Dopaminergic variants in siblings at high risk for autism: Associations with initiating joint attention
Corresponding Author
Devon N. Gangi
Department of Psychology, University of Miami, Florida
MIND Institute, University of California, Davis, California
Address for correspondence and reprints: Devon N. Gangi, PhD, MIND Institute, UC Davis Medical Center, 2825 50th Street, Sacramento, CA, 95817. E-mail: [email protected], [email protected]Search for more papers by this authorDaniel S. Messinger
Departments of Psychology, Pediatrics, Electrical & Computer Engineering, and Music Engineering, University of Miami, Florida
Search for more papers by this authorEden R. Martin
University of Miami Miller School of Medicine and Hussman Institute for Human Genomics, Florida
Search for more papers by this authorMichael L. Cuccaro
University of Miami Miller School of Medicine and Hussman Institute for Human Genomics, Florida
Search for more papers by this authorCorresponding Author
Devon N. Gangi
Department of Psychology, University of Miami, Florida
MIND Institute, University of California, Davis, California
Address for correspondence and reprints: Devon N. Gangi, PhD, MIND Institute, UC Davis Medical Center, 2825 50th Street, Sacramento, CA, 95817. E-mail: [email protected], [email protected]Search for more papers by this authorDaniel S. Messinger
Departments of Psychology, Pediatrics, Electrical & Computer Engineering, and Music Engineering, University of Miami, Florida
Search for more papers by this authorEden R. Martin
University of Miami Miller School of Medicine and Hussman Institute for Human Genomics, Florida
Search for more papers by this authorMichael L. Cuccaro
University of Miami Miller School of Medicine and Hussman Institute for Human Genomics, Florida
Search for more papers by this authorAbstract
Younger siblings of children with autism spectrum disorder (ASD; high-risk siblings) exhibit lower levels of initiating joint attention (IJA; sharing an object or experience with a social partner through gaze and/or gesture) than low-risk siblings of children without ASD. However, high-risk siblings also exhibit substantial variability in this domain. The neurotransmitter dopamine is linked to brain areas associated with reward, motivation, and attention, and common dopaminergic variants have been associated with attention difficulties. We examined whether these common dopaminergic variants, DRD4 and DRD2, explain variability in IJA in high-risk (n = 55) and low-risk (n = 38) siblings. IJA was assessed in the first year during a semi-structured interaction with an examiner. DRD4 and DRD2 genotypes were coded according to associated dopaminergic functioning to create a gene score, with higher scores indicating more genotypes associated with less efficient dopaminergic functioning. Higher dopamine gene scores (indicative of less efficient dopaminergic functioning) were associated with lower levels of IJA in the first year for high-risk siblings, while the opposite pattern emerged in low-risk siblings. Findings suggest differential susceptibility—IJA was differentially associated with dopaminergic functioning depending on familial ASD risk. Understanding genes linked to ASD-relevant behaviors in high-risk siblings will aid in early identification of children at greatest risk for difficulties in these behavioral domains, facilitating targeted prevention and intervention. Autism Res 2016, 9: 1142–1150. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
References
- Abrahams, B.S., & Geschwind, D.H. (2008). Advances in autism genetics: On the threshold of a new neurobiology. Nature Review Genetics, 9, 341–355.
- Anney, R., et al. (2010). A genome-wide scan for common alleles affecting risk for autism. Human Molecular Genetics, 19, 4072–4082.
- American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders: DSM-V. Washington, DC: American Psychiatric Association.
10.1176/appi.books.9780890425596 Google Scholar
- Auerbach, J.G., Benjamin, J., Faroy, M., Geller, V., & Ebstein, R. (2001a). DRD4 related to infant attention and information processing: A developmental link to ADHD? Psychiatric Genetics, 11, 31–35.
- Auerbach, J.G., Faroy, M., Ebstein, R., Kahana, M., & Levine, J. (2001b). The association of the dopamine D4 receptor gene (DRD4) and the serotonin transporter promoter gene (5-HTTLPR) with temperament in 12-month-old infants. Journal of Child Psychology and Psychiatry, 42, 777–783.
- Bakermans-Kranenburg, M.J., & van IJzendoorn, M.H. (2006). Gene-environment interaction of the dopamine D4 receptor (DRD4) and observed maternal insensitivity predicting externalizing behavior in preschoolers. Developmental Psychobiology, 48, 406–409.
- Bakermans-Kranenburg, M.J., & van IJzendoorn, M.H. (2011). Differential susceptibility to rearing environment depending on dopamine-related genes: New evidence and a meta-analysis. Development and Psychopathology, 23, 39–52.
- Beaulieu, J.-M., & Gainetdinov, R.R. (2011). The physiology, signaling, and pharmacology of dopamine receptors. Pharmacological Reviews, 63, 182–217.
- Belsky, J. (2005). Differential susceptibility to rearing influence: An evolutionary hypothesis and some evidence. In B. Ellis & D. Bjorklund (Eds.), Origins of the social mind: Evolutionary psychology and child development (pp. 139–163). New York: Guilford.
- Belsky, J., & Pluess, M. (2009). Beyond diathesis stress: Differential susceptibility to environmental influences. Psychological Bulletin, 135, 885–908.
- Belsky, J., Bakermans-Kranenburg, M.J., & van IJzendoorn, M.H. (2007). For better and for worse: Differential susceptibility to environmental influences. Current Directions in Psychological Science, 16, 300–304.
- Berument, S.K., Rutter, M., Lord, C., Pickles, A., & Bailey, A. (1999). Autism screening questionnaire: Diagnostic validity. The British Journal of Psychiatry, 175, 444–451.
- Betancur, C. (2011). Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting. Brain Research, 1380, 42–77.
- Buxbaum, J.D. (2009). Multiple rare variants in the etiology of autism spectrum disorders. Dialogues in Clinical Neuroscience, 11, 35–43.
- Carver, C.S., Johnson, S.L., & Joormann, J. (2009). Two-mode models of self-regulation as a tool for conceptualizing effects of the serotonin system in normal behavior and diverse disorders. Current Directions in Psychological Science, 18, 195–199.
- Cassel, T.D., Messinger, D.S., Ibanez, L.V., Haltigan, J.D., Acosta, S.I., & Buchman, A.C. (2007). Early social and emotional communication in the infant siblings of children with autism spectrum disorders: An examination of the broad phenotype. Journal of Autism and Developmental Disorders, 37, 122–132.
- CDC. (2014). Prevalence of autism spectrum disorder among children aged 8 years – Autism and developmental disabilities monitoring network, 11 sites, United States, 2010. Centers for disease control and prevention, morbidity and mortality weekly report, surveillance summaries, 63, 2.
- Chen, J. A., Peñagarikano, O., Belgard, T. G., Swarup, V., & Geschwind, D. H. (2015). The emerging picture of autism spectrum disorder: Genetics and pathology. Annual Review of Pathology: Mechanisms of Disease, 10, 111–144. doi:10.1146/annurev-pathol-012414-040405.
- Chen, J., et al. (2004). Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): Effects on mRNA, protein, and enzyme activity in postmortem human brain. American Journal of Human Genetics, 75, 807–821.
- Colvert, E., et al. (2015). Heritability of autism spectrum disorder in a UK population-based twin sample. JAMA Psychiatry, 72, 415–423.
- Dawson, G., Toth, K., Abbott, R., Osterling, J., Munson, J., Estes, A., & Liaw, J. (2004). Early social attention impairments in autism: Social orienting, joint attention, and attention to distress. Developmental Psychology, 40, 271–283.
- De Rubeis, S., et al. (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 515, 209–215.
- Devlin, B., Melhem, N., & Roeder, K. (2011). Do common variants play a role in risk for autism? Evidence and theoretical musings. Brain Research, 1380, 78–84.
- Fuke, S., Suo, S., Takahashi, N., Koike, H., Sasagawa, N., & Ishiura, S. (2001). The VNTR polymorphism of the human dopamine transporter (DAT1) gene affects gene expression. Pharmacogenomics Journal, 1, 152–156.
- Gangi, D.N., Ibañez, L.V., & Messinger, D.S. (2014). Joint attention initiation with and without positive affect: Risk group differences and associations with ASD symptoms. Journal of Autism and Developmental Disorders, 44, 1414–1424.
- Gaugler, T., et al. (2014). Most genetic risk for autism resides with common variation. Nature Genetics, 46, 881–885.
- Georgiades, S., et al. (2013). A prospective study of autistic-like traits in unaffected siblings of probands with autism spectrum disorder. JAMA Psychiatry, 70, 42–48.
- Geschwind, D.H. (2011). Genetics of autism spectrum disorders. Trends in Cognitive Sciences, 15, 409–416.
- Geschwind, D.H., & State, M.W. (2015). Gene hunting in autism spectrum disorder: On the path to precision medicine. The Lancet Neurology, 1109–1120.
- Gizer, I.R., Ficks, C., & Waldman, I.D. (2009). Candidate gene studies of ADHD: A meta-analytic review. Human Genetics, 126, 51–90.
- Goggi, J., Pullar, I.A., Carney, S.L., & Bradford, H.F. (2003). Signalling pathways involved in the short-term potentiation of dopamine release by BDNF. Brain Research, 968, 156–161.
- Goldberg, W.A., et al. (2005). Brief report: Early social communication behaviors in the younger siblings of children with autism. Journal of Autism and Developmental Disorders, 35, 657–664.
- Grønborg, T.K., Schendel, D.E., & Parner, E.T. (2013). Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: A population-based cohort study. JAMA Pediatrics,
- Hallmayer, J., et al. (2011). Genetic heritability and shared environmental factors among twin pairs with autism. Archives of General Psychiatry, 68, 1095–1102.
- Hettinger, J.A., et al. (2012). DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families. Behavioral and Brain Functions, 8(1), 19.
- Howlin, P., Goode, S., Hutton, J., & Rutter, M. (2004). Adult outcome for children with autism. Journal of Child Psychology and Psychiatry, 45, 212–229.
- Ibañez, L.V., Grantz, C.J., & Messinger, D.S. (2012). The development of referential communication and autism symptomatology in high-risk infants. Infancy, 18, 687–707.
- Iossifov, I., et al. (2014). The contribution of de novo coding mutations to autism spectrum disorder. Nature, 515, 216–221.
- Klei, L., et al. (2012). Common genetic variants, acting additively, are a major source of risk for autism. Molecular Autism, 3, 9.
- Lackner, C., Sabbagh, M.A., Hallinan, E., Liu, X., & Holden, J.J.A. (2012). Dopamine receptor D4 gene variation predicts preschoolers’ developing theory of mind. Developmental Science, 15, 272–280.
- Lord, C., et al. (2000). The autism diagnostic observation schedule—Generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30, 205–223.
- Malesa, E., Foss-Feig, J., Yoder, P., Warren, Z., Walden, T., & Stone, W. (2012). Predicting language and social outcomes at age 5 for later-born siblings of children with autism spectrum disorders. Autism, 17: 558–570.
- Mesman, J., Stoel, R., Bakermans-Kranenburg, M.J., IJzendoorn, M.H., Juffer, F., Koot, H.M., & Alink, L.R.A. (2009). Predicting growth curves of early childhood externalizing problems: Differential susceptibility of children with difficult temperament. Journal of Abnormal Child Psychology, 37, 625–636.
- Messinger, D., et al. (2013). Beyond autism: A baby siblings research consortium study of high-risk children at three years of age. Journal of the American Academy of Child and Adolescent Psychiatry, 52, 300–308.
- Muhle, R., Trentacoste, S.V., & Rapin, I. (2004). The genetics of autism. Pediatrics, 113, e472–e486.
- Mundy, P., Sigman, M., Ungerer, J., & Sherman, T. (1986). Defining the social deficits of autism: The contribution of non-verbal communication measures. Journal of Child Psychology and Psychiatry, 27, 657–669.
- Mundy, P., Delgado, C., Block, J., Venezia, M., Hogan, A., & Siebert, J. (2003). A manual for the abridged early social communication scales (ESCS). Department of Psychology, University of Miami, Coral Gables, Florida.
- Narita, M., Aoki, K., Takagi, M., Yajima, Y., & Suzuki, T. (2003). Implication of brain-derived neurotrophic factor in the release of dopamine and dopamine-related behaviors induced by methamphetamine. Neuroscience, 119, 767–775.
- Newschaffer, C.J., et al. (2012). Infant siblings and the investigation of autism risk factors. Journal of Neurodevelopmental Disorders, 4, 7.
- Nikolova, Y.S., Ferrell, R.E., Manuck, S.B., & Hariri, A.R. (2011). Multilocus genetic profile for dopamine signaling predicts ventral striatum reactivity. Neuropsychopharmacology, 36, 1940–1947.
- Ozonoff, S., et al. (2011). Recurrence risk for autism spectrum disorders: A baby siblings research consortium study. Pediatrics, 128, e488–e495.
- Pearson-Fuhrhop, K.M., et al. (2014). Dopamine genetic risk score predicts depressive symptoms in healthy adults and adults with depression. PLoS ONE, 9, e93772.
- Posner, M.I., Rothbart, M.K., & Sheese, B.E. (2007). Attention genes. Developmental Science, 10, 24–29.
- Rapin, I. (1991). Autistic children: Diagnosis and clinical features. Pediatrics, 87, 751–760.
- Risch, N., Hoffmann, T.J., Anderson, M., Croen, L.A., Grether, J.K., & Windham, G.C. (2014). Familial recurrence of autism spectrum disorder: Evaluating genetic and environmental contributions. American Journal of Psychiatry, 171: 1206–1213.
- Rodriguez, S., Gaunt, T.R., & Day, I.N.M. (2009). Hardy-Weinberg equilibrium testing of biological ascertainment for mendelian randomization studies. American Journal of Epidemiology, 169, 505–514.
- Rozga, A., Hutman, T., Young, G.S., Rogers, S.J., Ozonoff, S., Dapretto, M., & Sigman, M. (2011). Behavioral profiles of affected and unaffected siblings of children with autism: Contribution of measures of mother–infant interaction and nonverbal communication. Journal of Autism and Developmental Disorders, 41, 287–301.
- Rutter, M., & Schopler, E. (1987). Autism and pervasive developmental disorders: Concepts and diagnostic issues. Journal of Autism and Developmental Disorders, 17, 159–186.
- Salem, A.M., Ismail, S., Zarouk, W.A., Abdul, B., Olwya, S., Ahmed, A., Abd El-Hamid, S., & Salem, S. (2013). Genetic variants of neurotransmitter-related genes and miRNAs in Egyptian autistic patients. The Scientific World Journal, 2013, 7.
- Savitz, J., Solms, M., & Ramesar, R. (2006). The molecular genetics of cognition: dopamine, COMT and BDNF. Genes, Brain and Behavior, 5, 311–328.
- Schmidt, L.A., Fox, N.A., Perez-Edgar, K., Hu, S., & Hamer, D.H. (2001). Association of DRD4 with attention problems in normal childhood development. Psychiatric Genetics, 11, 25–29.
- Schmidt, L.A., Fox, N.A., Perez-Edgar, K., & Hamer, D.H. (2009). Linking gene, brain, and behavior: DRD4, frontal asymmetry, and temperament. Psychological Science, 20, 831–837.
- Schoots, O., & Van Tol, H.H.M. (2003). The human dopamine D4 receptor repeat sequences modulate expression. Pharmacogenomics Journal, 3, 343–348.
- Sheese, B.E., Voelker, P.M., Rothbart, M.K., & Posner, M.I. (2007). Parenting quality interacts with genetic variation in dopamine receptor D4 to influence temperament in early childhood. Development and Psychopathology, 19, 1039–1046.
- Stice, E., Yokum, S., Burger, K., Epstein, L., & Smolen, A. (2012). Multilocus genetic composite reflecting dopamine signaling capacity predicts reward circuitry responsivity. The Journal of Neuroscience, 32, 10093–10100.
- Talkowski, M.E., Minikel, E.V. & Gusella, J.F. (2014). Autism spectrum disorder genetics: Diverse genes with diverse clinical outcomes. Harvard Review of Psychiatry, 22, 65–75.
- Thompson, J., et al. (1997). D2 dopamine receptor gene (DRD2) Taql A polymorphism: Reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics and Genomics, 7, 479–484.
- Toth, K., Dawson, G., Meltzoff, A., Greenson, J., & Fein, D. (2007). Early social, imitation, play, and language abilities of young non-autistic siblings of children with autism. Journal of Autism and Developmental Disorders, 37, 145–157.
- Van IJzendoorn, M.H., & Bakermans-Kranenburg, M.J. (2006). DRD4 7-repeat polymorphism moderates the association between maternal unresolved loss or trauma and infant disorganization. Attachment & Human Development, 8, 291–307.
- Yirmiya, N., Gamliel, I., Pilowsky, T., Feldman, R., Baron-Cohen, S., & Sigman, M. (2006). The development of siblings of children with autism at 4 and 14 months: Social engagement, communication, and cognition. Journal of Child Psychology and Psychiatry, 47, 511–523.
- Yuen, R.K.C., et al. (2015). Whole-genome sequencing of quartet families with autism spectrum disorder. Nature Medicine, 21, 185–191.