Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder

Janette Tong; Leigh-Anne Mckinley; Tarrant D. R. Cummins; Beth Johnson; Natasha Matthews; Alasdair Vance; Helen Heussler; Michael Gill; Lindsey Kent; Mark A. Bellgrove; Ziarih Hawi

doi:10.3109/15622975.2015.1036771

Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder

Janette Tong, Leigh-Anne Mckinley, Tarrant D. R. Cummins, Beth Johnson, Natasha Matthews, Alasdair Vance, Helen Heussler, Michael Gill, Lindsey Kent, Mark A. Bellgrove, Ziarih Hawi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Objectives. Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency.

Methods. We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y.

Results. A SNP within the 3' untranslated region of DBH rs129882 showed a significant association with ADHD (χ2 = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (p <0.001) in luciferase activity.

Conclusions. These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD.

Original language	English
Pages (from-to)	610-618
Number of pages	9
Journal	World Journal of Biological Psychiatry
Volume	16
Issue number	8
Early online date	15 May 2015
DOIs	https://doi.org/10.3109/15622975.2015.1036771
Publication status	Published - 17 Nov 2015

Keywords

Attention Deficit Hyperactivity Disorder
Genetics
Gene expression
DBH
Polymorphism

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© 2015, Publisher / the Author(s). This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at www.tandfonlnie.com / https://dx.doi.org/10.3109/15622975.2015.1036771
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Tong, J., Mckinley, L.-A., Cummins, T. D. R., Johnson, B., Matthews, N., Vance, A., Heussler, H., Gill, M., Kent, L., Bellgrove, M. A., & Hawi, Z. (2015). Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder. World Journal of Biological Psychiatry, 16(8), 610-618. https://doi.org/10.3109/15622975.2015.1036771

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title = "Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder",

abstract = "Objectives. Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency.Methods. We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y.Results. A SNP within the 3' untranslated region of DBH rs129882 showed a significant association with ADHD (χ2 = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (p <0.001) in luciferase activity.Conclusions. These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD.",

keywords = "Attention Deficit Hyperactivity Disorder, Genetics, Gene expression, DBH, Polymorphism",

author = "Janette Tong and Leigh-Anne Mckinley and Cummins, {Tarrant D. R.} and Beth Johnson and Natasha Matthews and Alasdair Vance and Helen Heussler and Michael Gill and Lindsey Kent and Bellgrove, {Mark A.} and Ziarih Hawi",

year = "2015",

month = nov,

day = "17",

doi = "10.3109/15622975.2015.1036771",

language = "English",

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pages = "610--618",

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Tong, J, Mckinley, L-A, Cummins, TDR, Johnson, B, Matthews, N, Vance, A, Heussler, H, Gill, M, Kent, L, Bellgrove, MA & Hawi, Z 2015, 'Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder', World Journal of Biological Psychiatry, vol. 16, no. 8, pp. 610-618. https://doi.org/10.3109/15622975.2015.1036771

Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder. / Tong, Janette; Mckinley, Leigh-Anne; Cummins, Tarrant D. R. et al.
In: World Journal of Biological Psychiatry, Vol. 16, No. 8, 17.11.2015, p. 610-618.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder

AU - Tong, Janette

AU - Mckinley, Leigh-Anne

AU - Cummins, Tarrant D. R.

AU - Johnson, Beth

AU - Matthews, Natasha

AU - Vance, Alasdair

AU - Heussler, Helen

AU - Gill, Michael

AU - Kent, Lindsey

AU - Bellgrove, Mark A.

AU - Hawi, Ziarih

PY - 2015/11/17

Y1 - 2015/11/17

N2 - Objectives. Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency.Methods. We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y.Results. A SNP within the 3' untranslated region of DBH rs129882 showed a significant association with ADHD (χ2 = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (p <0.001) in luciferase activity.Conclusions. These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD.

AB - Objectives. Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency.Methods. We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y.Results. A SNP within the 3' untranslated region of DBH rs129882 showed a significant association with ADHD (χ2 = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (p <0.001) in luciferase activity.Conclusions. These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD.

KW - Attention Deficit Hyperactivity Disorder

KW - Genetics

KW - Gene expression

KW - DBH

KW - Polymorphism

U2 - 10.3109/15622975.2015.1036771

DO - 10.3109/15622975.2015.1036771

M3 - Article

SN - 1562-2975

VL - 16

SP - 610

EP - 618

JO - World Journal of Biological Psychiatry

JF - World Journal of Biological Psychiatry

IS - 8

ER -

Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder

Abstract

Keywords

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