118 Brief association letter

Family-based association study of ciliary neurotrophic factor receptor and norepinephrine transporter genes in attention-deficit hyperactivity disorder Ruu-Fen Tzanga,b,*, Cheng-Dien Hsuc,*, Ying-Jay Lioud,e, Chen-Jee Hongd,e and Shih-Jen Tsaid,e Tel: + 886 2 2875 7027; fax: + 886 2 2872 5643; e-mail: [email protected]

Psychiatric Genetics 2014, 24:118–119 a

b

Department of Psychiatry, Mackay Memorial Hospital, Department of Nursing, Mackay Medicine, Nursing and Management College, cDepartment of Psychiatry, Taiwan Adventist Hospital, dDepartment of Psychiatry, Taipei Veterans General Hospital and eDivision of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan

*Ruu-Fen Tzang and Cheng-Dien Hsu contributed equally to the writing of this article. Received 16 September 2013 Accepted 28 January 2014

Correspondence to Shih-Jen Tsai, MD, Department of Psychiatry, Taipei Veterans General Hospital, No. 201 Shih-Pai Road, Sec. 2, Taipei 11217, Taiwan

Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder of childhood with adverse consequences during adult life. Family, twin, and adoption studies suggest that genetic factors contribute toward its etiopathogenesis and that environmental factors also play a role. Neurotrophic factors, which are a family of proteins that are responsible for the growth and survival of developing neurons, might be involved in the genetic predisposition to ADHD. In a case–control association study in 546 ADHD patients (216 adults and 330 children) and 546 sex-matched unrelated control participants with 183 single nucleotide polymorphisms covering 10 genes encoding neurotrophic factors, Ribase´s et al. (2008) reported a significant difference in the genotype distributions and allele frequencies of rs7036351 in ciliary neurotrophic factor receptor (CNTFR) and both adulthood (P = 0.0077, odds ratio = 1.38) and childhood ADHD (P = 9.1e – 04, odds ratio = 1.40). CNTFR binds the ciliary neurotrophic factor. This receptor and its cognate ligand stimulate gene expression, cell survival, or differentiation in a variety of neuronal cell types. The norepinephrine transporter (NET) gene is an attractive candidate gene for ADHD because noradrenergic systems are critical to higher brain functions such as attention, which is defective in ADHD. Analysis using within family tests of association in a sample of 776 ADHD patients (Brookes et al., 2006) showed that rs3785143 in NET was nominally associated with ADHD. This association is further confirmed by another familybased association study (Kim et al., 2008). In the present study, we sought to replicate these findings in a Taiwanese sample by a family-based association study. Our sample comprised 284 Taiwanese families who had at least one child diagnosed with ADHD, and the sample has been reported in our previous study (Hsu et al., 2013). Each patient was diagnosed with c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0955-8829

ADHD according to the DSM-IV criteria by a senior board-certified child psychiatrist. Patients were excluded if there was any evidence of conduct disorder, mood disorder, anxiety disorder, Tourette’s syndrome, mental retardation (IQ < 70), pervasive developmental disorder, or neurological conditions. The study was approved by the Ethics Committee of the Taiwan Adventist Hospital. Written informed consent was obtained from all patients. We genotyped these two polymorphisms (rs7036351 and rs3785143) using high-throughput MALDI-TOF mass spectrometry (Sequenom Inc., San Diego, California, USA). Transmission disequilibrium test analyses for the three polymorphism in the ADHD trios were carried out using PLINK (http://pngu.mgh.harvard.edu/Bpurcell/plink/ index.shtml). Of the total 312 probands in 284 families, 257 (82.4%) were boys and 55 (17.6%) were girls. Their ages ranged from 6 to 24 years, with a mean age of 13.0± 2.9 years. Analysis of the transmission disequilibrium test in the ADHD parent–proband trios showed no significant differences in the frequency between transmitted and nontransmitted minor alleles for the two polymorphisms (CNTFR rs7036351-T: T/NT = 128/133, P = 0.757; NET rs3785143-T: T/NT = 70/75, P = 0.678; T = transmitted; NT = nontransmitted). Our family-based study showed no association between the CNTFR rs7036351, NET rs3785143 polymorphisms, and ADHD, and, therefore, does not support the earlier reports that described a significant association (Brookes et al., 2006; Kim et al., 2008; Ribase´s et al., 2008).

Acknowledgements Conflicts of interest

There are no conflicts of interest. DOI: 10.1097/YPG.0000000000000027

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CNTFR and NET in ADHD Tzang et al. 119

References Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N, et al. (2006). The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiatry 11:934–953. Hsu CD, Tzang RF, Liou YJ, Hong CJ, Tsai SJ (2013). Family-based association study of tryptophan hydroxylase 2 and serotonin 1A receptor genes in attention deficit hyperactivity disorder. Psychiatr Genet 23:38.

Kim JW, Biederman J, McGrath CL, Doyle AE, Mick E, Fagerness J, et al. (2008). Further evidence of association between two NET single-nucleotide polymorphisms with ADHD. Mol Psychiatry 13:624–630. Ribase´s M, Herva´s A, Ramos-Quiroga JA, Bosch R, Bielsa A, Gastaminza X, et al. (2008). Association study of 10 genes encoding neurotrophic factors and their receptors in adult and child attention-deficit/hyperactivity disorder. Biol Psychiatry 63:935–945.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Family-based association study of ciliary neurotrophic factor receptor and norepinephrine transporter genes in attention-deficit hyperactivity disorder.

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