title: Genetic neuropathology of obsessive psychiatric syndromes.
abstract: Anorexia nervosa (AN), bulimia nervosa (BN) and obsessive-compulsive disorder (OCD) are complex psychiatric disorders with shared obsessive features, thought to arise from the interaction of multiple genes of small effect with environmental factors. Potential candidate genes for AN, BN and OCD have been identified through clinical association and neuroimaging studies; however, recent genome-wide association studies of eating disorders (ED) so far have failed to report significant findings. In addition, few, if any, studies have interrogated postmortem brain tissue for evidence of expression quantitative trait loci (eQTLs) associated with candidate genes, which has particular promise as an approach to elucidating molecular mechanisms of association. We therefore selected single-nucleotide polymorphisms (SNPs) based on candidate gene studies for AN, BN and OCD from the literature, and examined the association of these SNPs with gene expression across the lifespan in prefrontal cortex of a nonpsychiatric control cohort (N=268). Several risk-predisposing SNPs were significantly associated with gene expression among control subjects. We then measured gene expression in the prefrontal cortex of cases previously diagnosed with obsessive psychiatric disorders, for example, ED (N=15) and OCD/obsessive-compulsive personality disorder or tics (OCD/OCPD/Tic; N=16), and nonpsychiatric controls (N=102) and identified 6 and 286 genes that were differentially expressed between ED compared with controls and OCD cases compared with controls, respectively (false discovery rate (FDR) <5%). However, none of the clinical risk SNPs were among the eQTLs and none were significantly associated with gene expression within the broad obsessive cohort, suggesting larger sample sizes or other brain regions may be required to identify candidate molecular mechanisms of clinical association in postmortem brain data sets.
authors.affiliation: Division of Clinical Sciences, Lieber Institute for Brain Development, Baltimore, MD, USA.
authors.forename: A E
authors.identifier: 0000000168861454
authors.initials: AE
authors.lastname: Jaffe
authors.affiliation: Division of Clinical Sciences, Lieber Institute for Brain Development, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Deep-Soboslay
authors.affiliation: Division of Clinical Sciences, Lieber Institute for Brain Development, Baltimore, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Tao
authors.affiliation: Section on Neuropathology, Clinical Brain Disorders Branch, NIMH, NIH, Bethesda, MD, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Hauptman
authors.affiliation: University of California, San Diego Eating Disorder Treatment and Research Program, San Diego, CA, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Kaye
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA.
authors.forename: V
authors.initials: V
authors.lastname: Arango
authors.affiliation: 1] Division of Clinical Sciences, Lieber Institute for Brain Development, Baltimore, MD, USA [2] Departments of Psychiatry, Neurology, Neuroscience and the Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: 1] Division of Clinical Sciences, Lieber Institute for Brain Development, Baltimore, MD, USA [2] Section on Neuropathology, Clinical Brain Disorders Branch, NIMH, NIH, Bethesda, MD, USA [3] Departments of Psychiatry, Neurology, Neuroscience and the Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: 1] Division of Clinical Sciences, Lieber Institute for Brain Development, Baltimore, MD, USA [2] Section on Neuropathology, Clinical Brain Disorders Branch, NIMH, NIH, Bethesda, MD, USA [3] Departments of Psychiatry, Neurology, Neuroscience and the Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Kleinman
mesh_terms: D000293:Adolescent; D000328:Adult; D000856:Anorexia Nervosa / Q000235:genetics* / Q000473:pathology*; D052018:Bulimia Nervosa / Q000235:genetics* / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009771:Obsessive-Compulsive Disorder / Q000235:genetics* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000473:pathology; D040641:Quantitative Trait Loci / Q000235:genetics; D012016:Reference Values; D013981:Tic Disorders / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult