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

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 ADHD in 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.

• Authors: X Xu, Z Hawi, K J Brookes, R Anney, M Bellgrove, B Franke, E Barry, W Chen, J Kuntsi, T Banaschewski, J Buitelaar, R Ebstein, M Fitzgerald, A Miranda, R D Oades, H Roeyers, A Rothenberger, J Sergeant, E Sonuga-Barke, H-C Steinhausen, S V Faraone, M Gill, P Asherson
• Journal: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics (Am J Med Genet B Neuropsychiatr Genet) Vol. 147B Issue 8 Pg. 1564-7 (Dec 05 2008) ISSN: 1552-485X [Electronic] United States
• PMID: 18937296 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2008 Wiley-Liss, Inc.

Chemical References

• Genetic Markers
• Norepinephrine Plasma Membrane Transport Proteins
• SLC6A2 protein, human

Topics

• Adolescent
• Alleles
• Attention Deficit Disorder with Hyperactivity (diagnosis, genetics)
• Case-Control Studies
• Chi-Square Distribution
• Child
• Child, Preschool
• Gene Frequency
• Genetic Markers
• Genetic Predisposition to Disease
• Genotype
• Heterozygote
• Humans
• Introns
• Mothers (statistics & numerical data)
• Multicenter Studies as Topic
• Norepinephrine Plasma Membrane Transport Proteins (genetics)
• Odds Ratio
• Parents
• Polymorphism, Single Nucleotide
• Siblings