Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype

Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype

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J Psychiatry Neurosci 2012;37(2):129-37

Sarojini M. Sengupta, PhD; Natalie Grizenko, MD; Geeta A. Thakur, BSc; Johanne Bellingham, BSc; Rosherrie DeGuzman, BSc; Sandra Robinson, BSc; Marina TerStepanian, MSc; Anna Poloskia, MSc; S.M. Shaheen, MSc, MBA; Marie-Eve Fortier, PhD; Zia Choudhry, MBBS; Ridha Joober, MD, PhD

Sengupta, Grizenko, Thakur, Bellingham, DeGuzman, Robinson, Fortier, Choudhry, Joober — Douglas Hospital Research Centre, Verdun; Grizenko, Joober — Department of Psychiatry, McGill University; Thakur — Integrated Program in Neuroscience, McGill University; TerStepanian, Poloskia — Department of Clinical Psychology, McGill University, Montréal, Que.; Shaheen — The Hospital for Sick Children, University of Toronto, Toronto, Ont.; Fortier, Choudhry, Joober — Department of Human Genetics, McGill University; Joober — Neurology and Neurosurgery, McGill University, Montréal, Que.


Background: Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD.
Methods: Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT.
Results: A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5′ region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplotype block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2.
Limitations: The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype.
Conclusion: The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.

Submitted July 14, 2011; Revised Oct. 11, 16, 20, 2011; Accepted Oct. 21, 2011.

Acknowledgments: This work was supported in part by grants from the Fonds de la recherche en santé du Québec and the Canadian Institutes of Health Research to R. Joober and N. Grizenko. S.M. Sengupta is a recipient of the 2008 NARSAD Young Investigator and 2009 Dr. Mortimer D. Sackler Developmental Psychology Investigator Awards. We thank Jacqueline Richard, Matthew Lebaron and Nicole Pawliuk for technical and clinical assistance. A special word of thanks to the families who participated in the research.

Conflict of interest: As above. N. Grizeko, G. Thakur, J. Bellingham, R. DeGuzman, S. Robinson, Z. Choudhry, M. TerStepanian, A.Poloskia, M.-E. Fortier and S.M. Shaheen declare having received travel support from the Canadian Institutes of Health Research. R. Joober sits on the advisory boards and speakers’ bureaus of Pfizer Canada, Janssen Ortho Canada and Shire Canada; he has received grant funding from them and from AstraZeneca and BMS Canada.He has received honoraria from Janssen Ortho Canada for CME pre-sentations and royalties for Henry Stewart talks.

Contributors: N. Grizenko and R. Joober designed the study. N. Grizenko, J. Bellingham, R. DeGuzman, S. Robinson, A. Poloskia, S.M. Shaheen, M.-E. Fortier, Z. Choudhry and R. Joober acquired the data. S.M. Sengupta, G.A. Thakur, M. TerStepanian, A. Poloskia and R. Joober analyzed the data. S.M. Sengupta and R. Joober wrote the article. N. Grizenko, G.A. Thakur, J. Bellingham, R. DeGuzman, S. Robinson, M. TerStepanian, A. Poloskia, S.M. Shaheen, M.-E. Fortier, Z. Choudhry and R. Joober reviewed the article. All authors approved its publication.

DOI: 10.1503/jpn.110073

Correspondence to: R. Joober, Douglas Hospital Research Centre, 6875 LaSalle Blvd., Verdun QC H4H 1R3; ridha.joober@douglas.mcgill.ca