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Items: 10

1.
Brain Topogr. 2018 Jul 21. doi: 10.1007/s10548-018-0664-5. [Epub ahead of print]

Response Hand and Motor Set Differentially Modulate the Connectivity of Brain Pathways During Simple Uni-manual Motor Behavior.

Author information

1
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Suite 5A, Tolan Park Medical Building, 3901 Chrysler Service Drive, Detroit, MI, 48201, USA.
2
Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, USA.
3
Department of Psychology, Wayne State University, Detroit, USA.
4
Institute of Gerontology, Wayne State University, Detroit, USA.
5
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Suite 5A, Tolan Park Medical Building, 3901 Chrysler Service Drive, Detroit, MI, 48201, USA. vdiwadka@med.wayne.edu.

Abstract

We investigated the flexible modulation of undirected functional connectivity (uFC) of brain pathways during simple uni-manual responding. Two questions were central to our interests: (1) does response hand (dominant vs. non-dominant) differentially modulate connectivity and (2) are these effects related to responding under varying motor sets. fMRI data were acquired in twenty right-handed volunteers who responded with their right (dominant) or left (non-dominant) hand (blocked across acquisitions). Within acquisitions, the task oscillated between periodic responses (promoting the emergence of motor sets) or randomly induced responses (disrupting the emergence of motor sets). Conjunction analyses revealed eight shared nodes across response hand and condition, time series from which were analyzed. For right hand responses connectivity of the M1 ←→ Thalamus and SMA ←→ Parietal pathways was more significantly modulated during periodic responding. By comparison, for left hand responses, connectivity between five network pairs (including M1 and SMA, insula, basal ganglia, premotor cortex, parietal cortex, thalamus) was more significantly modulated during random responding. uFC analyses were complemented by directed FC based on multivariate autoregressive models of times series from the nodes. These results were complementary and highlighted significant modulation of dFC for SMA → Thalamus, SMA → M1, basal ganglia → Insula and basal ganglia → Thalamus. The results demonstrate complex effects of motor organization and task demand and response hand on different connectivity classes of fMRI data. The brain's sub-networks are flexibly modulated by factors related to motor organization and/or task demand, and our results have implications for assessment of medical conditions associated with motor dysfunction.

KEYWORDS:

Functional connectivity; Granger causality; Motor organization; Right-handers; Uni-manual responses; fMRI

2.
J Am Acad Child Adolesc Psychiatry. 2018 Mar;57(3):209-211.e2. doi: 10.1016/j.jaac.2018.01.013.

Mental Health in Syrian Refugee Children Resettling in the United States: War Trauma, Migration, and the Role of Parental Stress.

Author information

1
Wayne State University School of Medicine, Detroit, MI; University of Michigan, Ann Arbor. Electronic address: ajavanba@med.wayne.edu.
2
Wayne State University School of Medicine, Detroit, MI.

Publication type

Publication type

3.
Psychiatry Res Neuroimaging. 2017 Feb 28;260:6-15. doi: 10.1016/j.pscychresns.2016.12.005. Epub 2016 Dec 13.

Brain network dysfunction in youth with obsessive-compulsive disorder induced by simple uni-manual behavior: The role of the dorsal anterior cingulate cortex.

Author information

1
Dept. of Psychiatry & Behavioral Neurosciences, Wayne State University, Detroit, MI, USA.
2
Dept. of Psychiatry and Mathison Centre for Mental Health Research & Education, University of Calgary, Calgary, Alberta, Canada.
3
Dept. of Psychiatry, University of Michigan, Ann Arbor, MI, USA.

Abstract

In an effort to elucidate differences in functioning brain networks between youth with obsessive-compulsive disorder and controls, we used fMRI signals to analyze brain network interactions of the dorsal anterior cingulate cortex (dACC) during visually coordinated motor responses. Subjects made a uni-manual response to briefly presented probes, at periodic (allowing participants to maintain a "motor set") or random intervals (demanding reactive responses). Network interactions were assessed using psycho-physiological interaction (PPI), a basic model of functional connectivity evaluating modulatory effects of the dACC in the context of each task condition. Across conditions, OCD were characterized by hyper-modulation by the dACC, with loci alternatively observed as both condition-general and condition-specific. Thus, dynamically driven task demands during simple uni-manual motor control induce compensatory network interactions in cortical-thalamic regions in OCD. These findings support previous research in OCD showing compensatory network interactions during complex memory tasks, but establish that these network effects are observed during basic sensorimotor processing. Thus, these patterns of network dysfunction may in fact be independent of the complexity of tasks used to induce brain network activity. Hypothesis-driven approaches coupled with sophisticated network analyses are a highly valuable approach in using fMRI to uncover mechanisms in disorders like OCD.

PMID:
27992792
PMCID:
PMC5302006
DOI:
10.1016/j.pscychresns.2016.12.005
[Indexed for MEDLINE]
Free PMC Article
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4.
Psychiatry Res Neuroimaging. 2016 Dec 30;258:30-36. doi: 10.1016/j.pscychresns.2016.10.012. Epub 2016 Nov 4.

Distinct differences in striatal dysmorphology between attention deficit hyperactivity disorder boys with and without a comorbid reading disability.

Author information

1
Banner Alzheimer's Institute, Banner Health, Phoenix, AZ, USA.
2
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
3
Department of Radiology and Department of Neurology, University of Colorado, Denver, CO, USA.
4
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: jeffrey.stanley@wayne.edu.

Abstract

There is evidence of greater cognitive deficits in attention deficit hyperactivity disorder with a comorbid reading disability (ADHD/+RD) compared to ADHD alone (ADHD/-RD). Additionally, the striatum has been consistently implicated in ADHD. However, the extent of morphological alterations in the striatum of ADHD/+RD is poorly understood, which is the main purpose of this study. Based on structural MRI images, the surface deformation of the caudate and putamen was assessed in 59 boys matching in age and IQ [19 ADHD/-RD, 15 ADHD/+RD and 25 typically developing controls (TDC)]. A vertex based analysis with multiple comparison correction was conducted to compare ADHD/-RD and ADHD/+RD to TDC. Compared to TDC, ADHD/+RD showed multiple bilateral significant clusters of surface compression. In contrast, ADHD/-RD showed fewer significant clusters of surface compression and restricted to the left side. Regarding the putamen, only ADHD/-RD showed significant clusters of surface compression. Results demonstrate for the first time a greater extent of morphological alterations in the caudate of ADHD/+RD than ADHD/-RD compared to TDC, which may suggest greater implicated cortical areas projecting to the caudate that are associated with the greater neuropsychological impairments observed in ADHD/+RD.

KEYWORDS:

ADHD; Caudate; Learning disability; Magnetic resonance imaging; Putamen; Shape analysis

PMID:
27835798
PMCID:
PMC5135620
DOI:
10.1016/j.pscychresns.2016.10.012
[Indexed for MEDLINE]
Free PMC Article
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5.
J Neurodev Disord. 2016 Oct 18;8:36. doi: 10.1186/s11689-016-9170-9. eCollection 2016.

Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation.

Author information

1
The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
2
Department of Psychiatry and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
3
Mathison Centre for Mental Health Research and Education and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB Canada.
4
Faculty of Medicine, University of Toronto, Toronto, ON Canada.
5
Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI USA.
6
Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI USA.
7
The Children's Hospital of Michigan, Detroit, MI USA.
8
Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, St. Joseph's Healthcare, Hamilton, ON Canada.
9
Departments of Psychiatry and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB Canada.
10
Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, ON Canada.
#
Contributed equally

Abstract

BACKGROUND:

Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD.

METHODS:

We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD.

RESULTS:

We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal p = 1.85 × 10-03; FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1 and PTPRD), and postsynaptic scaffolding (DLGAP1 and DLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified BTBD9 as a candidate gene for OCD. We also sequenced exomes of ten "CNV positive" trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion in DRD4.

CONCLUSIONS:

Our findings suggest that rare CNVs may contribute to the etiology of OCD.

KEYWORDS:

Copy number variation; Obsessive-compulsive disorder; Pediatrics; Whole-exome sequencing

6.
J Dev Behav Pediatr. 2016 Jul-Aug;37(6):491-5. doi: 10.1097/DBP.0000000000000290.

Treatment Efficacy of Combined Sertraline and Guanfacine in Comorbid Obsessive-Compulsive Disorder and Attention Deficit/Hyperactivity Disorder: Two Case Studies.

Author information

1
*Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI; †Department of Psychiatry, Children's Hospital of Michigan, Detroit, MI; ‡Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI.

Abstract

OBJECTIVE:

Treatment of obsessive-compulsive disorder (OCD) is complicated by comorbid psychiatric disorders. Successful treatment of 2 pediatric patients with severe OCD and comorbid attention deficit/hyperactivity disorder (ADHD) is described.

METHOD:

A report on 2 pediatric clinical cases (Ages 9 and 10) with comorbid OCD and ADHD was used to describe response to medication management through the serotonin transporter inhibitor, sertraline, and the noradrenergic α2A receptor agonist, guanfacine, along with cognitive behavioral therapy.

RESULTS:

Cognitive behavioral therapy combined with titrated doses of the serotonin transporter inhibitor, sertraline, and the noradrenergic α2A receptor agonist, guanfacine resolved OCD symptoms and the underlying ADHD.

CONCLUSION:

The novel observations support a focused psychological and pharmacological approach to successful treatment of complex symptoms in patients with comorbid OCD and ADHD. Limitations to generalizability are discussed.

PMID:
27011005
PMCID:
PMC4930387
DOI:
10.1097/DBP.0000000000000290
[Indexed for MEDLINE]
Free PMC Article
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7.
Brain Cogn. 2015 Oct;99:1-7. doi: 10.1016/j.bandc.2015.04.009. Epub 2015 Jul 16.

Neural dysfunction in ADHD with Reading Disability during a word rhyming Continuous Performance Task.

Author information

1
Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: bmohl@med.wayne.edu.
2
Institute of Gerontology and Department of Pediatrics, Wayne State University, Detroit, MI, USA. Electronic address: noa.ofen@wayne.edu.
3
Psychology, Wayne State University, Detroit, MI, USA. Electronic address: larajones@wayne.edu.
4
Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: arobin@med.wayne.edu.
5
Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: drosen@med.wayne.edu.
6
Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: vdiwadka@med.wayne.edu.
7
Psychology, University of Windsor, Windsor, ON, Canada. Electronic address: jecasey@uwindsor.ca.
8
Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: jeffrey.stanley@med.wayne.edu.

Abstract

BACKGROUND:

Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous, neurodevelopmental disorder which co-occurs often with Reading Disability (RD). ADHD with and without RD consistently have higher inattentive ratings compared with typically developing controls, with co-occurring ADHD and RD also demonstrating impaired phonological processing. Accordingly, inattention has been associated with greater phonological impairment, though the neural correlates of the association are poorly understood from a functional neuroimaging perspective. It was postulated that only the co-occurring subgroup would demonstrate hypoactivation of posterior, left hemispheric, reading-related areas and, to a lesser extent, alterations in right hemispheric, attention areas compared with controls.

METHODS:

A novel word rhyming Continuous Performance Task assesses functional activation differences in phonology- and attention-related areas between three groups: ten boys with ADHD and RD, fourteen boys with ADHD without RD, and fourteen typically developing controls. Subjects respond to words that rhyme with a target word as mono- and disyllabic, English words are visually presented over 90s blocks.

RESULTS:

Behavioral performance was not different between groups. Some hypoactivation of left hemispheric, reading-related areas was apparent in ADHD and RD, but not ADHD without RD, compared with controls. Right hemispheric, attention areas showed alterations in both ADHD subgroups relative to controls; however, the differences for each subgroup were dissimilar.

CONCLUSIONS:

The dorsal decoding subnetwork may not be grossly compromised in ADHD with Reading Disability. The role of cognitive impairments, including the level of inattention, on phonology requires clarification from a neuroimaging perspective.

KEYWORDS:

ADHD; Attention; CPT; Phonology; Reading disability; Rhyming

PMID:
26188845
DOI:
10.1016/j.bandc.2015.04.009
[Indexed for MEDLINE]
Icon for Elsevier Science
8.
Front Hum Neurosci. 2015 Mar 17;9:149. doi: 10.3389/fnhum.2015.00149. eCollection 2015.

Dysfunctional Activation and Brain Network Profiles in Youth with Obsessive-Compulsive Disorder: A Focus on the Dorsal Anterior Cingulate during Working Memory.

Author information

1
Department of Psychiatry and Behavioral Neurosciences, Brain Imaging Research Division, Wayne State University School of Medicine , Detroit, MI , USA.
2
Department of Psychiatry, Hospital for Sick Children, University of Toronto , Toronto, ON , Canada.
3
Department of Psychiatry, University of Michigan , Ann Arbor, MI , USA.

Abstract

Brain network dysfunction is emerging as a central biomarker of interest in psychiatry, in large part, because psychiatric conditions are increasingly seen as disconnection syndromes. Understanding dysfunctional brain network profiles in task-active states provides important information on network engagement in an experimental context. This in turn may be predictive of many of the cognitive and behavioral deficits associated with complex behavioral phenotypes. Here we investigated brain network profiles in youth with obsessive-compulsive disorder (OCD), contrasting them with a group of age-comparable controls. Network interactions were assessed during simple working memory: in particular, we focused on the modulation by the dorsal anterior cingulate cortex (dACC) of cortical, striatal, and thalamic regions. The focus on the dACC was motivated by its hypothesized role in the pathophysiology of OCD. However, its task-active network signatures have not been investigated before. Network interactions were modeled using psychophysiological interaction, a simple directional model of seed to target brain interactions. Our results indicate that OCD is characterized by significantly increased dACC modulation of cortical, striatal, and thalamic targets during working memory, and that this aberrant increase in OCD patients is maintained regardless of working memory demand. The results constitute compelling evidence of dysfunctional brain network interactions in OCD and suggest that these interactions may be related to a combination of network inefficiencies and dACC hyper-activity that has been associated with the phenotype.

KEYWORDS:

dorsal anterior cingulate cortex; fMRI; network analysis; obsessive-compulsive disorder; working memory

9.
Soc Cogn Affect Neurosci. 2015 Nov;10(11):1460-8. doi: 10.1093/scan/nsv030. Epub 2015 Apr 2.

Altered amygdala connectivity in urban youth exposed to trauma.

Author information

1
Merrill Palmer Skillman Institute for Child and Family Development, Wayne State University, Department of Pediatrics, Wayne State University School of Medicine, Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, moriah@wayne.edu.
2
Merrill Palmer Skillman Institute for Child and Family Development, Wayne State University, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, and.
3
Wayne State University School of Medicine, Detroit, MI 48202, USA.
4
Merrill Palmer Skillman Institute for Child and Family Development, Wayne State University.
5
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, and.

Abstract

Early life trauma exposure represents a potent risk factor for the development of mental illnesses such as anxiety, depression and post-traumatic stress disorder. Moreover, deleterious consequences of trauma are exacerbated in youth living in impoverished, urban environments. A priori probability maps were used to examine resting-state functional connectivity (FC) of the amygdala in 21 trauma-exposed, and 21 age- and sex-matched urban children and adolescents (youth) without histories of trauma. Intrinsic FC analyses focused on amygdala-medial prefrontal circuitry, a key emotion regulatory pathway in the brain. We discovered reduced negative amygdala-subgenual cingulate connectivity in trauma-exposed youth. Differences between groups were also identified in anterior insula and dorsal anterior cingulate to amygdala connectivity. Overall, results suggest a model in which urban-dwelling trauma-exposed youth lack negative prefrontal to amygdala connectivity that may be critical for regulation of emotional responses. Functional changes in amygdala circuitry might reflect the biological embedding of stress reactivity in early life and mediate enhanced vulnerability to stress-related psychopathology.

KEYWORDS:

adolescent; child; maltreatment; resting-state; urban

PMID:
25836993
PMCID:
PMC4631140
DOI:
10.1093/scan/nsv030
[Indexed for MEDLINE]
Free PMC Article
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10.
J Am Acad Child Adolesc Psychiatry. 2014 Aug;53(8):910-9. doi: 10.1016/j.jaac.2014.04.022. Epub 2014 Jun 24.

Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study.

McGrath LM1, Yu D2, Marshall C3, Davis LK4, Thiruvahindrapuram B3, Li B3, Cappi C5, Gerber G6, Wolf A6, Schroeder FA6, Osiecki L6, O'Dushlaine C7, Kirby A6, Illmann C6, Haddad S6, Gallagher P6, Fagerness JA6, Barr CL8, Bellodi L9, Benarroch F10, Bienvenu OJ11, Black DW12, Bloch MH13, Bruun RD14, Budman CL15, Camarena B16, Cath DC17, Cavallini MC18, Chouinard S19, Coric V13, Cullen B11, Delorme R20, Denys D21, Derks EM22, Dion Y19, Rosário MC23, Eapen V24, Evans P4, Falkai P25, Fernandez TV13, Garrido H26, Geller D6, Grabe HJ27, Grados MA11, Greenberg BD28, Gross-Tsur V29, Grünblatt E30, Heiman GA31, Hemmings SM32, Herrera LD33, Hounie AG23, Jankovic J34, Kennedy JL35, King RA13, Kurlan R36, Lanzagorta N37, Leboyer M38, Leckman JF13, Lennertz L39, Lochner C32, Lowe TL40, Lyon GJ41, Macciardi F42, Maier W39, McCracken JT43, McMahon W44, Murphy DL45, Naarden AL46, Neale BM2, Nurmi E43, Pakstis AJ13, Pato MT47, Pato CN47, Piacentini J43, Pittenger C13, Pollak Y29, Reus VI40, Richter MA48, Riddle M11, Robertson MM49, Rosenberg D50, Rouleau GA51, Ruhrmann S52, Sampaio AS53, Samuels J11, Sandor P8, Sheppard B40, Singer HS11, Smit JH54, Stein DJ55, Tischfield JA31, Vallada H5, Veenstra-VanderWeele J56, Walitza S57, Wang Y11, Wendland JR45, Shugart YY45, Miguel EC5, Nicolini H37, Oostra BA58, Moessner R39, Wagner M39, Ruiz-Linares A49, Heutink P59, Nestadt G11, Freimer N60, Petryshen T2, Posthuma D61, Jenike MA6, Cox NJ4, Hanna GL62, Brentani H5, Scherer SW3, Arnold PD3, Stewart SE63, Mathews CA40, Knowles JA47, Cook EH64, Pauls DL6, Wang K47, Scharf JM65.

Author information

1
Massachusetts General Hospital, Boston; American University, Washington, DC; Harvard-MIT Broad Institute, Boston.
2
Massachusetts General Hospital, Boston; Harvard-MIT Broad Institute, Boston.
3
University of Toronto and the Hospital for Sick Children, Toronto.
4
University of Chicago.
5
University of São Paulo Medical School.
6
Massachusetts General Hospital, Boston.
7
Harvard-MIT Broad Institute, Boston.
8
University of Toronto and the Hospital for Sick Children, Toronto; Toronto Western Research Institute, University Health Network, Toronto.
9
Università Vita-Salute San Raffaele, Milan.
10
Hadassah-Hebrew University Medical Center, Jerusalem.
11
Johns Hopkins University School of Medicine, Baltimore.
12
University of Iowa College of Medicine, Iowa City.
13
Yale University School of Medicine, New Haven, CT.
14
North Shore-Long Island Jewish Medical Center, New Hyde Park, NY; New York University Medical Center, New York.
15
North Shore-Long Island Jewish Medical Center, New Hyde Park, NY; Hofstra University School of Medicine, Hempstead, NY.
16
Instituto Nacional de Psiquiatría Ramon de la Fuente Muñiz, Mexico.
17
Utrecht University and VU Medical Center, Amsterdam.
18
Ospedale San Raffaele, Milan.
19
University of Montreal.
20
Robert Debre University Hospital, Paris and the French National Science Foundation, Creteil, France; Institut Pasteur, Paris.
21
Netherlands Institute for Neuroscience, Amsterdam; Academic Medical Center, Amsterdam.
22
Academic Medical Center, Amsterdam.
23
Federal University of São Paulo.
24
University of New South Wales, Australia.
25
University of Munich.
26
Hospital Nacional de Niños, San Jose, Costa Rica; Clinica Herrera Amighetti, Avenida Escazú, San José, Costa Rica.
27
University Medicine Greifswald, Greifswald, Germany.
28
Brown Medical School, Providence, RI.
29
Shaare Zedek Medical Center, Jerusalem.
30
University of Zurich.
31
Rutgers University, Piscataway Township, NJ.
32
University of Stellenbosch, South Africa.
33
Hospital Nacional de Niños, San Jose, Costa Rica.
34
Baylor College of Medicine, Houston.
35
Centre for Addiction and Mental Health, Toronto.
36
Atlantic Neuroscience Institute, Summit, NJ.
37
Carracci Medical Group, Mexico City.
38
Robert Debre University Hospital, Paris and the French National Science Foundation, Creteil, France; Institut Mondor de Recherche Biomédicale, Créteil, France.
39
University of Bonn, Germany.
40
University of California at San Francisco School of Medicine.
41
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
42
University of California, Irvine.
43
University of California, Los Angeles (UCLA) School of Medicine.
44
University of Utah, Salt Lake City.
45
National Institute of Mental Health (NIMH) Intramural Research Program, Bethesda, MD.
46
Medical City Dallas Hospital.
47
Zilkha Neurogenetic Institute, Los Angeles.
48
University of Toronto and the Hospital for Sick Children, Toronto; Sunnybrook Health Sciences Centre, Toronto.
49
University College London.
50
Wayne State University and Detroit Medical Center, Detroit.
51
Montreal Neurological Institute.
52
University of Cologne, Germany.
53
Federal University of São Paulo; Universidade Federal da Bahia, Salvador, Bahia, Brazil.
54
VU Amsterdam and Erasmus University Medical Centre, Rotterdam; VU University Amsterdam; VU Medical Center, Amsterdam.
55
University of Cape Town, South Africa.
56
Vanderbilt University, Nashville, TN.
57
University of Zurich; University of Würzburg.
58
Erasmus Medical Center Rotterdam, the Netherlands.
59
German Center for Neurodegenerative Diseases, Bonn and VU Medical Center Amsterdam.
60
University of California, Los Angeles (UCLA) School of Medicine; Semel Institute for Neuroscience and Human Behavior, UCLA.
61
VU Amsterdam and Erasmus University Medical Centre, Rotterdam.
62
University of Michigan, Ann Arbor, MI.
63
Massachusetts General Hospital, Boston; University of British Columbia, Vancouver.
64
University of Illinois at Chicago.
65
Massachusetts General Hospital, Boston; Brigham and Womens Hospital, Boston; Harvard-MIT Broad Institute, Boston. Electronic address: jscharf@partners.org.

Abstract

OBJECTIVE:

Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date.

METHOD:

The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios.

RESULTS:

Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%).

CONCLUSION:

Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.

KEYWORDS:

16p13.11; Tourette syndrome; copy number variation; genetics; obsessive-compulsive disorder

PMID:
25062598
PMCID:
PMC4218748
DOI:
10.1016/j.jaac.2014.04.022
[Indexed for MEDLINE]
Free PMC Article
Icon for Elsevier Science Icon for PubMed Central

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