Browsing by Author "Van Den Heuvel, Odile A."
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- ItemConcordance of genetic variation that increases risk for Tourette Syndrome and that influences its underlying neurocircuitry(Springer Nature, 2019) Mufford, Mary; Cheung, Josh; Jahanshad, Neda; Van Der Merwe, Celia; Ding, Linda; Groenewold, Nynke; Koen, Nastassja; Chimusa, Emile R.; Dalvie, Shareefa; Ramesar, Raj; Knowles, James A.; Lochner, Christine; Hibar, Derrek P.; Paschou, Peristera; Van Den Heuvel, Odile A.; Medland, Sarah E.; Scharf, Jeremiah M.; Mathews, Carol A.; Thompson, Paul M.; Stein, Dan J.; Psychiatric Genomics Consortium - Tourette Syndrome working groupENGLISH ABSTRACT: There have been considerable recent advances in understanding the genetic architecture of Tourette Syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variation that increases risk for TS—and its main symptom dimensions—influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS. We obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4644 cases and 8695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP effect concordance analysis (SECA) was used to examine genetic pleiotropy—the same SNP affecting two traits—and concordance—the agreement in single nucelotide polymorphism (SNP) effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage disequilibrium score regression (LDSR) was used as validation of the SECA method. SECA revealed significant pleiotropy between TS and putamen (p = 2 × 10−4) and caudate (p = 4 × 10−4) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p = 1 × 10−3). LDSR lent additional support for the association between TS and thalamus volume (p = 5.85 × 10−2). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamus volume (p = 1 × 10−3), as well as concordance between symmetry behaviour and greater putamen volume (p = 7 × 10−4). Conditional FDR analysis further revealed novel variants significantly associated with TS (p < 8 × 10−7) when conditioning on intracranial (rs2708146, q = 0.046; and rs72853320, q = 0.035) and hippocampal (rs1922786, q = 0.001) volumes, respectively. These data indicate concordance for genetic variation involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.
- ItemToward identifying reproducible brain signatures of obsessive-compulsive profiles : rationale and methods for a new global initiative(BMC (part of Springer Nature), 2020-02-14) Simpson, Helen Blair; Van Den Heuvel, Odile A.; Miguel, Euripedes C.; Reddy, Y. C. J.; Stein, Dan J.; Lewis-Fernandez, Roberto; Shavitt, Roseli Gedanke; Lochner, Christine; Pouwels, Petra J. W.; Narayanawamy, Janardhanan C.; Venkatasubramanian, Ganesan; Hezel, Dianne M.; Vriend, Chris; Batistuzzo, Marcelo C.; Hoexter, Marcelo Q.; De Joode, Niels T.; Costa, Daniel Lucas; De Mathis, Maria Alice; Sheshachala, Karthik; Narayan, Madhuri; Van Balkom, Anton J. L. M.; Batelaan, Neeltje M.; Venkataram, Shivakumar; Cherian, Anish; Marincowitz, Clara; Pannekoek, Nienke; Stovezky, Yael R.; Mare, Karen; Liu, Feng; Otaduy, Maria Concepcion Garcia; Pastorello, Bruno; Rao, Rashmi; Katechis, Martha; Van Meter, Page; Wall, MelanieBackground: Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2–3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results. Methods: We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations. Discussion: Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it. Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2–3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results. Methods We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations. Discussion Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it.