Browsing by Author "Koen, Nastassja"

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    Concordance 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 group
    ENGLISH 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.
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    International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci
    (Nature Research (part of Springer Nature), 2019) Nievergelt, Caroline M.; Maihofer, Adam X.; Klengel, Torsten; Atkinson, Elizabeth G.; Chen, Chia-Yen; Choi, Karmel W.; Coleman, Jonathan R. I.; Dalvie, Shareefa; Duncan, Laramie E.; Gelernter, Joel; Levey, Daniel F.; Logue, Mark W.; Polimanti, Renato; Provost, Allison C.; Ratanatharathorn, Andrew; Stein, Murray B.; Torres, Katy; Aiello, Allison E.; Almli, Lynn M.; Amstadter, Ananda B.; Andersen, Soren B.; Andreassen, Ole A.; Arbisi, Paul A.; Ashley-Koch, Allison E.; Austin, S. Bryn; Avdibegovic, Esmina; Babic, Dragan; Bækvad-Hansen, Marie; Baker, Dewleen G.; Beckham, Jean C.; Bierut, Laura J.; Bisson, Jonathan I.; Boks, Marco P.; Bolger, Elizabeth A.; Borglum, Anders D.; Bradley, Bekh; Brashear, Megan; Breen, Gerome; Bryant, Richard A.; Bustamante, Angela C.; Bybjerg-Grauholm, Jonas; Calabrese, Joseph R.; Caldas-de-Almeida, Jose M.; Dale, Anders M.; Daly, Mark J.; Daskalakis, Nikolaos P.; Deckert, Jurgen; Delahanty, Douglas L.; Dennis, Michelle F.; Disner, Seth G.; Domschke, Katharina; Dzubur-Kulenovic, Alma; Erbes, Christopher R.; Evans, Alexandra; Farrer, Lindsay A.; Feeny, Norah C.; Flory, Janine D.; Forbes, David; Franz, Carol E.; Galea, Sandro; Garrett, Melanie E.; Gelaye, Bizu; Geuze, Elbert; Gillespie, Charles; Uka, Aferdita Goci; Goci, Aferdita; Guffanti, Guia; Hammamieh, Rasha; Harnal, Supriya; Hauser, Michael A.; Heath, Andrew C.; Hemmings, Sian M. J.; Hougaard, David Michael; Jakovljevic, Miro; Jett, Marti; Johnson, Eric Otto; Jones, Ian; Jovanovic, Tanja; Qin, Xue-Jun; Junglen, Angela G.; Karstoft, Karen-Inge; Kaufman, Milissa L.; Kessler, Ronald C.; Khan, Alaptagin; Kimbre, Nathan A.; King, Anthony P.; Koen, Nastassja; Kranzler, Henry R.; Kremen, William S.; Lawford, Bruce R.; Lebois, Lauren A. M.; Lewis, Catrin E.; Linnstaedt, Sarah D.; Lori, Adriana; Lugonja, Bozo; Luykx, Jurjen J.; Lyons, Michael J.; Maples-Keller, Jessica; Marmar, Charles; Martin, Alicia R.; Maurer, Douglas; Mavissakalian, Matig R.; McFarlane, Alexander; McGlinchey, Regina E.; McLaughlin, Katie A.; McLean, Samuel A.; McLeay, Sarah; Mehta, Divya; Milberg, William P.; Miller, Mark W.; Morey, Rajendra A.; Morris, Charles Phillip; Mors, Ole; Mortensen, Preben B.; Neale, Benjamin M.; Nelson, Elliot C.; Nordentoft, Merete; Norman, Sonya B.; O'Donnell, Meaghan; Orcutt, Holly K.; Panizzon, Matthew S.; Peters, Edward S.; Peterson, Alan L.; Peverill, Matthew; Pietrzak, Robert H.; Polusny, Melissa A.; Rice, John P.; Ripke, Stephan; Risbrough, Victoria B.; Roberts, Andrea L.; Rothbaum, Alex O.; Rothbaum, Barbara O.; Roy-Byrne, Peter; Ruggiero, Ken; Rung, Ariane; Rutten, Bart P. F.; Saccone, Nancy L.; Sanchez, Sixto E.; Schijven, Dick; Seedat, Soraya, 1966-; Seligowski, Antonia V.; Seng, Julia S.; Sheerin, Christina M.; Smith, Alicia K.; Smoller, Jordan W.; Sponheim, Scott R.; Stein, Dan J.; Stevens, Jennifer S.; Sumner, Jennifer A.; Teicher, Martin H.; Thompson, Wesley K.; Trapido, Edward; Uddin, Monica; Ursano, Robert J.; Van Den Heuvel, Leigh Luella; Van Hooff, Miranda; Vermetten, Eric; Vinkers, Christiaan H.; Voisey, Joanne; Wang, Yunpeng; Wang, Zhewu; Werge, Thomas; Williams, Michelle A.; Williamson, Douglas E.; Winternitz, Sherry; Wolf, Christiane; Wolf, Erika J.; Wolff, Jonathan D.; Yehuda, Rachel; Young, Ross McD; Young, Keith A.; Zhao, Hongyu; Zoellner, Lori A.; Liberzon, Israel; Ressler, Kerry J.; Haas, Magali; Koenen, Karestan C.
    The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
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    White matter microstructural integrity and neurobehavioral outcome of HIV-exposed uninfected neonates
    (Wolters Kluwer Health, 2016-01) Tran, Linh T.; Roos, Annerine; Fouche, Jean-Paul; Koen, Nastassja; Woods, Roger P.; Zar, Heather J.; Narr, Katherine L.; Stein, Dan J.; Donald, Kirsten A.
    The successful implementation of prevention programs for mother-to-child human immunodeficiency virus (HIV) transmission has dramatically reduced the prevalence of infants infected with HIV while increasing that of HIV-exposed uninfected (HEU) children. Neuropsychological assessments indicate that HEU children may exhibit differences in neurodevelopment compared to unexposed children (HUU). Pathological mechanisms leading to such neurodevelopmental delays are not clear. In this observational birth cohort study we explored the integrity of regional white matter microstructure in HEU infants, shortly after birth. Microstructural changes in white matter associated with prenatal HIV exposure were evaluated in HEU infants (n = 15) and matched controls (n = 22) using diffusion tensor imaging and tract-based spatial statistics. Additionally, diffusion values were extracted and compared for white matter tracts of interest, and associations with clinical outcomes from the Dubowitz neonatal neurobehavioral tool were investigated. Higher fractional anisotropy in the middle cerebellar peduncles of HEU compared to HUU neonates was found after correction for age and gender. Scores on the Dubowitz abnormal neurological signs subscale were positively correlated with FA (r = 0.58, P = 0.038) in the left uncinate fasciculus in HEU infants. This is the first study to present data suggesting that prenatal HIV exposure without infection is associated with altered white matter microstructural integrity in the neonatal period. Longitudinal studies of HEU infants as their brains mature are necessary to understand further the significance of prenatal HIV and antiretroviral treatment exposure on white matter integrity and neurodevelopmental outcomes.