Variation in serotonin neurotransmission genes affects neural activation during response inhibition in adolescents and young adults with ADHD and healthy controls

Abstract

Objectives. Deficits in response inhibition have been associated with attention-deficit/hyperactivity disorder (ADHD). Given the role of serotonin in ADHD and impulsivity, we postulated that genetic variants within the serotonin pathway might influence response inhibition. Methods. We measured neural activation during stop-signal task performance in adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and healthy controls (N = 124), and investigated the relationship of two serotonin gene polymorphisms (the rs6296 SNP of the HTR1B gene and HTTLPR variants of the 5-HTT gene) with the neural correlates of response inhibition. Results. The whole-brain analyses demonstrated large scale neural activation differences in the inferior and medial frontal and temporal/parietal regions of the response inhibition network between the different variants of both the HTR1B and 5HTT genes. Activation in these regions was significantly associated with stop-task performance, but not with ADHD diagnosis or severity. No associations were found between HTR1B and 5HTT variants and ADHD or ADHD-related neural activation. Conclusions. These results provide novel evidence that serotonin may play an important role in the neurobiology of response inhibition. Although response inhibition is strongly linked to ADHD, serotonin linked genetic variants associated with response inhibition and its neural correlates do not explain variance of the ADHD phenotype.

Key words::

• ADHD
• response inhibition
• 5HT
• siblings
• endophenotype

Acknowledgements

We acknowledge the department of Pediatrics of the VU University Medical Center for having the opportunity to use the mock scanner for preparation of our participants. We thank Roshan Cools for her invaluable advice and input in this manuscript.

Statement of Interest

This work was supported by NIH Grant R01MH62873 (to Stephen V. Faraone), NWO Large Investment Grant 1750102007010 and NWO Brain & Cognition an Integrative Approach grant (433-09-242) (to Jan Buitelaar), and grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and VU University Amsterdam.

Jan K. Buitelaar has been in the past 3 years 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 or stock shareholder of any of these companies. In the past 3 years, Jaap Oosterlaan had an investigator-initiated grant from Shire pharmaceuticals and Pieter J. Hoekstra an investigator-initiated grant from Shire and was a member of the advisory board of Eli Lilly and Shire.

Supplementary materials available online

Supplementary methods

Determining diagnostic status in the NeuroIMAGE sample

Participant inclusion

Genotyping

fMRI acquisition and preprocessing

fMRI single subject analysis

Supplementary results

fMRI task activation

Between group differences in fMRI activation

Genetic effects on between-group differences in fMRI activation

Role of genetic effects in whole-brain fMRI activation and stop-task performance

Supplementary Tables 1–5.

Supplementary Figures 1–3. Available online at http://dx.doi.org/10.3109/15622975.2015.1067371.