Suchergebnisse

CurePSP Foundation, the Peebler PSP Research Foundation, and National Institutes on Health (NIH) grants R37 AG 11762, R01 PAS-03-092, P50 NS72187, P01 AG17216 [National Institute on Aging(NIA)/NIH], MH057881 and MH077930 [National Institute of Mental Health (NIMH)]. Work was also supported in part by the NIA Intramural Research Program, the German National Genome Research Network (01GS08136-4) and the Deutsche Forschungsgemeinschaft (HO 2402/6-1), Prinses Beatrix Fonds (JCvS, 01–0128), the Reta Lila Weston Trust and the UK Medical Research Council (RdS: G0501560). The Newcastle Brain Tissue Resource provided tissue and is funded in part by a grant from the UK Medical Research Council (G0400074), by the Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases to the Newcastle upon Tyne Hospitals NHS Foundation Trust, and by a grant from the Alzheimer's Society and Alzheimer's Research Trust as part of the Brains for Dementia Resarch Project. We acknowledge the contribution of many tissue samples from the Harvard Brain Tissue Resource Center. We also acknowledge the 'Human Genetic Bank of Patients affected by Parkinson Disease and parkinsonism' (http://www.parkinson.it/dnabank.html) of the Telethon Genetic Biobank Network, supported by TELETHON Italy (project n. GTB07001) and by Fondazione Grigioni per il Morbo di Parkinson. The University of Toronto sample collection was supported by grants from Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. Brain-Net-Germany is supported by BMBF (01GI0505). RdS, AJL and JAH are funded by the Reta Lila Weston Trust and the PSP (Europe) Association. RdS is funded by the UK Medical Research Council (Grant G0501560) and Cure PSP+. ZKW is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF)Research Committee CR programs (MCF #90052030 and MCF #90052030), and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052). The Mayo Clinic College of Medicine would like to acknowledge Matt Baker, Richard Crook, Mariely DeJesus-Hernandez and Nicola Rutherford for their preparation of samples. PP was supported by a grant from the Government of Navarra ("Ayudas para la Realización de Proyectos de Investigación" 2006–2007) and acknowledges the "Iberian Atypical Parkinsonism Study Group Researchers", i.e. Maria A. Pastor, Maria R. Luquin, Mario Riverol, Jose A. Obeso and Maria C Rodriguez-Oroz (Department of Neurology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain), Marta Blazquez (Neurology Department, Hospital Universitario Central de Asturias, Oviedo, Spain), Adolfo Lopez de Munain, Begoña Indakoetxea, Javier Olaskoaga, Javier Ruiz, José Félix Martí Massó (Servicio de Neurología, Hospital Donostia, San Sebastián, Spain), Victoria Alvarez (Genetics Department, Hospital Universitario Central de Asturias, Oviedo, Spain), Teresa Tuñon (Banco de Tejidos Neurologicos, CIBERNED, Hospital de Navarra, Navarra, Spain), Fermin Moreno (Servicio de Neurología, Hospital Ntra. Sra. de la Antigua, Zumarraga, Gipuzkoa, Spain), Ainhoa Alzualde (Neurogenétics Department, Hospital Donostia, San Sebastián, Spain).

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. in addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. in addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. the results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures. ; Judah Foundation ; NIH ; Tourette Syndrome Association International Consortium for Genetics (TSAICG) ; New Jersey Center for Tourette Syndrome and Associated Disorders ; NIMH ; Obsessive Compulsive Foundation ; Ontario Mental Health Foundation ; Tourette Syndrome Association ; American Academy of Child and Adolescent Psychiatry (AACAP) ; Anxiety Disorders Association of America (ADAA) ; University of British Columbia ; Michael Smith Foundation ; American Recovery and Re-investment Act (ARRA) ; Australian Research Council ; Australian National Health and Medical Research Council ; German Research Foundation ; NIH Genes, Environment and Health Initiative [GEI] ; Gene Environment Association Studies (GENEVA) under GEI ; NIH GEI ; National Institute on Alcohol Abuse and Alcoholism ; National Institute on Drug Abuse ; Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA ; Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat,Sch Med, Psychiat & Neurodev Genet Unit,Ctr Human Genet Re, Boston, MA USA ; Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA ; Univ Chicago, Dept Med, Chicago, IL 60637 USA ; Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA ; Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands ; Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA ; Univ Queensland, Diamantina Inst, Brisbane, Qld 4072, Australia ; Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia ; Univ Hlth Network, Toronto Western Res Inst, Toronto, ON, Canada ; Hosp Sick Children, Toronto, ON M5G 1X8, Canada ; Univ Vita Salute San Raffaele, Milan, Italy ; Hadassah Hebrew Univ Med Ctr, Herman Dana Div Child & Adolescent Psychiat, Jerusalem, Israel ; Univ Pontificia Bolivariana, Univ Antioquia, Medellin, Colombia ; Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA ; Yale Univ, Dept Psychiat, New Haven, CT 06520 USA ; Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA ; North Shore Long Isl Jewish Med Ctr, Manhasset, NY USA ; NYU Med Ctr, New York, NY 10016 USA ; North Shore Long Isl Jewish Hlth Syst, Manhasset, NY USA ; Hofstra Univ, Sch Med, Hempstead, NY 11550 USA ; Inst Nacl Psiquiatria Ramon de la Fuente Muniz, Mexico City, DF, Mexico ; UCL, London, England ; Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China ; Univ São Paulo, Sch Med, Dept Psychiat, São Paulo, Brazil ; Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands ; Univ Utrecht, Dept Clin & Hlth Psychol, Utrecht, Netherlands ; Altrecht Acad Anxiety Ctr, Utrecht, Netherlands ; Univ Milan, Osped San Raffaele, I-20127 Milan, Italy ; Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA ; Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA ; Univ Montreal, Montreal, PQ, Canada ; Univ Calif Los Angeles, Keck Sch Med, Div Biostat, Dept Preventat Med, Los Angeles, CA USA ; Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA ; Univ Ghent, Lab Pharmaceut Biotechnol, B-9000 Ghent, Belgium ; Inst Pasteur, Paris, France ; French Natl Sci Fdn, Fondat Fondamental, Creteil, France ; Hop Robert Debre, AP HP, Dept Child & Adolescent Psychiat, F-75019 Paris, France ; Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada ; Univ Wurzburg, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-97070 Wurzburg, Germany ; Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany ; Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA ; Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp,OCD Program, Boston, MA 02115 USA ; Univ Med Greifswald, Helios Hosp Stralsund, Dept Psychiat & Psychotherapy, Greifswald, Germany ; Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA ; Shaare Zedek Med Ctr, Neuropediatr Unit, Jerusalem, Israel ; Rutgers State Univ, Dept Genet, Human Genet Inst New Jersey, Piscataway, NJ USA ; Univ Stellenbosch, Dept Psychiat, ZA-7600 Stellenbosch, South Africa ; Univ São Paulo, Fac Med, Dept Psychiat, BR-05508 São Paulo, Brazil ; Baylor Coll Med, Dept Neurol, Parkinsons Dis Ctr, Houston, TX 77030 USA ; Baylor Coll Med, Dept Neurol, Movement Disorders Clin, Houston, TX 77030 USA ; Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA ; Ctr Addict & Mental Hlth, Neurogenet Sect, Toronto, ON, Canada ; Univ Toronto, Dept Psychiat, Toronto, ON, Canada ; Yale Univ, Sch Med, Dept Genet, Yale Child Study Ctr, New Haven, CT 06510 USA ; Overlook Hosp, Atlantic Neurosci Inst, Summit, NJ USA ; Carracci Med Grp, Mexico City, DF, Mexico ; Inst Mondor Rech Biomed, Creteil, France ; Yale Univ, Ctr Child Study, New Haven, CT 06520 USA ; Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany ; Univ Illinois, Dept Psychiat, Inst Human Genet, Chicago, IL 60612 USA ; Univ Stellenbosch, Dept Psychiat, MRC Unit Anxiety & Stress Disorders, ZA-7600 Stellenbosch, South Africa ; Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA ; UCI, Sch Med, Dept Psychiat & Human Behav, Irvine, CA USA ; Univ Utah, Salt Lake City, UT USA ; NIMH Intramural Res Program, Clin Sci Lab, Bethesda, MD USA ; Med City Dallas Hosp, Dept Clin Res, Dallas, TX USA ; Univ Med Ctr, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, Netherlands ; Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA ; Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA ; Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA ; Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA ; Yale Univ, Dept Psychol, New Haven, CT 06520 USA ; Partners Psychiat & McLean Hosp, Boston, MA USA ; Sunnybrook Hlth Sci Ctr, Frederick W Thompson Anxiety Disorders Ctr, Toronto, ON M4N 3M5, Canada ; St George Hosp, London, England ; Sch Med, London, England ; Hosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa Rica ; Universidade Federal de São Paulo, Dept Psychiat, Child & Adolescent Psychiat Unit UPIA, São Paulo, Brazil ; Wayne State Univ, Dept Psychiat & Behav Neurosci, Detroit, MI 48207 USA ; Detroit Med Ctr, Detroit, MI USA ; McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada ; Univ Cologne, Dept Psychiat & Psychotherapy, D-50931 Cologne, Germany ; Univ Fed Bahia, Univ Hlth Care Serv SMURB, Salvador, BA, Brazil ; Youthdale Treatment Ctr, Toronto, ON, Canada ; Johns Hopkins Univ Sch Med, Baltimore, MD USA ; Univ Cape Town, ZA-7925 Cape Town, South Africa ; Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands ; Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Psychiat, Nashville, TN 37235 USA ; Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Pediat & Pharmacol, Nashville, TN 37235 USA ; Vanderbilt Univ, Inst Brain, Nashville, TN 37235 USA ; Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland ; Univ Wurzburg, Dept Child & Adolescent Psychiat, D-97070 Wurzburg, Germany ; Univ Amsterdam, Acad Med Ctr, Ctr Psychiat, NL-1105 BC Amsterdam, Netherlands ; Inst Royal Netherlands Acad Arts & Sci NIN KNAW, Netherlands Inst Neurosci, Amsterdam, Netherlands ; NIMH Intramural Res Program, Unit Stat Genom, Bethesda, MD USA ; Univ Utah, Dept Psychiat, Salt Lake City, UT USA ; Natl Inst Genom Med SAP, Carracci Med Grp, Mexico City, DF, Mexico ; Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, Netherlands ; Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands ; Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands ; Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA ; Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands ; German Ctr Neurodegenerat Dis, Tubingen, Germany ; Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada ; Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands ; Univ British Columbia, British Columbia Mental Hlth & Addict Res Inst, Vancouver, BC V5Z 1M9, Canada ; Brigham & Womens Hosp, Div Cognit & Behav Neurol, Boston, MA 02115 USA ; Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA ; Universidade Federal de São Paulo, Dept Psychiat, Child & Adolescent Psychiat Unit UPIA, São Paulo, Brazil ; NIH: NS40024 ; NIH: NS16648 ; NIH: MH079489 ; NIH: MH073250 ; NIH: NS037484 ; NIH: 1R01MH079487-01A1 ; NIH: K20 MH01065 ; NIH: R01 MH58376 ; NIH: MH085057 ; NIH: MH079494 ; NIH: HHSN268200782096C ; NIMH: R01MH092293 ; American Recovery and Re-investment Act (ARRA): NS40024-07S1 ; American Recovery and Re-investment Act (ARRA): NS16648-29S1 ; Australian Research Council: FT0991360 ; Australian Research Council: DE130100614 ; Australian National Health and Medical Research Council: 1047956 ; Australian National Health and Medical Research Council: 1052684 ; German Research Foundation: DFG GR 1912/1-1 ; NIH Genes, Environment and Health Initiative [GEI]: U01 HG004422 ; NIH GEI: U01HG004438 ; : R01 MH090937 ; : P50MH094267 ; Web of Science

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.