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Genome-wide association study of blood pressure response to methylphenidate treatment of attention-deficit/hyperactivity disorder
Authors:Mick Eric  McGough James J  Middleton Frank A  Neale Benjamin  Faraone Stephen V
Affiliation:
  • a Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School; 55 Fruit St - Warren 705, Boston, MA 02114, United States
  • b UCLA Semel Institute for Neuroscience & Human Behavior; 300 UCLA Medical Plaza - Suite 1414, Los Angeles, CA 90095, United States
  • c Departments of Psychiatry and Neuroscience & Physiology, SUNY Upstate Medical University; 750 East Adams St, Syracuse, NY 13210, United States
  • d Center for Human Genetic Research, Massachusetts General Hospital; 185 Cambridge St - CPZN, Boston, MA 02114, United States
  • e The Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, MA 02142, United States
    		•
    Abstract:

    Objective

    We conducted a genome-wide association study of blood pressure in an open-label study of the methylphenidate transdermal system (MTS) for the treatment of attention-deficit/hyperactivity disorder (ADHD).

    Method

    Genotyping was conducted with the Affymetrix Genome-Wide Human SNP Array 6.0. Multivariate association analyses were conducted using the software package PLINK. After data cleaning and quality control we tested 316,934 SNPs in 140 children with ADHD.

    Results

    We observed no genome-wide statistically significant findings, but a SNP in a K+-dependent Na+/Ca2+ exchanger expressed in vascular smooth muscle (SLC24A3) was included in our top associations at p < 1E-04. Genetic enrichment analyses of genes with ≥ 1 SNP significant at p < 0.01, implicated several functional categories (FERM domain, p = 5.0E-07; immunoglobulin domain, p = 8.1E-06; the transmembrane region, p = 4.4E-05; channel activity, p = 2.0E-04; and type-III fibronectins, p = 2.7E-05) harboring genes previously associated with related cardiovascular phenotypes.

    Conclusions

    The hypothesis generating results from this study suggests that polymorphisms in several genes consistently associated with cardiovascular diseases may impact changes in blood pressure observed with methylphenidate pharmacotherapy in children with ADHD.
    Keywords:ADHD, attention-deficit/hyperactivity disorder   MTS, methylphenidate transdermal system   SNP, Single Nucleotide Polymorphism   FERM, Protein 4.1, Ezrin, Radixin, Moesin   bpm, beats per minute   bp, Base Paur   VNTR, Variable Number Tandem Repeat   DSM-IV-TR, Diagnostic and Statistical Manual for Mental Disorders-IV-Text Revision   ADHD-RS-IV, ADHD Rating Scale-IV   BMI, Body Mass Index   CNS, Central Nervous System   HWE, Hardy-Weinberg Equilibrium   SD, Standard Deviation   MDS, multi-dimensional scaling   DAVID, Database for Annotation, Visualization and Integrated Discovery   UTR, Untranslated Region   EASE, Expression Analysis Systematic Explorer   GWAS, genome-wide association study   MAF, Minor Allele Frequency
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