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Family-Based Genome-Wide Association Scan of Attention-Deficit/Hyperactivity Disorder

https://doi.org/10.1016/j.jaac.2010.02.014Get rights and content

Objective

Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD.

Method

Families were ascertained at Massachusetts General Hospital (MGH; N = 309 trios), Washington University at St. Louis (WASH-U; N = 272 trios), and University of California at Los Angeles (UCLA; N = 156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families.

Results

Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p = 6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9.

Conclusions

We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders.

Section snippets

Subjects

Families were ascertained at Massachusetts General Hospital (MGH; N = 309 trios), Washington University at St Louis (WASH-U; N = 272 trios), and University of California at Los Angeles (UCLA; N = 156 trios). Children were 6 to 17 years of age at initial assessment and met criteria for DSM-IV-TR ADHD. All study procedures were reviewed and approved by the subcommittee for human subjects of each respective institution. All subjects' parents or guardians signed written informed consent forms and

Results

After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV-TR ADHD trios from 732 families; clinical demographics of the sample are presented in Table 2. Subjects recruited at WASH-U were older (p < .001) and more likely to be diagnosed with predominantly inattentive ADHD (p < .001) compared with both the MGH and the UCLA samples. Subjects recruited at UCLA were less likely to be Caucasian compared with both the MGH and WASH-U samples (p < .001).

Discussion

We failed to identify any statistically significant genome-wide findings, but we found some additional evidence for a role of SLC9A9 in the etiology of ADHD. SLC9A9 codes a hydrogen/sodium exchanger located in the membranes of subcellular structures and is expressed in the brain, heart and skeletal muscle, placenta, kidney, and liver.18 SLC9A9 was first identified at a break point in a family in which ADHD symptoms were correlated with a chromosome 3 inversion.18 It was also associated with

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  • Cited by (0)

    This article was reviewed under and accepted by Ad Hoc Editor James F. Leckman, M.D.

    Genotyping was conducted by Genizon BioSciences Inc. with the financial support of Pfizer Inc. Subject ascertainment and assessment was supported by the following sources: National Institutes of Health (NIH) grants R13MH059126, R01MH62873, U01MH085518 and R01MH081803 to S.V.Faraone; National Institute of Neurological Disorders and Stroke (NINDS) grant NS054124 S. Loo; National Institute of Mental Health (NIMH) grant MH01966 to J. McGough; National Institute on Drug Abuse (NIDA) grant K24 DA016264 to T. Wilens; NIMH grant MH63706 to S. Smalley; and NIMH grants K08MH001503 and R01MH066237 to J. Wozniak.

    This article is one of several articles published in the August and September issues of the Journal of the American Academy of Child and Adolescent Psychiatry that explores the intersection of genetics and mental health disorders in children and adolescents. The editors invite the reader to investigate the additional articles on this burgeoning area of developmental psychopathology.

    Disclosure: Dr. Mick receives research support from Ortho-McNeil Janssen Scientific Affairs, Pfizer, Shire Pharmaceuticals, and has served on the advisory board for Shire Pharmaceuticals.

    Dr. Biederman receives research support from Alza, AstraZeneca, Bristol Myers Squibb, Eli Lilly and Co., Janssen Pharmaceuticals Inc., McNeil, Merck, Organon, Otsuka, Shire, the National Institute of Mental Health (NIMH), and the National Institute of Child Health and Human Development (NICHD). He has served on the speakers' bureau for Fundacion Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association. In previous years, Dr. Biederman received research support, consultation fees, or speaker's fees for/from Abbott, AstraZeneca, Celltech, Cephalon, Eli Lilly and Co., Esai, Forest, Glaxo, Gliatech, Janssen, McNeil, NARSAD, National Institute on Drug Abuse (NIDA), New River, Novartis, Noven, Neurosearch, Pfizer, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma, Inc., and Wyeth.

    Dr. McCracken has received research support from Bristol-Myers Squibb, Aspect, and Seaside Pharmaceuticals. He has served as a consultant to Novopharm and BioMarin, and has received speaker honoraria from the Tourette Syndrome Association, Veritas, and CME Outfitters.

    Dr. McGough has served as a consultant to and received research support and consulting honoraria from Eli Lilly and Co. and Shire Pharmaceuticals.

    Dr. Wilens has received grant support from Abbott, McNeil, Eli Lilly and Co., the National Institutes of Health (NIH), the National Institute on Drug Abuse (NIDA), Merck, and Shire. He has served on the speakers' bureaus for Eli Lilly and Co., McNeil, Novartis, and Shire. He has served as a consultant for Abbott, AstraZeneca, McNeil, Eli Lilly and Co., the NIH/NIDA, Novartis, Merck, and Shire. Dr. Wilens receives royalties from Guilford Press for his book, Straight Talk About Psychiatric Medications for Kids.

    Dr. Wozniak receives royalties from Bantam Books for her book, Is Your Child Bipolar? Dr. Wozniak has served on the speakers' bureau for McNeil, Primedia/Massachusetts General Hospital (MGH), Psychiatry Academy, and Eli Lilly and Co. Dr. Wozniak is on the advisory board and has served as a consultant for Pfizer and Shire. She receives research support from McNeil, Shire, and Eli Lilly and Co.

    Dr. Faraone has, in the past year, received consulting fees and has been on advisory boards for Eli Lilly and Co., Ortho-McNeil and Shire Development and has received research support from Eli Lilly and Co., Pfizer, Shire and the National Institutes of Health. In previous years, Dr. Faraone has received consulting fees or has been on Advisory Boards or has been a speaker for Shire, McNeil, Janssen, Novartis, Pfizer and Eli Lilly and Co. In previous years he has received research support from Eli Lilly and Co., Shire, Pfizer, and the National Institutes of Health.

    Drs. Todorov, Smalley, Hu, Loo, Todd (deceased), Dechairo, Nelson, Reiersen, Neale, and Ms. Byrne, and Mr. Guiney report no biomedical financial interests or potential conflicts of interest.

    This article is discussed in an editorial by Drs. James J. Hudziak and Stephen V. Faraone on page 729 of the August 2010 issue.

    Supplemental material cited in this article is available online.

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