Testing differential susceptibility: Plasticity genes, the social environment, and their interplay in adolescent response inhibition

Abstract

Objectives: Impaired inhibitory control is a key feature of attention-deficit/hyperactivity disorder (ADHD). We investigated gene–environment interaction (GxE) as a possible contributing factor to response inhibition variation in context of the differential susceptibility theory. This states individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments.

Methods: Behavioural and neural measures of response inhibition were assessed during a Stop-signal task in participants with (N = 197) and without (N = 295) ADHD, from N = 278 families (age M = 17.18, SD =3.65). We examined GxE between candidate plasticity genes (DAT1, 5-HTT, DRD4) and social environments (maternal expressed emotion, peer affiliation).

Results: A DRD4 × Positive peer affiliation interaction was found on the right fusiform gyrus (rFG) activation during successful inhibition. Further, 5-HTT short allele carriers showed increased rFG activation during failed inhibitions. Maternal warmth and positive peer affiliation were positively associated with right inferior frontal cortex activation during successful inhibition. Deviant peer affiliation was positively related to the error rate.

Conclusions: While a pattern of differential genetic susceptibility was found, more clarity on the role of the FG during response inhibition is warranted before firm conclusions can be made. Positive and negative social environments were related to inhibitory control. This extends previous research emphasizing adverse environments.

Keywords:

• ADHD
• response inhibition
• gene–environment interaction
• social environment
• functional MRI

Acknowledgements

The International Multisite ADHD Genetics (IMAGE) project is a multi-site, international effort. Funding support for the IMAGE project was provided by NIH [grant numbers R01MH62873 and R01MH081803] to Dr. Faraone and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The dataset used for the analyses described in this manuscript was obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number #20726-2. This work was further supported by a NWO Large Investment Grant [grant number 1750102007010] and NWO Brain & Cognition an Integrative Approach grant [grant number 433-09-242] (to Dr. Buitelaar), and grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and VU University Amsterdam. The research leading to these results also received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) [grant numbers 278948 (TACTICS) and 602450 (IMAGEMEND)]. Dr. Franke is supported by a Vici grant from NWO [grant number 016-130-669] and she and Dr. Buitelaar received funding from the National Institutes of Health (NIH) Consortium [grant number U54 EB020403], supported by a cross-NIH alliance that funds Big Data to Knowledge Centers of Excellence. Dr. Faraone is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Community's Seventh Framework Programme (FP7/2007-2013) [grant number 602805] and NIMH grants [grant numbers R13MH059126 and R01MH094469].

Statement of interest

In the past year, Dr. Faraone received income, travel expenses and/or research support from and/or has been on an Advisory Board for Pfizer, Ironshore, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA Pharma, Neurovance, Impax, NeuroLifeSciences and research support from the National Institutes of Health (NIH). His institution is seeking a patent for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by: Shire, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. Dr. Faraone receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health and Oxford University Press: Schizophrenia: The Facts. In the past 3 years, Dr. Buitelaar has been a consultant to/member of advisory board of/and/or speaker for Janssen Cilag BV, Eli Lilly, Bristol-Myer Squibb, Shering Plough, UCB, Shire, Novartis and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. In the past 3 years, Dr. Hoekstra has been a consultant to/member of advisory board of Eli Lilly and Shire. Dr. Oosterlaan has received an unrestricted investigator initiated research grant from Shire. Dr. Franke received a speaker fee from Merck. Mr. van der Meer and Drs. Richards, van Rooij, Heslenfeld, Arias Vásquez and Hartman have no conflicts of interest do declare.