K, van den Bree M, Rutter M, Harold G (2009) Prenatal smoking might not cause attention-deficit/hyperactivity disorder: evidence from a novel design. Biol Psychiatry 66(8):722–727

    Article  PubMed  CAS  Google Scholar 

  • Wakschlag LS, Kistner EO, Pine DS, Biesecker G, Pickett KE, Skol AD, et al. (2010) Interaction of prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior. Mol Psychiatry 15(9):928–937

    Google Scholar 

  • Wakschlag LS, Pickett KE, Cook E Jr, Benowitz NL, Leventhal BL (2002) Maternal smoking during pregnancy and severe antisocial behavior in offspring: a review. Am J Public Health 92(6):966–974

    Article  PubMed  Google Scholar 

  • Wakschlag LS, Pickett KE, Middlecamp MK, Walton LL, Tenzer P, Leventhal BL (2003) Pregnant smokers who quit, pregnant smokers who don't: does history of problem behavior make a difference? Soc Sci Med 56(12):2449–2460

    Article  PubMed  Google Scholar 

  • Wakschlag LS, Pickett KE, Kasza KE, Loeber R (2006) Is prenatal smoking associated with a developmental pattern of conduct problems in young boys? J Am Acad Child Adolesc Psychiatry 45(4):461–467

    Article  PubMed  Google Scholar 

  • Wang X, Tager IB, Van Vunakis H, Speizer FE, Hanrahan JP (1997) Maternal smoking during pregnancy, urine cotinine concentrations, and birth outcomes. A prospective cohort study. Int J Epidemiol 26(5):978–988

    Article  PubMed  CAS  Google Scholar 

  • Widom CS, Brzustowicz LM (2006) MAOA and the "cycle of violence:" childhood abuse and neglect, MAOA genotype, and risk for violent and antisocial behavior. Biol Psychiatry 60(7):684–689

    Article  PubMed  CAS  Google Scholar 

  • Xue F, Tian XC, Du F, Kubota C, Taneja M, Dinnyes A, Dai Y, Levine H, Pereira LV, Yang X (2002) Aberrant patterns of X chromosome inactivation in bovine clones. Nat Genet 31(2):216–220

    Article  PubMed  CAS  Google Scholar 

  • Zoccolillo M (1993) Gender and the development of conduct disorder. Dev Psychopathol 5:65–78

    Article  Google Scholar 

  • Zoccolillo M, Paquette D, Azar R, Cote S, Tremblay RE (2004) Parenting as an important outcome of conduct disorder in girls. In: Putallaz M, Bierman KL (eds) Aggression, antisocial behavior and violence among girls. Guilford Press, New York, pp 242–261

    Google Scholar 

  • Zuckerman M (1994) Impulsive unsocialized sensation seeking: the biological foundations of a basic dimension of personality. In: Bates JE, Wachs TD (eds) Temperament: individual differences at the interface of biology and behavior. American Psychological Association, Washington, DC

    Google Scholar 

  • Zuckerman M (2002) An alternative five-factorial model. In: Raad BD, M. P (eds) Big Five Assessment. Hogrefe and Huber, Ashland, OH, pp. 377-396

  • Zucker RA, Noll RB, Ham HP, Fitzgerald HE, Sullivan LS (1994) Assessing antisociality with the Antisocial Behavior Checklist: Reliability and validity studies. (Unpublished manuscript)

  • Zung BJ (1982) Evaluation of the Michigan Alcoholism Screening Test (MAST) in assessing lifetime and recent problems. J Clin Psychol 38(2):425–439

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry and Center for Human Genetic Research, Massachusetts General Hospital/Harvard Medical School, Simches Research Building 6th floor, 185 Cambridge Street, Boston, MA, 02114, USA

    L. M. McGrath

  2. Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    B. Mustanski & L. S. Wakschlag

  3. Department of Psychology, West Virginia University, Morgantown, WV, USA

    A. Metzger

  4. Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, MD, USA

    D. S. Pine

  5. Division of Biostatistics and Epidemiology, Medical University of South Carolina, Charleston, SC, USA

    E. Kistner-Griffin

  6. Department of Psychiatry, Institute for Juvenile Research, University of Illinois at Chicago, Chicago, IL, USA

    E. Cook

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  1. L. M. McGrath
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  2. B. Mustanski
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  3. A. Metzger
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  6. E. Cook
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  7. L. S. Wakschlag
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McGrath, L.M., Mustanski, B., Metzger, A. et al. A latent modeling approach to genotype–phenotype relationships: maternal problem behavior clusters, prenatal smoking, and MAOA genotype. Arch Womens Ment Health 15, 269–282 (2012). https://doi.org/10.1007/s00737-012-0286-y

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