Skip to main content Accessibility help
×
Home

Neuropsychological performance measures as intermediate phenotypes for attention-deficit/hyperactivity disorder: A multiple mediation analysis

  • Jaclyn M. Kamradt (a1), Joel T. Nigg (a2), Karen H. Friderici (a3) and Molly A. Nikolas (a1)

Abstract

Genetic influences on dopaminergic neurotransmission have been implicated in attention-deficit hyperactivity disorder (ADHD) and are theorized to impact cognitive functioning via alterations in frontal–striatal circuitry. Neuropsychological functioning has been proposed to account for the potential associations between dopamine candidate genes and ADHD. However, to date, this mediation hypothesis has not been directly tested. Participants were 498 youth ages 6–17 years (mean M = 10.8 years, SD = 2.4 years, 55.0% male). All youth completed a multistage, multiple-informant assessment procedure to identify ADHD and non-ADHD cases, as well as a comprehensive neuropsychological battery. Youth provided a saliva sample for DNA analyses; the 480 base pair variable number of tandem repeat polymorphism of the dopamine active transporter 1 gene (DAT1) and the 120 base pair promoter polymorphism of the dopamine receptor D4 gene (DRD4) were genotyped. Multiple mediation analysis revealed significant indirect associations between DAT1 genotype and inattention, hyperactivity–impulsivity, and oppositionality, with specific indirect effects through response inhibition. The results highlight the role of neurocognitive task performance, particularly response inhibition, as a potential intermediate phenotype for ADHD, further elucidating the relationship between genetic polymorphisms and externalizing psychopathology.

Copyright

Corresponding author

Address correspondence and reprint requests to: Jaclyn Kamradt, Department of Psychology, E11 SSH, University of Iowa, Iowa City, IA 52242; E-mail: jaclyn-kamradt@uiowa.edu.

References

Hide All
Albrecht, B., Brandeis, D., von Sandersleben, H. U., Valko, L., Heinrich, H., Xu, X., et al. (2014). Genetics of preparation and response control in ADHD: The role of DRD4 and DAT1. Journal of Child Psychology and Psychiatry, 55, 914923.
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: Author.
Asghari, V., Sanyal, S., Buchwaldt, S., Paterson, A., Jovanovic, V., & Van Tol, H. H. M. (1995). Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. Journal of Neurochemistry, 65, 11571165.
Barr, C. L., Xu, C., Kroft, J., Feng, Y., Wigg, K., Zai, G., et al. (2001). Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder. Biological Psychiatry, 49, 333339.
Baving, L., Rellum, T., Laucht, M., & Schmidt, M. H. (2006). Children with oppositional-defiant disorder display deviant attentional processing independent of ADHD symptoms. Journal of Neural Transmission, 113, 685693.
Beauchaine, T. P., & McNulty, T. (2013). Comorbidities and continuities as ontogenic processes: Toward a developmental spectrum model of externalizing psychopathology. Development and Psychopathology, 25, 15051528.
Bellgrove, M. A., Hawi, Z., Lowe, N., Kirley, A., Robertson, I. H., & Gill, M. (2005). DRD4 gene variants and sustained attention in attention deficit hyperactivity disorder (ADHD): Effects of associated alleles at the VNTR and −521 SNP. American Journal of Medical Genetics, 136B, 8186.
Benjamin, J., Li, L., Patterson, C., Greenberg, B. D., Murphy, D. L., & Hamer, D. H. (1996). Population and familial association between the D4 dopamine receptor gene and measures of novelty seeking. Nature Genetics, 12, 8184.
Bidwell, L. C., Willcutt, E. G., DeFries, J. C., & Pennington, B. F. (2007). Testing for neuropsychological endophenotypes in siblings discordant for attention-deficit/hyperactivity disorder. Biological Psychiatry, 62, 991998.
Bruxel, E. M., Akutagava-Martins, G. C., Salatino-Oliveira, A., Contini, V., Kieling, C., Hutz, M. H., et al. (2014). ADHD pharmacogenetics across the life cycle: New findings and perspectives. American Journal of Medical Genetics, 165B, 263282.
Burt, A. (2009). A mechanistic explanation of popularity: Genes, rule breaking, and evocative gene-environment correlations. Journal of Personality and Social Psychology, 96, 783.
Caspi, A., Langley, K., Milne, B., Moffitt, T. E., O'Donovan, M., Owen, M. J., et al. (2008). A replicated molecular genetic basis for subtyping antisocial behavior in children with attention-deficit/hyperactivity disorder. Archives of General Psychiatry, 65, 203210.
Cerin, E., & MacKinnon, D. P. (2009). A commentary on current practice in mediating variable analyses in behavioural nutrition and physical activity. Public Health Nutrition, 12, 11821188.
Chang, Z., Lichtenstein, P., Asherson, P. J., & Larsson, H. (2013). Developmental twin study of attention problems: High heritabilities throughout development. JAMA Psychiatry, 70, 311318.
Collins, L. M., Graham, J. J., & Flaherty, B. P. (1998). An alternative framework for defining mediation. Multivariate Behavioral Research, 33, 295312.
Comings, D. E., Gade-Andavolu, R., Gonzalez, N., Wu, S., Muhleman, D., Blake, H., et al. (2000). Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD, ODD and conduct disorder: Multivariate regression analysis of 20 genes. Clinical Genetics, 57, 178196.
Conners, C. K. (1997). Conners’ Rating Scales—Revised. Toronto: Multi-Health Systems.
Cornblatt, B. A., Risch, N. J., Faris, G., Friedman, D., & Erlenmeyer-Kimling, L. (1988). The continuous performance test, identical pairs version (CPT-IP): I. New findings about sustained attention in normal families. Psychiatry Research, 26, 223238.
Cornish, K. M., Manly, T., Savage, R., Swanson, J., Morisano, D., Butler, N., et al. (2005). Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample. Molecular Psychiatry, 10, 686698.
Crosbie, J., & Schachar, R. (2001). Deficient inhibition as a marker for familial ADHD. American Journal of Psychiatry, 158, 18841890.
Delis, D. C., Kaplan, E., & Kramer, J. H. (2001). Delis–Kaplan Executive Function System (DKEFS). San Antonio, TX: Psychological Corporation.
DuPaul, G. J., Anastopoulos, A. D., Power, T. J., Reid, R., Ikeda, M. J., & McGoey, K. E. (1998). Parent ratings of attention-deficit/hyperactivity disorder symptoms: Factor structure and normative data. Journal of Psychopathology and Behavioral Assessment, 20, 83102.
Ebstein, R. P., Novick, O., Umansky, R., Priel, B., Osher, Y., Blaine, D., et al. (1996). Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of novelty seeking. Nature Genetics, 12, 7880.
Engle, R. W. (2002). Working memory capacity as executive attention. Current Directions in Psychological Science, 11, 1923.
Faraone, S. V., & Biederman, J. (1998). Neurobiology of attention-deficit hyperactivity disorder. Biological Psychiatry, 44, 951958.
Faraone, S. V., Biederman, J., Weiffenbach, B., Keith, T., Chu, M. P., Weaver, A., et al. (1999). Dopamine D4 gene 7-repeat allele and attention deficit hyperactivity disorder. American Journal of Psychiatry, 156, 768770.
Faraone, S. V., & Mick, E. (2010). Molecular genetics of attention deficit hyperactivity disorder. Psychiatric Clinics of North America, 33, 159180.
Forbes, E. E., Brown, S. M., Kimak, M., Ferrell, R. E., Manuck, S. B., & Hariri, A. R. (2007). Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity. Molecular Psychiatry, 14, 6070.
Gau, S. S.-F., & Shang, C.-Y. (2010). Executive functions as endophenotypes in ADHD: Evidence from the Cambridge Neuropsychological Test Battery (CANTAB). Journal of Child Psychology and Psychiatry, 51, 838849.
Giros, B., Jaber, M., Jones, S. R., Wightman, R. M., & Caron, M. G. (1996). Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature, 379(6566), 606612.
Gizer, I. R., Ficks, C., & Waldman, I. D. (2009). Candidate gene studies of ADHD: A meta-analytic review. Human Genetics, 126, 5190.
Gizer, I. R., & Waldman, I. D. (2012). Double dissociation between lab measures of inattention and impulsivity and the dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4). Journal of Abnormal Psychology, 121, 10111023.
Goos, L. M., Crosbie, J., Psych, C., Payne, S., & Schachar, R. (2009). Validation and extension of the endophenotype model in ADHD patterns of inheritance in a family study of inhibitory control. American Journal of Psychiatry, 166, 711717.
Gottesman, I. I., & Gould, T. D. (2003). The endophenotype concept in psychiatry: Etymology and strategic intentions. American Journal of Psychiatry, 160, 636645.
Hayes, A. F. (2009). Beyond Baron and Kenny: Statistical mediation analysis in the new millennium. Communication Monographs, 76, 408420.
Jensen, P. S., Kettle, L., Roper, M. T., Sloan, M. T., Dulcan, M. K., Hoven, C., et al. (1999). Are stimulants overprescribed? Treatment of ADHD in four US communities. Journal of the American Academy of Child & Adolescent Psychiatry, 38, 797804.
Johnson, K. A., Kelly, S. P., Robertson, I. H., Barry, E., Mulligan, A., Daly, M., et al. (2008). Absence of the 7-repeat variant of the DRD4 VNTR is associated with drifting sustained attention in children with ADHD but not in controls. American Journal of Medical Genetics, 147B, 927937.
Kebir, O., Tabbane, K., Sengupta, S., & Joober, R. (2009). Candidate genes and neuropsychological phenotypes in children with ADHD: Review of association studies. Journal of Psychiatry & Neuroscience, 34, 88101.
Kereszturi, E., Kiraly, O., Csapo, Z., Tarnok, Z., Gadoros, J., Sasvari-Szekely, M., et al. (2007). Association between the 120-bp duplication of the dopamine D4 receptor gene and attention deficit hyperactivity disorder: Genetic and molecular analyses. American Journal of Medical Genetics, 144B, 231236.
Kieling, C., Roman, T., Doyle, A. E., Hutz, M. H., & Rohde, L. A. (2006). Association between DRD4 gene and performance of children with ADHD in a test of sustained attention. Biological Psychiatry, 60, 11631165.
Kirley, A., Lowe, N., Mullins, C., McCarron, M., Daly, G., Waldman, I., et al. (2002). Phenotype studies of the DRD4 gene polymorphisms in ADHD: Association with oppositional defiant disorder and positive family history. American Journal of Medical Genetics, 131B, 3842.
Kustanovich, V., Ishii, J., Crawford, L., Yang, M., McGough, J. J., McCracken, J. T., et al. (2003). Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: Confirmation of association of ADHD with DRD4 and DRD5. Molecular Psychiatry, 9, 711717.
Lahey, B. B., Pelham, W. E., Loney, J., Lee, S. S., & Willcutt, E. (2005). Instability of the DSM-IV subtypes of ADHD from preschool through elementary school. Archives of General Psychiatry, 62, 896902.
Langley, K., Marshall, L., van den Bree, M., Thomas, H., Dphil, O., O'Donovan, M., et al. (2004). ADHD children with and without the dopamine D4 receptor 7-repeat allele: Evidence of differences in performance on neuropsychological tests. American Journal of Psychiatry, 161, 133138.
Larsson, H., Chang, Z., D'Onofrio, B. M., & Lichtenstein, P. (2014). The heritability of clinically diagnosed attention deficit hyperactivity disorder across the lifespan. Psychological Medicine, 44, 22232229.
Li, D., Sham, P. C., Owen, M. J., & He, L. (2006). Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Human Molecular Genetics, 15, 22762284.
Li, Z., Chang, S., Zhang, L., Gao, L., & Wang, J. (2014). Molecular genetic studies of ADHD and its candidate genes: A review. Psychiatry Research, 219, 1024.
Logan, G. D. (1994). On the ability to inhibit thought and action: A users’ guide to the stop signal paradigm. In Dagenbach, D. & Carr, T. H. (Eds.), Inhibitory processes in attention, memory, and language (pp. 189239). San Diego, CA: Academic Press.
Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J., et al. (2009). Finding the missing heritability of complex diseases. Nature, 461, 747753.
Manor, I., Tyano, S., Eisenberg, J., Bachner-Melman, R., Kotler, M., & Ebstein, R. P. (2002). The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in a family-based design and impair performance on a continuous performance test (TOVA). Molecular Psychiatry, 7, 790794.
Martel, M. M., Nikolas, M., Jernigan, K., Friderici, K., Waldman, I., & Nigg, J. T. (2010). The dopamine receptor D4 gene (DRD4) moderates family environmental effects on ADHD. Journal of Abnormal Child Psychology, 39, 110.
Martel, M. M., Schimmack, U., Nikolas, M., & Nigg, J. T. (2015). Integration of symptom ratings from multiple informants in ADHD diagnosis: A psychometric model with clinical utility. Psychological Assessment, 27, 10601071.
Martinussen, R., & Tannock, R. (2006). Working memory impairments in children with attention-deficit hyperactivity disorder with and without comorbid language learning disorders. Journal of Clinical and Experimental Neuropsychology, 28, 10731094.
McCracken, J. T., Smalley, S. L., McGough, J. J., Crawford, L., Del'Homme, M., Cantor, R. M., et al. (2000). Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD). Molecular Psychiatry, 5, 531536.
Meulenbelt, I., Droog, S., Trommelen, G. J., Boomsma, D. I., & Slagboom, P. E. (1995). High-yield noninvasive human genomic DNA isolation method for genetic studies in geographically dispersed families and populations. American Journal of Human Genetics, 57, 12521254.
Muthen, L. K., & Muthen, B. O. (2011). Mplus user's guide. (6th ed.). Los Angeles, CA: Author.
Neale, B. M., Medland, S. E., Ripke, S., Asherson, P., Franke, B., Lesch, K.-P., et al. (2010). Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 49, 884897.
Nigg, J., Nikolas, M., & Burt, S. A. (2010). Measured gene-by-environment interaction in relation to attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 49, 863873.
Nigg, J. T. (2012). Future directions in ADHD etiology research. Journal of Clinical Child and Adolescent Psychology, 41, 524533.
Nigg, J. T., Blaskey, L. G., Stawicki, J. A., & Sachek, J. (2004). Evaluating the endophenotype model of ADHD neuropsychological deficit: Results for parents and siblings of children with ADHD combined and inattentive subtypes. Journal of Abnormal Psychology, 113, 614625.
Nikolas, M. A., & Burt, S. A. (2010). Genetic and environmental influences on ADHD symptom dimensions of inattention and hyperactivity: A meta-analysis. Journal of Abnormal Psychology, 119, 117.
Nikolas, M. A., & Nigg, J. T. (2013). Neuropsychological performance and attention-deficit hyperactivity disorder subtypes and symptom dimensions. Neuropsychology, 27, 107120.
Nikolas, M. A., & Nigg, J. T. (2015). Moderators of neuropsychological mechanism in attention-deficit hyperactivity disorder. Journal of Abnormal Child Psychology, 43, 271281.
Noaín, D., Avale, M. E., Wedemeyer, C., Calvo, D., Peper, M., & Rubinstein, M. (2006). Identification of brain neurons expressing the dopamine D4 receptor gene using BAC transgenic mice. European Journal of Neuroscience, 24, 24292438.
Pajer, K., Chung, J., Leininger, L., Wang, W., Gardner, W., & Yeates, K. (2008). Neuropsychological function in adolescent girls with conduct disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 47, 416425.
Pauli-Pott, U., Dalir, S., Mingebach, T., Roller, A., & Becker, K. (2013). Do different ADHD-related etiological risks involve specific neuropsychological pathways? An analysis of mediation processes by inhibitory control and delay aversion. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 54, 800809.
Pelham, W. E., Gnagy, E. M., Greenslade, K. E., & Milich, R. (1992). Teacher ratings of DSM-III-R symptoms for the disruptive behavior disorders. Journal of the American Academy of Child & Adolescent Psychiatry, 31, 210218.
Preacher, K. J., & Hayes, A. F. (2008). Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behavior Research Methods, 40, 879891.
Puig-Antich, J., & Ryan, N. (1986). Kiddie Schedule for Affective Disorders and Schizophrenia. Pittsburgh, PA: Western Psychiatric Institute.
Ridderinkhof, K. R., van den Wildenberg, W. P. M., Segalowitz, S. J., & Carter, C. S. (2004). Neurocognitive mechanisms of cognitive control: The role of prefrontal cortex in action selection, response inhibition, performance monitoring, and reward-based learning. Brain and Cognition, 56, 129140.
Rubinstein, M., Phillips, T. J., Bunzow, J. R., Falzone, T. L., Dziewczapolski, G., Zhang, G., et al. (1997). Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell, 90, 9911001.
Rucker, D. D., Preacher, K. J., Tormala, Z. L., & Petty, R. E. (2011). Mediation analysis in social psychology: Current practices and new recommendations. Social and Personality Psychology Compass, 5, 359371.
Sergeant, J. A., Geurts, H., & Oosterlaan, J. (2002). How specific is a deficit of executive functioning for attention-deficit/hyperactivity disorder? Behavioural Brain Research, 130, 328.
Shrout, P. E., & Bolger, N. (2002). Mediation in experimental and nonexperimental studies: New procedures and recommendations. Psychological Methods, 7, 422.
Solanto, M. V. (2002). Dopamine dysfunction in AD/HD: Integrating clinical and basic neuroscience research. Behavioural Brain Research, 130, 6571.
Sonuga-Barke, E., Bitsakou, P., & Thompson, M. (2010). Beyond the dual pathway model: Evidence for the dissociation of timing, inhibitory, and delay-related impairments in attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 49, 345355.
Stark, R., Bauer, E., Merz, C. J., Zimmermann, M., Reuter, M., Plichta, M. M., et al. (2011). ADHD related behaviors are associated with brain activation in the reward system. Neuropsychologia, 49, 426434.
Stergiakouli, E., & Thapar, A. (2010). Fitting the pieces together: Current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Neuropsychiatric Disease and Treatment, 6, 551560.
Swanson, J., Oosterlaan, J., Murias, M., Schuck, S., Flodman, P., Spence, M. A., et al. (2000). Attention deficit hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention. Proceedings of the National Academy of Sciences, 97, 47544759.
Szatmari, P., Maziade, M., Zwaigenbaum, L., Mérette, C., Roy, M. A., Joober, R., et al. (2007). Informative phenotypes for genetic studies of psychiatric disorders. American Journal of Medical Genetics, 144B, 581588.
Thapar, A., Langley, K., & Fowler, T. (2005). Catechol-O-methyltransferase gene variant and birth weight predict early-onset antisocial behavior in children with attention-deficit/hyperactivity disorder. Archives of General Psychiatry, 62, 12751278.
Thissen, A. J., Rommelse, N. N. J., Hoekstra, P. J., Hartman, C., Heslenfeld, D., Luman, M., et al. (2014). Attention deficit hyperactivity disorder (ADHD) and executive functioning in affected and unaffected adolescents and their parents: Challenging the endophenotype construct. Psychological Medicine, 44, 881892.
Tol, H. H., Wu, C. M., Guan, H.-C., Ohara, K., Bunzow, J. R., Civelli, O., et al. (1992). Multiple dopamine D4 receptor variants in the human population. Nature, 358, 149152.
Toplak, M. E., & Tannock, R. (2005). Tapping and anticipation performance in attention deficit hyperactivity disorder. Perceptual and Motor Skills, 100, 659675.
Vandenbergh, D. J., Persico, A. M., Hawkins, A. L., Griffin, C. A., Li, X., Jabs, E. W., et al. (1992). Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics, 14, 11041106.
van der Sluis, S., Verhage, M., Posthuma, D., & Dolan, C. V. (2010). Phenotypic complexity, measurement bias, and poor phenotypic resolution contribute to the missing heritability problem in genetic association studies. PLOS ONE, 5, e13929.
Volkow, N. D., Ding, Y. S., Fowler, J. S., Wang, G. J., Logan, J., Gatley, J. S., et al. (1995). Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Archives of General Psychiatry, 52, 456463.
Volkow, N. D., Wang, G. J., Fowler, J. S., Tomasi, D., & Baler, R. (2011). Food and drug reward: Overlapping circuits in human obesity and addiction. Current Topics in Behavioral Neuroscience, 11, 124.
Waldman, I. D. (2005). Statistical approaches to complex phenotypes: Evaluating neuropsychological endophenotypes for attention-deficit/hyperactivity disorder. Biological Psychiatry, 57, 13471356.
Wechsler, D. (2001). Wechsler Individual Achievement Test (2nd ed.). San Antonio, TX: Psychological Corporation.
Wechsler, D. (2003). Wechsler Intelligence Scale for Children—WISC-IV. San Antonio, TX: Psychological Corporation.
Wilens, T. E., Biederman, J., & Spencer, T. J. (2002). Attention deficit/hyperactivity disorder across the lifespan. Annual Review of Medicine, 53, 113131.
Willcutt, E. G., Nigg, J. T., Pennington, B. F., Solanto, M. V., Rohde, L. A., Tannock, R., et al. (2012). Validity of DSM-IV attention deficit/hyperactivity disorder symptom dimensions and subtypes. Journal of Abnormal Psychology, 121, 991.
Wood, A. C., Asherson, P., van der Meere, J. J., & Kuntsi, J. (2010). Separation of genetic influences on attention deficit hyperactivity disorder symptoms and reaction time performance from those on IQ. Psychological Medicine, 40, 10271037.
Young, S. E., Friedman, N. P., Miyake, A., Willcutt, E. G., Corley, R. P., Haberstick, B. C., et al. (2009). Behavioral disinhibition: Liability for externalizing spectrum disorders and its genetic and environmental relation to response inhibition across adolescence. Journal of Abnormal Psychology, 118, 117.
Zhao, X., Lynch, J. G., & Chen, Q. (2010). Reconsidering Baron and Kenny: Myths and truths about mediation analysis. Journal of Consumer Research, 37, 197206.

Neuropsychological performance measures as intermediate phenotypes for attention-deficit/hyperactivity disorder: A multiple mediation analysis

  • Jaclyn M. Kamradt (a1), Joel T. Nigg (a2), Karen H. Friderici (a3) and Molly A. Nikolas (a1)

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed