Document Detail

Comprehensive phenotype/genotype analyses of the norepinephrine transporter gene (SLC6A2) in ADHD: relation to maternal smoking during pregnancy.
MedLine Citation:
PMID:  23185385     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Despite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD.
METHODS: Children (6-12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families.
RESULTS: A highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z=3.74, P=0.0002), behavioral assessments by parents (CBCL, P=0.00008), as well as restless-impulsive subscale scores on Conners'-teachers (P=0.006) and parents (P=0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z=3.28, P=0.001), parents (Z=2.62, P=0.009), as well as evaluation in the simulated academic environment (Z=3.58, P=0.0003).
CONCLUSIONS: By using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information - Clinical and Pharmacogenetic Study of Attention Deficit with Hyperactivity Disorder (ADHD);; NCT00483106.
Geeta A Thakur; Sarojini M Sengupta; Natalie Grizenko; Zia Choudhry; Ridha Joober
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-20
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-11-27     Completed Date:  2013-05-22     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e49616     Citation Subset:  IM    
Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.
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MeSH Terms
Attention Deficit Disorder with Hyperactivity / genetics*,  metabolism*
Child Behavior
Double-Blind Method
Maternal Exposure
Methylphenidate / pharmacology
Norepinephrine Plasma Membrane Transport Proteins / biosynthesis*,  genetics*
Polymorphism, Single Nucleotide
Grant Support
//Canadian Institutes of Health Research
Reg. No./Substance:
0/Norepinephrine Plasma Membrane Transport Proteins; 0/Placebos; 0/SLC6A2 protein, human; 113-45-1/Methylphenidate

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