The role of glucocorticoid receptor gene in the association between attention deficit-hyperactivity disorder and smaller brain structures

Cibele E Bandeira; Eugenio H Grevet; Renata B Cupertino; Maria E de Araujo Tavares; Clara S Gusmão; Djenifer B Kappel; Eduardo S Vitola; Felipe A Picon; Luís A Rohde; Bruna S da Silva; Claiton H D Bau; Diego L Rovaris

doi:10.1007/s00702-021-02425-w

The role of glucocorticoid receptor gene in the association between attention deficit-hyperactivity disorder and smaller brain structures

J Neural Transm (Vienna). 2021 Dec;128(12):1907-1916. doi: 10.1007/s00702-021-02425-w. Epub 2021 Oct 5.

Authors

Cibele E Bandeira^{1

2}, Eugenio H Grevet^{2

3

4}, Renata B Cupertino⁵, Maria E de Araujo Tavares^{1

2}, Clara S Gusmão⁶, Djenifer B Kappel^{1

2}, Eduardo S Vitola^{2

3}, Felipe A Picon^{2

3}, Luís A Rohde^{3

4}, Bruna S da Silva^{1

2}, Claiton H D Bau^#^{7

8

9

10}, Diego L Rovaris^#^{11

12}

Affiliations

¹ Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
² ADHD Outpatient Program, Adult Division, Hospital de Clínicas de Porto Alegre, Avenida Bento Gonçalves, 9500, Porto Alegre, RS, Brazil.
³ Departament of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
⁴ Laboratory of Developmental Psychiatry, Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
⁵ Department of Psychiatry, University of Vermont, Burlington, VT, USA.
⁶ Departamento de Fisiologia e Biofísica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, São Paulo, Brazil.
⁷ Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. [email protected].
⁸ ADHD Outpatient Program, Adult Division, Hospital de Clínicas de Porto Alegre, Avenida Bento Gonçalves, 9500, Porto Alegre, RS, Brazil. [email protected].
⁹ Departament of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. [email protected].
¹⁰ Laboratory of Developmental Psychiatry, Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil. [email protected].
¹¹ ADHD Outpatient Program, Adult Division, Hospital de Clínicas de Porto Alegre, Avenida Bento Gonçalves, 9500, Porto Alegre, RS, Brazil. [email protected].
¹² Departamento de Fisiologia e Biofísica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, São Paulo, Brazil. [email protected].

^# Contributed equally.

PMID: 34609638
DOI: 10.1007/s00702-021-02425-w

Abstract

ADHD is associated with smaller subcortical brain volumes and cortical surface area, with greater effects observed in children than adults. It is also associated with dysregulation of the HPA axis. Considering the effects of the glucocorticoid receptor (NR3C1) in neurophysiology, we hypothesize that the blurred relationships between brain structures and ADHD in adults could be partly explained by NR3C1 gene variation. Structural T1-weighted images were acquired on a 3 T scanner (N = 166). Large-scale genotyping was performed, and it was followed by quality control and pruning procedures, which resulted in 48 independent NR3C1 gene variants analyzed. After a stringent Bonferroni correction, two SNPs (rs2398631 and rs72801070) moderated the association between ADHD and accumbens and amygdala volumes in adults. The significant SNPs that interacted with ADHD appear to have a role in gene expression regulation, and they are in linkage disequilibrium with NR3C1 variants that present well-characterized physiological functions. The literature-reported associations of ADHD with accumbens and amygdala were only observed for specific NR3C1 genotypes. Our findings reinforce the influence of the NR3C1 gene on subcortical volumes and ADHD. They suggest a genetic modulation of the effects of a pivotal HPA axis component in the neuroanatomical features of ADHD.

Keywords: Amygdala; Attention deficit-hyperactivity disorder; Glucocorticoid receptor; Neuroimaging; Nucleus accumbens.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Attention Deficit Disorder with Hyperactivity* / diagnostic imaging
Attention Deficit Disorder with Hyperactivity* / genetics
Brain / diagnostic imaging
Brain / metabolism
Glucocorticoids
Humans
Hypothalamo-Hypophyseal System / metabolism
Magnetic Resonance Imaging
Pituitary-Adrenal System
Receptors, Glucocorticoid* / genetics
Receptors, Glucocorticoid* / metabolism

Substances

Glucocorticoids
NR3C1 protein, human
Receptors, Glucocorticoid