Attention-deficit hyperactivity disorder (ADHD) is a heritable disorder, prevalent from childhood through adulthood. Although the noradrenergic (NA) system is thought to mediate a portion of the pathophysiology of ADHD, genes in this pathway have not been investigated as frequently as those in the dopaminergic system. Previous association studies of one candidate gene in the NA system, ADRA2A, showed inconsistent results with regard to an MspI polymorphism. In the current study, two nearby single-nucleotide polymorphisms, which define HhaI and DraI restriction fragment length polymorphisms, were also genotyped and were in significant linkage disequilibrium with the MspI RFLP. Transmission disequilibrium tests (TDTs) in a sample of 177 nuclear families showed significant association and linkage of the DraI polymorphism with the ADHD combined subtype (P ¼ 0.03), and the quantitative TDT showed association of this polymorphism with the inattentive (P ¼ 0.003) and hyperactiveimpulsive (P ¼ 0.015) symptom dimensions. The haplotype that contained the less common allele of the DraI polymorphism likewise showed a strong relationship with the inattentive (P ¼ 0.001) and hyperactive-impulsive (P ¼ 0.004) symptom dimensions. This study supports the hypothesis that an allele of the ADRA2A gene is associated and linked with the ADHD combined subtype and suggests that the DraI polymorphism of ADRA2A is linked to a causative polymorphism. Molecular Psychiatry (2005) 10, 572-580.

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Few studies of gene-environment interactions for the serotonin transporter promoter polymorphism (5-HTTLPR), life stressors and depression have considered women separately or examined specific types of stressful life events. None have looked at depression during pregnancy. In the Pregnancy Outcomes and Community Health (POUCH) Study, women were queried about history of stressful life events and depressive symptoms at the time of enrollment (15-27 weeks gestation). Stressful life events were grouped a priori into ''subconstructs'' (e.g. economic, legal, abuse, loss) and evaluated by subconstruct, total subconstruct score and total stressful life event score. The effect of genotype on the association between stressful life events and elevated depressive symptoms was assessed in 568 white non-Hispanic participants. The relationship between exposure to abuse and elevated depressive symptoms was more pronounced in the s/s group (OR 5 24.5) than in the s/ l group (OR 5 3.0) and the l/l group (OR 5 7.7), but this significant interaction was detected only after excluding 73 (13%) women with recent use of psychotropic medications. There was no evidence of gene-environment interaction in analytic models with other stressful life events subconstructs, total subconstruct score or total stressful life events score. These data offer modest support to other reports of gene-environment interaction and highlight the importance of considering specific stressful life events.

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Background: ␤-Mannosidosis is a rare inborn error of metabolism with various phenotypes, including mental retardation, behavioral problems, hearing loss, and recurrent airway infections in childhood. To our knowledge, there is no published description of Gilles de la Tourette syndrome in association with this enzymatic deficiency. Objective: To describe a unique case of Gilles de la Tourette syndrome associated with ␤-mannosidosis. Setting: University hospital. Patient: An 18-year-old man exhibited motor and vocal tics since childhood, attention-deficit/hyperactivity disorder, impulsivity, and aggressiveness compatible with Gilles de la Tourette syndrome. A screen for inborn errors of metabolism was made because of the atypical association with slight mental retardation and bilateral perceptive hypoacousia. Results: Urinary analysis showed disacchariduria, and leukocyte analysis revealed a profound deficit in ␤-mannosidase activity. Two novel mutations in the ␤-mannosidase gene were found: a new splice mutation in one allele, and a unique 10-base-pair insertion in the other. Conclusions: This case illustrates the phenotypic variability of inborn errors of metabolism in adults and demonstrates the need to screen inborn errors of metabolism in atypical Gilles de la Tourette syndrome.