Gene × environment interactions for ADHD: synergistic effect of 5HTTLPR genotype and youth appraisals of inter-parental conflict
Tóm tắt
Serotonin genes have been hypothesized to play a role in the etiology of attention-deficit hyperactivity disorder (ADHD); prior work suggests that serotonin may interact with psychosocial stressors in ADHD, perhaps via mechanisms involved in emotional dysregulation. Because the development of behavioral and emotional regulation depends heavily both on the child's experience within the family context and the child's construals of that experience, children's appraisals of inter-parental conflict are a compelling candidate potentiator of the effects of variation within the serotonin transporter gene promoter polymorphism (5HTTLPR) on liability for ADHD. 304 youth from the local community underwent a multi-informant diagnostic assessment procedure to identify ADHD cases and non-ADHD controls. Youth also completed the Children's Perception of Inter-Parental Conflict (CPIC) scale to assess appraisals of self-blame in relation to their parents' marital disputes. The trialleic configuration of 5HTTLPR (long/short polymorphism with A> G substitution) was genotyped and participants were assigned as having high (La/La N = 78), intermediate (La/Lg, La/short, N = 137), or low (Lg/Lg, Lg/short, short/short, N = 89) serotonin transporter activity genotypes. Teacher reported behavior problems were examined as the target outcome to avoid informant overlap for moderator and outcome measures. Hierarchical linear regression analyses indicated significant 5HTTLPR × self-blame interactions for ADHD symptoms. Examination of the interactions indicated positive relations between reports of self-blame and ADHD symptoms for those with the high and low serotonin activity genotypes. There was no relation between self-blame and ADHD for those with intermediate activity 5HTTLPR genotypes. Both high and low serotonergic activity may exert risk for ADHD when coupled with psychosocial distress such as children's self-blame in relation to inter-parental conflict. Results are discussed in relation to the role of serotonin in the etiology of the ADHD and related externalizing behaviors.
Tài liệu tham khảo
Nigg JT, Hinshaw SP, Huang-Pollock C: Disorders of attention and impulse regulation. Developmental Psychopathology, Risk, disorder, and adaptation. Edited by: Cicchetti D, Cohen DJ. 2006, Hoboken, NJ: John Wiley & Sons, 3: 358-403. 2
Rutter M, Silberg J: Gene-environment interplay in relation to emotional and behavioral disturbance. Annu Rev Psychol. 2002, 53: 463-490. 10.1146/annurev.psych.53.100901.135223.
Bergen SE, Gardner CO, Kendler KS: Age-related changes in heritability of behavioral phenotypes over adolescence and young adulthood: A meta-analysis. Twin Res Human Genet. 2007, 10: 423-433. 10.1375/twin.10.3.423.
Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P: Molecular genetics of ADHD. Biol Psychiatry. 2005, 57: 1313-1323. 10.1016/j.biopsych.2004.11.024.
Gizer IR, Ficks C, Waldman ID: Candidate gene studies of ADHD: A meta-analytic review. Hum Genet. 2009, 126: 51-90. 10.1007/s00439-009-0694-x.
Purcell S: Variance component models for gene-environment interaction in twin analysis. Twin Res. 2002, 5: 554-571. 10.1375/136905202762342026.
Banerjee TD, Middleton F, Faraone SV: Environmental risk factors for attention-deficit hyperactivity disorder. Acta Pediatri. 2007, 96: 1269-74. 10.1111/j.1651-2227.2007.00430.x.
Nigg JT: What causes ADHD? Understanding what goes wrong and why. 2006, New York: The Guilford Press
Pennington BF, McGrath LM, Rosenberg J, Barnard H, Smith SD, Willcutt EG, Friend A, DeFries JC, Olson RK: Gene X environment interactions for reading disability and attention-deficit hyperactivity disorder. Dev Psychol. 2009, 45: 77-89. 10.1037/a0014549.
Spencer T, Biederman J, Wilens T: Pharmacoptherapy of attention deficit hyperactivity disorder. Child Adolesc Psychiatr Clin N Am. 2000, 9: 77-97.
Nigg JT, Casey BJ: An integrative theory of attention-deficit hyperactivity disorder based on the cognitive and affective neurosciences. Dev Psychopathol. 2006, 17: 785-806.
Evans J, Platts S, Lightman S, Nutt D: Impulsiveness and the prolactin response to d-flenfluramine. Psychopharmacology. 2000, 149: 147-152. 10.1007/s002139900361.
Moffitt TE, Brammer GL, Caspi A, Fawcett JP, Raleigh M, Yuwiler A, Silva P: Whole blood serotonin relates to violence in an epidemiological study. Biol Psychiatry. 1998, 43: 446-457. 10.1016/S0006-3223(97)00340-5.
Depue RA, Spoont MR: Conceptualizing a serotonin trait: A behavioral dimension of constraint. Ann NY Acad Sci. 1980, 487: 47-62. 10.1111/j.1749-6632.1986.tb27885.x.
Frankle WG, Huang Y, Hwang DR, Talbot PS, Slifstein M, Van Heertum R, Abi-Dargham A, Laruelle M: Comparative evaluation of serotonin transporter radioligands 11C-DASB and 11C-McN 5652 in healthy humans. J Nucl Med. 2004, 45: 682-694.
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL: Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996, 274: 1527-1531. 10.1126/science.274.5292.1527.
Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL: Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet. 1999, 88: 83-87. 10.1002/(SICI)1096-8628(19990205)88:1<83::AID-AJMG15>3.0.CO;2-0.
Bennet A, Lesch KP, Heils A, Long JC, Lorenz JG, Schoaf SE, Champoux M, Suomi SJ, Linnoila MV, Higley JD: Early experience and serotonin transporter gene interact to influence primate CNS function. Mol Psychiatry. 2002, 7: 118-122. 10.1038/sj/mp/4000949.
Manuck SB, Flory JD, Ferrell RE, Muldoon RF: Socio-economic status covaries with central nervous system serotonergic responsivity as a function of allelic variation in the serotonin transporter gene-linked polymorphic region. Psychoneuroendocrinology. 2004, 29: 651-668. 10.1016/S0306-4530(03)00094-5.
Sonuga-Barke EJ, Lasky-Su J, Neale B, Oades R, Chen W, Franke B, Buitelaar J, Banaschewski T, Ebstein R, Gill M, Anney R, Miranda A, Mulas F, Roeyers H, Rothenberger A, Sergeant J, Steinhausen HC, Thompson M, Asherson P, Faraone SV: Does parental expressed emotion moderate genetic effects in ADHD? An exploration using a genome wide association scan. Am J Med Genet B Neuropsychiatr Genet. 2008, 147B: 1359-68. 10.1002/ajmg.b.30860.
Hallikainen T, Saito T, Lachman HM, Volavka J, Pohjalainen T, Ryynanen OP, Kauhanen J, Syvalahti E, Hietala J, Tiihonen J: Association between low activity serotonin transporter promoter genotype and early-onset alcoholism with habitual violent impulsive behavior. Mol Psychiatry. 1999, 4: 385-388. 10.1038/sj.mp.4000526.
Beitchman JH, Baldassarra L, Mik H, DeLuca V, King N, Bender D, Ehtesham S, Kennedy JL: Serotonin transporter polymorphisms and persistent, pervasive childhood aggression. Am J Psychiatry. 2006, 163: 1103-1105. 10.1176/appi.ajp.163.6.1103.
Haberstick BC, Smolen A, Hewitt JK: Family-based association test of 5HTTLPR and aggressive behavior in a general population sample of children. Biol Psychiatry. 2006, 59: 836-843. 10.1016/j.biopsych.2005.10.008.
Sakai JT, Young SE, Stallings MC, Timberlake D, Smolen A, Stelter GL, Crowley TJ: Case-control and within-family tests for an association between conduct disorder and 5HTTLPR. Am J Med Genet B Neuropsychiatr Genet. 2006, 141B: 825-832. 10.1002/ajmg.b.30278.
Kruesi MJ, Rapoport JL, Hamburger S, Hibbs E, Potter WZ, Lenane M, Brown GL: Cerebrospinal fluid monamine metabolites, aggression, and impulsivity in disruptive behavior disorders of children and adolescents. Arch Gen Psychiatry. 1990, 47: 419-426.
Kruesi MJ, Hibbs ED, Zahn TP, Keysor CS, Hamburger SD, Bartko JJ, Rapoport JL: A 2-year prospective follow-up study of children and adolescents with disruptive behavior disorders: Prediction by cerebrospinal fluid 5-hydroxyinoleacetic acid, homovanillic acid, and autonomic measures?. Arch Gen Psychiatry. 1992, 49: 429-435.
Clarke RA, Murphy DL, Constantino JN: Serotonin and externalizing behavior in young children. Psychiatry Res. 1999, 86: 29-40. 10.1016/S0165-1781(99)00022-0.
Flory JD, Newcorn JH, Miller C, Harty S, Halperin JM: Serotonergic function in children with attention-deficit hyperactivity disorder: Relationship to later antisocial personality disorder. Br J Psychiatry. 2007, 190: 410-414. 10.1192/bjp.bp.106.027847.
Stoff DM, Pasatiempo AP, Yeung J, Cooper TB, Bridger WH, Rabinovich H: Neuroendocrine responses to challenge with d-fenfluramine and aggression in disruptive behavior disorders of children and adolescents. Psychiatry Res. 1992, 43: 263-276. 10.1016/0165-1781(92)90059-C.
Castellanos FX, Elia J, Kruesi MJ, Gulotta CS, Mefford IN, Potter WZ, Ritchie GF, Rapoport JL: Cerebrospinal fluid monoamine metabolites in boys with a attention-deficit hyperactivity disorder. Psychiatry Res. 1994, 52: 305-316. 10.1016/0165-1781(94)90076-0.
Halperin JM, Sharma V, Siever LJ, Schwartz ST, Matier K, Wornell G, Newcorn JH: Serotonergic function in aggressive and nonaggressive boys with attention-deficit hyperactivity disorder. Am J Psychiatry. 1994, 151: 243-248.
Coccaro EF, Siever LJ, Klar HM, Maurer G, Cochrane K, Cooper TB, Mohs RC, Davis KL: Serotonergic studies in patients with affective and personality disorders: Correlates with suicidal and impulsive aggressive behavior. Arch Gen Psychiatry. 1989, 46: 587-599.
O'Keane V, Maloney E, O'Neil H, O'Connor A, Smith C, Dinan TG: Blunted prolactin response to d-fenfluramine in sociopathy: Evidence for subsensitivity of central serotonergic function. Br J Psychiatry. 1992, 160: 643-646. 10.1192/bjp.160.5.643.
Manuck SB, Flory JD, Muldoon MF, Ferrell RE: Central nervous system serotonergic responsivity and aggressive disposition in men. Physiol Behav. 2002, 77: 705-709. 10.1016/S0031-9384(02)00922-8.
Retz W, Retz-Jungunger P, Supprian T, Thome J, Rosler M: Association with serotonin transporter gene polymorphism with violence: Relation with personality disorders, impulsivity, and childhood ADHD psychopathology. Behav Sci Law. 2004, 22: 415-425. 10.1002/bsl.589.
Nakamura M, Ueno S, Sano A, Tanabe H: The human serotonin transporter gene linked polymorphism (5HTTLPR) shows ten novel allelic variants. Mol Psychiatry. 2000, 5: 32-38. 10.1038/sj.mp.4000698.
Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D: Serotonin transporter promoter gain-of-function genotypes are linked obsessive-compulsive disorder. Am J Hum Genet. 2006, 78: 815-826. 10.1086/503850.
Kraft JM, Slager SL, McGrath PJ, Hamilton SP: Sequence analysis of the serotonin transporter and associations with antidepressant response. Biol Psychiatry. 2005, 58: 374-381. 10.1016/j.biopsych.2005.04.048.
Wigg KG, Takhar A, Ickowicz A, Tannock R, Kennedy JL, Pathare T, Malone M, Schachar R, Barr C: Gene for the serotonin transporter and ADHD: No association with two functional polymorphisms. Am J Med Genet B Neuropsychiatr Genet. 2006, 141B: 566-570. 10.1002/ajmg.b.30247.
Oades RD, Lasky-Su J, Christiansen H, Faraone SV, Sonuga-Barke EJS, Banaschewski T, Chen W, Anney RJL, Buitelaar JK, Ebstein RP, Franke B, Gill M, Miranda A, Roeyers H, Rothenberger A, Sergeant JA, Steinhausen H, Taylor EA, Thompson M, Asherson P: The influence of serotonin-and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis. Behav Brain Funct. 2008, 4: 48-10.1186/1744-9081-4-48.
Nikolas M, Burt SA: Genetic and environmental influences on ADHD symptom dimensions of inattention and hyperactivity: A meta-analysis. J Abnorm Psychology. 2010, 119: 1-17. 10.1037/a0018010.
Retz W, Freitag CM, Retz-Junginger P, Wenzler D, Schneider M, Kissling C, Thome J, Rosler M: A functional serotonin transporter gene polymorphism increases ADHD symptoms in delinquents: Interaction with adverse child environment. Psychiatry Res. 2008, 158: 123-131. 10.1016/j.psychres.2007.05.004.
Arnsten AF, Goldman-Rakic PS: Noise impairs prefrontal cortical cognitive function in monkeys: Evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry. 1998, 55: 362-368. 10.1001/archpsyc.55.4.362.
Grych JH, Fincham FD: Marital conflict and children's adjustment: A cognitive-contextual framework. Psychol Bull. 1990, 108: 267-290. 10.1037/0033-2909.108.2.267.
Cummings EM, Davies PT: Children and marital conflict: The impact of marital dispute and resolution. 1994, New York: The Guilford Press
Grych JH, Fincham FD, Jouriles EN, McDonald RN: Interparental conflict and child adjustment: Testing the mediational role of appraisals in the cognitive-contextual framework. Child Dev. 2000, 71: 1648-1661. 10.1111/1467-8624.00255.
Jouriles EN, Collazos Spiller L, Stephens N, McDonald R, Swank P: Variability in adjustment of child of battered women: The Role of child appraisals of interparental conflict. Cognit Ther Res. 2000, 24: 233-249. 10.1023/A:1005402310180.
Counts CA, Nigg JT, Stawicki JA, Rappley MD, Von Eye A: Family adversity in DSM-IV ADHD Combined and Inattentive subtypes as associated disruptive behavior problems. J Am Acad Child Adolesc Psychiatry. 2005, 44: 690-698. 10.1097/01.chi.0000162582.87710.66.
Gerard JM, Beuhler C, Franck K, Anderson O: In the eyes of the beholder: Cognitive appraisals as mediators of the association between interparental conflict and youth maladjustment. J Fam Psychol. 2005, 19: 376-384. 10.1037/0893-3200.19.3.376.
Skopp NA, McDonald R, Manke B, Jouriles EN: Siblings in domestically violent families: Experiences of interparent conflict and adjustment problems. J Fam Psychol. 2005, 19: 324-333. 10.1037/0893-3200.19.2.324.
Buehler C, Lange G, Franck KL: Adolescents' cognitive and emotional responses to marital hostility. Child Dev. 2007, 78: 775-789. 10.1111/j.1467-8624.2007.01032.x.
Wymbs BT, Pelham WE, Molina BSG, Gnagy EM: Mother and adolescent reports of interparental discord among parents of adolescents with and without attention-deficit/hyperactivity disorder. J Emot Behav Disord. 2008, 16: 29-41. 10.1177/1063426607310849.
Grych JH, Seid M, Fincham FD: Assessing marital conflict from the child's perspective: The Children's Perception of Interparental Conflict Scale. Child Dev. 1992, 63: 558-572. 10.2307/1131346.
Cummings EM, Davies PT, Simpson KS: Marital conflict, gender, and children's appraisals and coping efficacy as mediators of child adjustment. J Fam Psychol. 1994, 8: 141-149. 10.1037/0893-3200.8.2.141.
Davies PT, Sturge-Apple ML, Cicchetti D, Cummings EM: Adrenocorticol underpinnings of children's psychological reactivity to interparental conflict. Child Dev. 2008, 79: 1693-1706. 10.1111/j.1467-8624.2008.01219.x.
El-Sheikh M, Kouros CD, Erath S, Cummings EM, Keller P, Staton L: Interactions among marital conflict, sympathetic, and parasympathetic nervous system activity in the prediction of children's externalizing problems. Monogr Soc Res Child Dev. 2009, 74: 19-34. 10.1111/j.1540-5834.2009.00503.x.
Rhoades KA: Children's responses to interparental conflict: A meta-analysis of their associations with child adjustment. Child Dev. 2008, 79: 1942-1956. 10.1111/j.1467-8624.2008.01235.x.
Connors CK: Connors' Rating Scales - Revised. 1997, Toronto, Ontario, Canada: Multi-Health Systems, Inc
DuPaul GJ, Power TJ, Anastopoulos AD, Reid R: The ADHD rating scale -IV:Checklists, norms, and clinical interpretation. 1998, New York: Guilford Press
Puig-Antich J, Ryan N: The Schedule for Affective Disorders and Schizophrenia for School-Age Children (Kiddie-SADS). 1986, Pittsburgh, Pennsylvania. Western Psychiatric Institute and Clinic
McDonald R, Grych JH: Young children's appraisals of interparental confict and links with adjustment problems. J Fam Psychol. 2006, 20: 88-99. 10.1037/0893-3200.20.1.88.
Wechsler D: Handbook for the Wechsler Individual Achievement Test. 2005, London: Harcourt Asessment, 2
Nigg JT, Nikolas M, Miller T, Burt SA, Klump KL, von Eye A: Factor structure of the Child Perception of Interparental Conflict Scale for studies of youth with externalizing behavior problems. Psychol Assess. 2009
Porter B, O'Leary KD: Marital discord and child behavior problems. J Abnorm Child Psychol. 1980, 8: 287-295. 10.1007/BF00916376.
Meulenbelt I, Droog S, Trommelen GJ, Boomsma DI, Slagboom P: High-yield non-invasive human genomic DNA isolation method for genetic studies in geographically dispersed families and populations. Am J Hum Genet. 1995, 57: 1252-1254.
Eaves LJ: Genotype × environment interaction in psychopathology: Fact or artifact?. Twin Res Hum Genet. 2006, 9: 1-8. 10.1375/183242706776403073.
Duncan GJ, Dowsett CJ, Claessens A, Magnuson J, Huston AC, Klebanoc P, Pagani L, Feinstein L, Engel M, Brooks-Gunn J, Sexton H, Duckworth K, Japel C: School readiness and later achievement. Dev Psychol. 2007, 43: 1428-1446. 10.1037/0012-1649.43.6.1428.
Breslau J, Lane M, Sampson N, Kessler RC: Mental disorders and subsequent educational attainment in a US National Sample. Journal of Psychiatr Res. 2008, 42: 708-716. 10.1016/j.jpsychires.2008.01.016.
Breslau N, Breslau J, Peterson E, Miller E, Lucia VC, Bonhert K, Nigg J: Shifts in academic achievement from age 11 to age 17: The role of early development of attention problems. Pediatrics. 2009, 123: 1472-1476. 10.1542/peds.2008-1406.
Keppel G, Wickens TD: Design and analysis: A researcher's handbook. 2004, Upper Saddle River, NJ: Pearson/Prentice Hall, 4
Spear LP: The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev. 2000, 24: 417-463. 10.1016/S0149-7634(00)00014-2.
Angold A, Costello EJ, Erkanli A, Worthman CP: Pubertal changes in hormone levels and depression in girls. Psych Medicine. 1999, 29: 1043-1053. 10.1017/S0033291799008946.
Sonuga-Barke EJS: Causal models of attention-deficit/hyperactivity disorder: From common simple deficits to multiple developmental pathways. Biol Psychiatry. 2005, 57: 1231-1238. 10.1016/j.biopsych.2004.09.008.
Martel MM, Nigg JT: Child ADHD and personality/temperament traits of reactive and effortful control, resiliency, and emotionality. J Child Psychol Psychiatry. 2006, 47: 1175-1183. 10.1111/j.1469-7610.2006.01629.x.
Lahey BB, Rathouz PJ, Van Hulle C, Urbano RC, Krueger RF, Applegate B, Garriock HA, Chapman DA, Waldman ID: Testing structural models of DSM-IV symptoms of common forms of child and adolescent psychopathology. J Abnorm Child Psychol. 2008, 36: 187-206. 10.1007/s10802-007-9169-5.
Manor I, Eisenberg J, Tyano S, Sever Y, Cohen H, Ebstein RP, Kotler M: Family-based association study of the serotonin transporter promoter polymorphism (5-HTTLPR) in attention-deficit hyperactivity disorder. Am J Med Genet. 2001, 105: 91-95. 10.1002/1096-8628(20010108)105:1<91::AID-AJMG1069>3.0.CO;2-V.
Seeger G, Schloss P, Schmidt MH: Functional polymorphism within the promoter of the serotonin transporter gene is associated with severe hyperkinetic disorders. Mol Psychiatry. 2001, 6: 235-238. 10.1038/sj.mp.4000820.
Kent L, Doerry U, Hardy E, Parmar R, Gingell K, Hawi Z, Kirley A, Lowe N, Fitzgerald M, Gill M, Craddock N: Evidence that variation at the serotonin transporter gene influences susceptibility to attention deficit hyperactivity disorder (ADHD): Analysis and pooled analysis. Mol Psychiatry. 2002, 7: 908-912. 10.1038/sj.mp.4001100.
Barry RA, Kochanska G, Philibert RA: GxE interaction in the organization of attachment: Mothers' responsiveness as a moderator of children's genotypes. J Child Psychol Psychiatry. 2008, 49: 1313-1320. 10.1111/j.1469-7610.2008.01935.x.
Pauli-Pott U, Friedl S, Hinney A, Hebebrand J: Serotonin transporter gene polymorphism (5HTTLPR), environmental conditions, and developing negative emotionality and fear in early childhood. J Neural Transm. 2009, 116: 503-512. 10.1007/s00702-008-0171-z.
Keller MC, Miller G: Resolving the paradox of common, harmful, heritable mental disorders: Which evolutionary genetic models work best?. Behav Brain Sci. 2006, 29: 385-404.
Reif A, Rosler M, Schneider M, Eujen A, Kissling C, Jacob CP, Retz-Junginger P, Thome J, Lesch KP, Retz W: Nature and nuture predispose to violent behavior: Serotonergic genes and adverse child environment. Neuropsychopharmacology. 2007, 32: 2375-2383. 10.1038/sj.npp.1301359.