A Potential Role for the STXBP5-AS1 Gene in Adult ADHD Symptoms

A Arias-Vásquez; A J Groffen; S Spijker; K G Ouwens; M Klein; D Vojinovic; T E Galesloot; J Bralten; J J Hottenga; P J van der Most; V M Kattenberg; R Pool; I M Nolte; B W J H Penninx; I O Fedko; C V Dolan; M G Nivard; A den Braber; C M van Duijn; P J Hoekstra; J K Buitelaar; L A Kiemeney; M Hoogman; C M Middeldorp; H H M Draisma; S H Vermeulen; C Sánchez-Mora; J A Ramos-Quiroga; M Ribasés; EAGLE-ADHD Consortium; C A Hartman; J J S Kooij; N Amin; A B Smit; B Franke; D I Boomsma

doi:10.1007/s10519-018-09947-2

A Potential Role for the STXBP5-AS1 Gene in Adult ADHD Symptoms

Behav Genet. 2019 May;49(3):270-285. doi: 10.1007/s10519-018-09947-2. Epub 2019 Jan 18.

Authors

A Arias-Vásquez^{1

2

3}, A J Groffen⁴, S Spijker⁵, K G Ouwens^{5

6}, M Klein⁷, D Vojinovic⁸, T E Galesloot⁹, J Bralten⁷, J J Hottenga^{5

6}, P J van der Most⁹, V M Kattenberg⁵, R Pool^{5

6}, I M Nolte⁹, B W J H Penninx¹⁰, I O Fedko^{5

6}, C V Dolan⁵, M G Nivard^{5

6}, A den Braber⁵, C M van Duijn⁸, P J Hoekstra¹¹, J K Buitelaar^{12

13}, L A Kiemeney¹⁴, M Hoogman⁷, C M Middeldorp^{5

15

16}, H H M Draisma⁵, S H Vermeulen¹⁴, C Sánchez-Mora^{17

18

19}, J A Ramos-Quiroga^{18

19

20}, M Ribasés^{17

18

19}; EAGLE-ADHD Consortium; C A Hartman²¹, J J S Kooij²², N Amin⁸, A B Smit⁵, B Franke^{23

7}, D I Boomsma^{5

6}

Affiliations

¹ Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Alejandro.AriasVasquez@radboudumc.nl.
² Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Route 855, Postbus 9101, 6500 HB, Nijmegen, The Netherlands. Alejandro.AriasVasquez@radboudumc.nl.
³ Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Alejandro.AriasVasquez@radboudumc.nl.
⁴ Department of Functional Genomics and Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam and VU Medical Center Amsterdam, Amsterdam, The Netherlands.
⁵ Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
⁶ Amsterdam Public Health, Amsterdam, The Netherlands.
⁷ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Route 855, Postbus 9101, 6500 HB, Nijmegen, The Netherlands.
⁸ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁹ Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁰ Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
¹¹ Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹² Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
¹³ Karakter, Child and Adolescent Psychiatry University Centre, Nijmegen, The Netherlands.
¹⁴ Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁵ Child Health Research Centre, University of Queensland, Brisbane, Australia.
¹⁶ Child and Youth Mental Health Service, Children's Health Queensland Hospital and Health Services, Brisbane, Australia.
¹⁷ Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
¹⁸ Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
¹⁹ Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
²⁰ Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
²¹ Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
²² Psycho-Medical Programs, PsyQ, Program Adult ADHD, The Hague, The Netherlands.
²³ Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

PMID: 30659475
DOI: 10.1007/s10519-018-09947-2

Abstract

We aimed to detect Attention-deficit/hyperactivity (ADHD) risk-conferring genes in adults. In children, ADHD is characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity and may persists into adulthood. Childhood and adulthood ADHD are heritable, and are thought to represent the clinical extreme of a continuous distribution of ADHD symptoms in the general population. We aimed to leverage the power of studies of quantitative ADHD symptoms in adults who were genotyped. Within the SAGA (Study of ADHD trait genetics in adults) consortium, we estimated the single nucleotide polymorphism (SNP)-based heritability of quantitative self-reported ADHD symptoms and carried out a genome-wide association meta-analysis in nine adult population-based and case-only cohorts of adults. A total of n = 14,689 individuals were included. In two of the SAGA cohorts we found a significant SNP-based heritability for self-rated ADHD symptom scores of respectively 15% (n = 3656) and 30% (n = 1841). The top hit of the genome-wide meta-analysis (SNP rs12661753; p-value = 3.02 × 10^-7) was present in the long non-coding RNA gene STXBP5-AS1. This association was also observed in a meta-analysis of childhood ADHD symptom scores in eight population-based pediatric cohorts from the Early Genetics and Lifecourse Epidemiology (EAGLE) ADHD consortium (n = 14,776). Genome-wide meta-analysis of the SAGA and EAGLE data (n = 29,465) increased the strength of the association with the SNP rs12661753. In human HEK293 cells, expression of STXBP5-AS1 enhanced the expression of a reporter construct of STXBP5, a gene known to be involved in "SNAP" (Soluble NSF attachment protein) Receptor" (SNARE) complex formation. In mouse strains featuring different levels of impulsivity, transcript levels in the prefrontal cortex of the mouse ortholog Gm28905 strongly correlated negatively with motor impulsivity as measured in the five choice serial reaction time task (r² = - 0.61; p = 0.004). Our results are consistent with an effect of the STXBP5-AS1 gene on ADHD symptom scores distribution and point to a possible biological mechanism, other than antisense RNA inhibition, involved in ADHD-related impulsivity levels.

Keywords: ADHD symptoms; Adults; GWAS; STXBP5-AS1 gene.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Attention Deficit Disorder with Hyperactivity / genetics*
Attention Deficit Disorder with Hyperactivity / metabolism
Cohort Studies
DNA, Antisense / genetics
DNA, Antisense / metabolism
Female
Genetic Predisposition to Disease / genetics
Genetics, Population / methods
Genome-Wide Association Study
Genotype
HEK293 Cells
Humans
Male
Mice
Nerve Tissue Proteins / genetics*
Phenotype
Polymorphism, Single Nucleotide / genetics
R-SNARE Proteins / genetics*
RNA, Long Noncoding / genetics*
RNA, Long Noncoding / metabolism
Risk Factors

Substances

DNA, Antisense
Nerve Tissue Proteins
R-SNARE Proteins
RNA, Long Noncoding
STXBP5 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding