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

Janette Ho Shuen Tong, Leigh-Anne McKinley, Tarrant Cummins, Beth Patricia Johnson, Natasha L Matthews, Alasdair Lachlan Angus Vance, Helen Somerset Heussler, Michael Gill, Lindsey S W Kent, Mark Andrew Bellgrove, Ziarih Hawi

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

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 (?2 = 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 languageEnglish
Pages (from-to)610 - 618
Number of pages9
JournalWorld Journal of Biological Psychiatry
Volume16
Issue number8
DOIs
Publication statusPublished - 2015

Cite this

Tong, Janette Ho Shuen ; McKinley, Leigh-Anne ; Cummins, Tarrant ; Johnson, Beth Patricia ; Matthews, Natasha L ; Vance, Alasdair Lachlan Angus ; Heussler, Helen Somerset ; Gill, Michael ; Kent, Lindsey S W ; Bellgrove, Mark Andrew ; Hawi, Ziarih. / Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder. In: World Journal of Biological Psychiatry. 2015 ; Vol. 16, No. 8. pp. 610 - 618.
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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 (?2 = 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",
author = "Tong, {Janette Ho Shuen} and Leigh-Anne McKinley and Tarrant Cummins and Johnson, {Beth Patricia} and Matthews, {Natasha L} and Vance, {Alasdair Lachlan Angus} and Heussler, {Helen Somerset} and Michael Gill and Kent, {Lindsey S W} and Bellgrove, {Mark Andrew} and Ziarih Hawi",
year = "2015",
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language = "English",
volume = "16",
pages = "610 -- 618",
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Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder. / Tong, Janette Ho Shuen; McKinley, Leigh-Anne; Cummins, Tarrant; Johnson, Beth Patricia; Matthews, Natasha L; Vance, Alasdair Lachlan Angus; Heussler, Helen Somerset; Gill, Michael; Kent, Lindsey S W; Bellgrove, Mark Andrew; Hawi, Ziarih.

In: World Journal of Biological Psychiatry, Vol. 16, No. 8, 2015, p. 610 - 618.

Research output: Contribution to journalArticleResearchpeer-review

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

AU - Tong, Janette Ho Shuen

AU - McKinley, Leigh-Anne

AU - Cummins, Tarrant

AU - Johnson, Beth Patricia

AU - Matthews, Natasha L

AU - Vance, Alasdair Lachlan Angus

AU - Heussler, Helen Somerset

AU - Gill, Michael

AU - Kent, Lindsey S W

AU - Bellgrove, Mark Andrew

AU - Hawi, Ziarih

PY - 2015

Y1 - 2015

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 (?2 = 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 (?2 = 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

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