title: Whole-genome association analysis of treatment response in obsessive-compulsive disorder.
abstract: Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.
authors.affiliation: Unit on Statistical Genomics, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Qin
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Samuels
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Epidemiology, Tulane University, School of Public Health and Tropical Medicine, New Orleans, LA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Grados
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Riddle
authors.affiliation: Department of Psychiatry and Human Behavior, Brown Medical School, Butler Hospital, Brown University, Providence, RI, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Greenberg
authors.affiliation: Department of Psychiatry, Keck Medical School, University of Southern California, Los Angeles, CA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Knowles
authors.affiliation: College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Fyer
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: McCracken
authors.affiliation: Laboratory of Clinical Science, NIMH, NIH, Bethesda, MD, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Murphy
authors.affiliation: Department of Psychiatry and Human Behavior, Brown Medical School, Butler Hospital, Brown University, Providence, RI, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Rasmussen
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Cullen
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Piacentini
authors.affiliation: Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Geller
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
authors.forename: S E
authors.initials: SE
authors.lastname: Stewart
authors.affiliation: Department of Psychiatry and Human Behavior, Brown Medical School, Butler Hospital, Brown University, Providence, RI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Pauls
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: O J
authors.initials: OJ
authors.lastname: Bienvenu
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: F S
authors.initials: FS
authors.lastname: Goes
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: B
authors.initials: B
authors.lastname: Maher
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Pulver
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Molecular Biology & Genetics, Johns Hopkins University School of Medicine, Institute of Human Genetics, Baltimore, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Valle
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.|Department of Genomic Mathematics, University of Bonn, Bonn, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Lange
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.|Department of Genomic Mathematics, University of Bonn, Bonn, Germany.|Department of Biomedicine and Center for Integrated Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.
authors.forename: M
authors.identifier: http://orcid.org/0000-0002-8442-493X
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: N C
authors.initials: NC
authors.lastname: McLaughlin
authors.affiliation: Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: K-Y
authors.initials: KY
authors.lastname: Liang
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Jane and Terry Semel Institute of Neuroscience and Human Behavior, Los Angeles, CA, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Nurmi
authors.affiliation: Department of Psychiatry and Human Behavior, Butler Hospital, Warren Alpert School of Medicine of Brown University, Providence, RI, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Askland
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Nestadt
authors.affiliation: Unit on Statistical Genomics, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Shugart
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009771:Obsessive-Compulsive Disorder / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D057566:Self Report; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D008565:Membrane Proteins; D017367:Selective Serotonin Reuptake Inhibitors
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