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

ABSTRACT: 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.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.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 haplo-type block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2.The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype.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.

SUBMITTER: Sengupta SM

PROVIDER: S-EPMC3297073 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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

Sengupta Sarojini M SM Grizenko Natalie N Thakur Geeta A GA Bellingham Johanne J DeGuzman Rosherrie R Robinson Sandra S TerStepanian Marina M Poloskia Anna A Shaheen S M SM Fortier Marie-Eve ME Choudhry Zia Z Joober Ridha R

Journal of psychiatry & neuroscience : JPN 20120201 2

<h4>Background</h4>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.<h4>Methods</h4>Family-based association tests were conducted with the categorical diagnosis of ADHD, as ...[more]

PMID: 22297068

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Project description:ObjectiveDespite 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.MethodsChildren (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.ResultsA 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).ConclusionsBy 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); www.clinicaltrials.gov; NCT00483106.

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

Publications

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

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