Replication of a rare protective allele in the noradrenaline transporter gene and ADHD

Xaiohui Xu, Ziarih Hawi, Keeley J Brookes, Richard J Anney, Mark Andrew Bellgrove, Barbara Franke, Edwina Barry, Wai Chen, Jonna Kuntsi, Tobias Banaschewski, Jan K Buitelaar, R P Ebstein, Michael F Fitzgerald, Ana Lucia Miranda, Robert D Oades, Herbert Roeyers, Aribert Rothenberger, Joseph A Sergeant, Edmund Sonuga-Barke, Hans Christoph Steinhausen & 3 others Stephen V Faraone, Michael Gill, Philip J Asherson

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)

Abstract

Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHDin a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.
Original languageEnglish
Pages (from-to)1564 - 1567
Number of pages4
JournalAmerican Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume147
Issue number8
DOIs
Publication statusPublished - 2008
Externally publishedYes

Cite this

Xu, Xaiohui ; Hawi, Ziarih ; Brookes, Keeley J ; Anney, Richard J ; Bellgrove, Mark Andrew ; Franke, Barbara ; Barry, Edwina ; Chen, Wai ; Kuntsi, Jonna ; Banaschewski, Tobias ; Buitelaar, Jan K ; Ebstein, R P ; Fitzgerald, Michael F ; Miranda, Ana Lucia ; Oades, Robert D ; Roeyers, Herbert ; Rothenberger, Aribert ; Sergeant, Joseph A ; Sonuga-Barke, Edmund ; Steinhausen, Hans Christoph ; Faraone, Stephen V ; Gill, Michael ; Asherson, Philip J. / Replication of a rare protective allele in the noradrenaline transporter gene and ADHD. In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2008 ; Vol. 147, No. 8. pp. 1564 - 1567.
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abstract = "Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHDin a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.",
author = "Xaiohui Xu and Ziarih Hawi and Brookes, {Keeley J} and Anney, {Richard J} and Bellgrove, {Mark Andrew} and Barbara Franke and Edwina Barry and Wai Chen and Jonna Kuntsi and Tobias Banaschewski and Buitelaar, {Jan K} and Ebstein, {R P} and Fitzgerald, {Michael F} and Miranda, {Ana Lucia} and Oades, {Robert D} and Herbert Roeyers and Aribert Rothenberger and Sergeant, {Joseph A} and Edmund Sonuga-Barke and Steinhausen, {Hans Christoph} and Faraone, {Stephen V} and Michael Gill and Asherson, {Philip J}",
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Xu, X, Hawi, Z, Brookes, KJ, Anney, RJ, Bellgrove, MA, Franke, B, Barry, E, Chen, W, Kuntsi, J, Banaschewski, T, Buitelaar, JK, Ebstein, RP, Fitzgerald, MF, Miranda, AL, Oades, RD, Roeyers, H, Rothenberger, A, Sergeant, JA, Sonuga-Barke, E, Steinhausen, HC, Faraone, SV, Gill, M & Asherson, PJ 2008, 'Replication of a rare protective allele in the noradrenaline transporter gene and ADHD', American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, vol. 147, no. 8, pp. 1564 - 1567. https://doi.org/10.1002/ajmg.b.30872

Replication of a rare protective allele in the noradrenaline transporter gene and ADHD. / Xu, Xaiohui; Hawi, Ziarih; Brookes, Keeley J; Anney, Richard J; Bellgrove, Mark Andrew; Franke, Barbara; Barry, Edwina; Chen, Wai; Kuntsi, Jonna; Banaschewski, Tobias; Buitelaar, Jan K; Ebstein, R P; Fitzgerald, Michael F; Miranda, Ana Lucia; Oades, Robert D; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph A; Sonuga-Barke, Edmund; Steinhausen, Hans Christoph; Faraone, Stephen V; Gill, Michael; Asherson, Philip J.

In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, Vol. 147, No. 8, 2008, p. 1564 - 1567.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Replication of a rare protective allele in the noradrenaline transporter gene and ADHD

AU - Xu, Xaiohui

AU - Hawi, Ziarih

AU - Brookes, Keeley J

AU - Anney, Richard J

AU - Bellgrove, Mark Andrew

AU - Franke, Barbara

AU - Barry, Edwina

AU - Chen, Wai

AU - Kuntsi, Jonna

AU - Banaschewski, Tobias

AU - Buitelaar, Jan K

AU - Ebstein, R P

AU - Fitzgerald, Michael F

AU - Miranda, Ana Lucia

AU - Oades, Robert D

AU - Roeyers, Herbert

AU - Rothenberger, Aribert

AU - Sergeant, Joseph A

AU - Sonuga-Barke, Edmund

AU - Steinhausen, Hans Christoph

AU - Faraone, Stephen V

AU - Gill, Michael

AU - Asherson, Philip J

PY - 2008

Y1 - 2008

N2 - Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHDin a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.

AB - Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHDin a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.

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DO - 10.1002/ajmg.b.30872

M3 - Article

VL - 147

SP - 1564

EP - 1567

JO - American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

JF - American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

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