Genome-wide association study of response to methylphenidate in 187 children with attention-deficit/hyperactivity disorder.
We conducted a genome-wide association study of symptom response in an open-label study of a methylphenidate transdermal system (MTS). All DNA extraction and genotyping was conducted at SUNY Upstate Medical University using the Affymetrix Genome-Wide Human SNP Array 6.0. All quality control and association analyses were conducted using the software package PLINK. After data cleaning and quality control, there were 187 subjects (72% (N = 135) male) with mean age 9.2 +/- 2.0 years and 319,722 SNPs available for analysis. The most statistically significant association (rs9627183 and rs11134178; P = 3 x 10(-6)) fell short of the threshold for a genome-wide significant association. The most intriguing association among suggestive findings (rs3792452; P = 2.6 x 10(-5)) was with the metabotropic glutamate receptor 7 gene (GRM7) as it is expressed in brain structures also previously associated with ADHD. Among the 102 available SNPs covering previously studied candidate genes, two SNPs within the norepinephrine transporter gene (NET, SLC6A2) were significant at P < or = 1 x 10(-2). These results should be considered preliminary until replicated in larger adequately powered, controlled samples but do suggest that noradrenergic and possibly glutaminergic genes may be involved with response to methylphenidate.
Mick
Eric
E
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. mick@helix.mgh.harvard.edu
Neale
Benjamin
B
Middleton
Frank A
FA
McGough
James J
JJ
Faraone
Stephen V
SV
D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000494:pharmacology*; D016009:Chi-Square Distribution; D002648:Child; D017327:Clinical Trials, Phase IV as Topic; D004247:DNA / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005819:Genetic Markers; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000009:adverse effects / Q000494:pharmacology*; D015337:Multicenter Studies as Topic; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics; D021141:Nucleic Acid Amplification Techniques; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics
D000697:Central Nervous System Stimulants; D005819:Genetic Markers; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018094:Receptors, Metabotropic Glutamate; C493227:SLC6A2 protein, human; C102719:metabotropic glutamate receptor 7; D008774:Methylphenidate; D004247:DNA