The quantitative nature of deficits in reciprocal social behavior
Our SDS laboratory developed and advanced methods for measuring variation in reciprocal social behavior as a quantitative trait, by devising a new system of questionnaire-based measurement, the Social Responsiveness Scale, now in its second edition.
The SRS-2 has been translated into over 30 foreign languages and is used worldwide as a standard for rapid, feasible quantitative ascertainment of autistic traits. This has allowed patterns of transmission of autistic social impairments to be traced in families and populations. These studies have helped elucidate the factoral and genetic structure of autistic syndromes, and the nature of the pronounced sex ratio observed for most forms of autism.
Most recently these measurements have proven capable of specifying elevations in offspring risk for autism and variation in social-adaptive functioning across diverse child psychiatric syndromes. These findings have significant implications for gene discovery, the identification of molecular targets for biological intervention, genetic counselling, and preventing functional impairment incurred by psychiatric conditions of childhood.
Constantino JN and Todd RD. Autistic traits in the general population: A twin study. Archives of General Psychiatry 2003;60:524-530.
Constantino JN, Gruber CP, Davis S, Hayes S, Passanante N and Przybeck T. The factor structure of autistic traits. Journal of Child Psychology and Psychiatry 2004;45(4):719-726.
Constantino JN. The quantitative nature of autistic social impairment. Pediatric Research. 2011 May 69(5Pt 2):55R-62R. PMCID: PMC3086844
Lyall K, Constantino JN, Weisskopf MG, Roberts AL, Ascherio A, Santangelo SL. Parental social responsiveness and risk of autism spectrum disorder in offspring. JAMA Psychiatry 2014 Aug;71(8):936-42.
Frazier TW, Youngstrom EA, Hardan AY, Georgiades S, Constantino JN, Eng C. Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families. Molecular Autism. 2015 Oct 27; 6:58. PMID: 26512313.
Kamio Y, Inada N, Moriwaki A, Kuroda M, Koyama T, Tsujii H, Dawakubo Y, Kuwabara H, Tsuchiya KJ, Uno Y, Constantino JN. Quantitative autistic traits ascertained in a national survey of 22,529 Japanese schoolchildren. Acta Psychiatrica Scandinavica. 2013 Jul;128(1):45-53 PMID: 23171198 – PubMed PMCID:PMC3604131
Frazier TW, Ratliff KR, Gruber C, Zhang Y, Law PA, Constantino JN. Confirmatory factor analytic structure and measurement invariance of quantitative autistic traits measured by the Social Responsiveness Scale-2. Autism 2014 Jan;18(1):31-44. PMID: 24019124; PubMed – in process.
Cerebrospinal Fluid Monoamine Metabolites as Biomarkers of Inherited Liability to Antisocial Behavior
In the late 1990’s, the SDS laboratory led a series of studies in collaboration with the National Institutes of Health Clinical Laboratory, which demonstrated that variations in CSF 5-HIAA, the principal metabolite of serotonin, when ascertained in the neonatal period, was associated with inherited liability to antisocial behavior and to future development of aggression.
The magnitude of the association clarified that multiple factors were at play in mediating both inherited liability and early syndromes of antisocial behavior. These findings have stood the test of time and have, in turn, stimulated a prevention approach in which families of children who are particularly vulnerable to the deleterious effects of adverse life experience are targeted for the provision of strategic supports.
Constantino JN, Morris JA, and Murphy DL. CSF 5-HIAA and Family History of Antisocial Personality Disorder in Newborns. American Journal of Psychiatry 1997;154:1771-1773.
Constantino JN, Liberman M, and Kincaid M. Effects of serotonin reuptake inhibitors on aggressive behavior in psychiatrically hospitalized adolescents: Results of an open trial. J Child Adolesc Psychopharmacol 1997;7:31-44.
Constantino JN, Murphy DL, and Morris JA. Family history, cerebrospinal fluid monoamine metabolites, and temperament in infants. Biological Psychiatry 1999;45:626-632.
Clarke RA, Murphy DL and Constantino JN. Serotonin and externalizing behavior in young children. Psychiatry Research 1999; 86:29-40.
The Genetic Structure of Autism and Related Disorders
The rapid evolution of genomic technologies, coupled with the development of large registries and study samples related to autism created opportunities to integrate quantitative assessment methods with genetically-informative studies designed to elucidate the biological causes of autism.
Our SDS laboratory designed and executed a series of studies that were uniquely characterized by the inclusion of both affected and unaffected individuals in families of children with autism, who could be feasibly phenotyped for sub clinical autistic traits using the quantitative trait measures designed by our laboratory. This resulted in substantially increased statistical power to specify patterns of intergenerational transmission and molecular genetic variants that conferred risk to autism.
One of the remarkable findings that arose from this approach was the phenomenon of sex-based modulation of inherited liability to the social impairment of autism, the so-called “female protective effect,” which appears to underlie the universally-observed 4:1 male:female sex ratio in autism spectrum disorders. These findings have critically informed and enhanced gene discovery efforts, the identification of “carrier” states in unaffected females, and have motivated a next generation of experiments in our laboratory (and others), designed to understand the nature of sex-based modulation of inherited liability to autism.
Given that this phenomenon operates across a vast and heterogeneous array of newly-identified genetic pathways to autism, understanding of its biology carries with it the prospect of the identification of novel treatment approaches that might emulate this effect in a majority of males affected by familial ASD syndromes.
Constantino JN, Zhang Y, Abbacchi A, Frazier TW and Law P. Sibling recurrence and the genetic epidemiology of autism. American Journal of Psychiatry. 2010 Nov;167(11):1349-56. PMCID: PMC2970737
Constantino JN, Todorov A, Hilton C, Law P, Zhang Y, Molloy E, Fitzgerald R and Geschwind D. Autism recurrence in half siblings: strong support for genetic mechanisms of transmission in ASD. Molecular Psychiatry, 2013 18(2):137-8. PMID: 22371046.
Lowe JK, Werling DM, Constantino JN, Cantor RM, Geschwind DH. Social responsiveness, an autism endophenotype: genomewide significant linkage to two regions on chromosome 8.American Journal of Psychiatry. 2015 Mar 1;172(3):266-75. PMID: 25727539
Gockley J, Willsey AJ, Dong S, Dougherty JD, Constantino JN, Sanders SJ. The female protective effect in autism spectrum disorder is not mediated by a single genetic locus. Molecular Autism, 2015 May 13;6:25. PMID:25973162
Constantino JN, Charman T. Diagnosis of Autism Spectrum Disorder: Reconciling the syndrome, its diverse origins, and variation-in-expression. The Lancet Neurology, October 2015. PMID:26497771
Mous SE, Jiang A, Agrawal A, Constantino JN. Attention and motor deficits index non-specific background liabilities that predict autism recurrence in siblings. J Neurodev Disord. 2017 Sep 5;9(1):32. PMID: 28870164; PMCID: PMC5583755.
Constantino JN, Kennon-McGill S, Weichselbaum C, Marrus N, Haider A, Glowinski AL, Gillespie S, Klaiman C, Klin A, Jones W. Infant viewing of social scenes is under genetic control and is atypical in autism. Nature. 2017 Jul 20;547(7663):340-344. PMID: 28700580.
Social Attachment, Psychopathology, and the Prevention of Child Maltreatment
In addition to our work on genetic susceptibility, a continuous theme of our SDS laboratory has been the characterization and prevention of environmental (i.e. non-inherited) influences on risk and resilience for social impairment in childhood. Our studies have helped to clarify the highly influential roles of a) insecure attachment; and b) child maltreatment on antisocial development in childhood, by uniquely controlling for the effects of inherited influence on behavioral outcome.
This research has established the rationale for pragmatic approaches to the simultaneous prevention of child abuse and promotion of social attachment among young children at risk for antisocial development. A first series of studies demonstrated the success of novel methods to engage families of high-risk infants in potent preventive intervention (eg. paraprofessional home visitation), and a meta-analysis demonstrated that parent-focused interventions that reduce antisocial behaviors in children are equally effective among those with and without inherited liabilities.
These efforts have laid the groundwork for a comprehensive approach to identifying and supporting the families of young infants at risk for antisocial development, which is currently being tested through active grants from the U.S. Administration for Children and Families and from municipal government sources. An ongoing effort to prevent child maltreatment recidivism for young children in foster care, the SYNCHRONY Project, is an active collaboration between our Division, the St. Louis County Family Court, and the Missouri Department of Social Services.
Constantino JN, Chackes LM, Wartner UG, Gross M, Brophy SL, Vitale J and Heath AC. Mental representations of attachment in identical female twins with and without conduct problems. Child Psychiatry and Human Development 2006; 37(1):65-72.
Constantino JN, Hashemi N, Solis E, Alon T, Haley S, McClure S, Nordlicht N, Constantino MA, Elmen J and Carlson VK. Supplementation of urban home visitation with a series of group meetings for parents and infants: results of a “real-world” randomized, controlled trial. Child Abuse & Neglect 2001;25:1571-1581.
Jonson-Reid M, Presnall N, Drake B, Fox L, Bierut L, Reich W, Kane P, Todd R and Constantino JN. The effects of child maltreatment and inherited liability on antisocial development: an official records study. Journal of the American Academy of Child and Adolescent Psychiatry, 2010 49(4):321-32. PMCID: PMC2878182.
Presnall N, Webster-Stratton C, Constantino JN. Parent Training: Equivalent Improvement in Externalizing Behavior With and Without Familial Risk. Journal of the American Academy of Child and Adolescent Psychiatry, 2014 Aug;53(8):879-87, 887.e1-2. doi: 10.1016/j.jaac.2014.04.024
Constantino JN, Ben-David V, Navsaria N, Spiegel TE, Glowinski AL, Rogers CE, Jonson-Reid M. Two–Generation Psychiatric Intervention in the Prevention of Early Childhood Maltreatment Recidivism. Am J Psychiatry. 2016 Jun 1;173(6):566-73
Jonson-Reid M, Drake B, Constantino JN, Tandon M, Pons L, Kohl P, Roesch S, Wideman E, Dunnigan A, Auslander W. A Randomized Trial of Home Visitation for CPS-Involved Families: The Moderating Impact of Maternal Depression and CPS History. Child Maltreat. 2018 Jan 1:1077559517751671. doi: 10.1177/1077559517751671. PMID: 29325427.