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1. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Author

Marie‐Gabrielle Duperron, Maria J. Knol, Quentin Le Grand, Tavia E Evans, Aniket Mishra, Gennady V. Roshchupkin, Takahiro Konuma, David Alexandre Tregouët, Jose Rafael Romero, Stefan Frenzel, Michelle Luciano, Edith Hofer, Mathieu Bourgey, Nicole D Dueker, Pilar Delgado, Saima Hilal, Rick M. Tankard, Florian Dubost, Jean Shin, Yasaman Saba, Christopher Chen, Tatjana Rundek, Alexander Teumer, Ami Tsuchida, Helena Schmidt, Perminder S. Sachdev, Wei Wen, Anne Joutel, Claudia L Satizabal, Ralph Sacco, Guillaume Bourque, Mark Lathrop, Tomas Paus, Israel Fernandez‐Cadenas, Bernard Mazoyer, Yukinori Okada, Hans J. Grabe, Karen A Mather, Reinhold Schmidt, M. Arfan Ikram, Christophe Tzourio, Joanna M Wardlaw, Sudha Seshadri, Hieab H.H. Adams, and Stéphanie Debette

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022
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2. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Author

Pilar Delgado, Shuo Li, Matthew Paradise, Qiong Yang, Ami Tsuchida, Uwe Völker, Maria J. Knol, Wanting Zhao, Wei Wen, Marie-Gabrielle Duperron, David-Alexandre Trégouët, Mark E. Bastin, Hans J. Grabe, Aniket Mishra, Jean Shin, Stefan Frenzel, Alexa S. Beiser, Jiyang Jiang, Mathieu Bourgey, Henry Brodaty, Jayandra J. Himali, Hieab H.H. Adams, Ralph L. Sacco, Murali Sargurupremraj, Nicole Dueker, Margaret J. Wright, Quentin Le Grand, Christopher Chen, Tomáš Paus, Katharina Wittfeld, Stéphanie Debette, Tavia E. Evans, Constance Bordes, Nicola J. Armstrong, Parva Pedram, M. Arfan Ikram, Gennady V. Roshchupkin, Pascale Marquis, Tatjana Rundek, Anbupalam Thalamuthu, Helena Schmidt, Sudha Seshadri, Takahiro Konuma, Anne Joutel, Joanna M. Wardlaw, Michelle Luciano, Israel Fernandez-Cadenas, Robin Bülow, Jose R. Romero, Maria del C. Valdés Hernández, Meike W. Vernooij, Melissa Macalli, Claudia L. Satizabal, Caty Carrera, Ching-Yu Cheng, Piyush G. Gampawar, Ycheng Zhu, Karen A. Mather, Alexander Teumer, Ian J. Deary, Guillaume Bourque, Saima Hilal, Rick M. Tankard, Reinhold E. Schmidt, Yukinori Okada, Yasaman Saba, Sabrina Schilling, Julian N. Trollor, Tien Yin Wong, Perminder S. Sachdev, Mark Lathrop, Omar (Tbc) Soukarieh, Junyi Zhang, Zoe Morris, Edith Hofer, Christophe Tzourio, Florian Dubost, Bernard Mazoyer, and Susanna Muñoz Maniega

Subjects
Pathology, medicine.medical_specialty, medicine.anatomical_structure, cardiovascular system, medicine, Genomics, Disease, Small vessel, Biology, Perivascular space
Abstract

Perivascular space burden (PVS) is an emerging and possibly the earliest magnetic resonance imaging (MRI)-marker of cerebral small vessel disease (cSVD), a leading cause of stroke and dementia. Its molecular underpinnings are unknown. Genome-wide and whole-exome association studies in 40,095 participants (21 population-based cohorts, 66.3±8.6 years) revealed 24 genome-wide significant PVS risk loci. These showed association with white matter PVS already at age 20, suggesting an important role of early-life factors. PVS loci were enriched in genes causing early-onset leukodystrophies and genes expressed in fetal brain endothelial cells. Mendelian randomization analyses supported causal associations of high blood pressure with basal ganglia (BG) and hippocampal PVS, and of BG PVS with stroke. Transcriptome-wide association studies suggest causal implication of 11 genes, to prioritize for experimental follow-up as putative biotargets for cSVD. Two-thirds of PVS loci point to novel pathways, involving extracellular matrix, membrane transport, and developmental processes, with enrichment in targets of existing drugs for vascular/cognitive disorders.

Published
2021
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3. Gray matter heritability in family-based and population-based studies using voxel-based morphometry

Author

Edith Hofer, Reinhold Schmidt, Wiro J. Niessen, Najaf Amin, Sven J. van der Lee, Yasaman Saba, M. Arfan Ikram, Gennady V. Roshchupkin, Helena Schmidt, Hieab H.H. Adams, Meike W. Vernooij, Albert Hofman, and Cornelia M. van Duijn

Subjects
0301 basic medicine, education.field_of_study, Radiological and Ultrasound Technology, Correlation coefficient, Population, Voxel-based morphometry, Heritability, computer.software_genre, Brain mapping, Lateralization of brain function, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, Voxel, Brain size, Radiology, Nuclear Medicine and imaging, Neurology (clinical), Anatomy, Psychology, education, Neuroscience, Cartography, computer, 030217 neurology & neurosurgery
Abstract

Background The combination of genetics and imaging has improved their understanding of the brain through studies of aggregate measures obtained from high-resolution structural imaging. Voxel-wise analyses have the potential to provide more detailed information of genetic influences on the brain. Here they report a large-scale study of the heritability of gray matter at voxel resolution (1 × 1 × 1 mm). Methods Validated voxel-based morphometry (VBM) protocols were applied to process magnetic resonance imaging data of 3,239 unrelated subjects from a population-based study and 491 subjects from two family-based studies. Genome-wide genetic data was used to estimate voxel-wise gray matter heritability of the unrelated subjects and pedigree-structure was used to estimate heritability in families. They subsequently associated two genetic variants, known to be linked with subcortical brain volume, with most heritable voxels to determine if this would enhance their association signals. Results Voxels significantly heritable in both estimates mapped to subcortical structures, but also voxels in the language areas of the left hemisphere were found significantly heritable. When comparing regional patterns of heritability, family-based estimates were higher than population-based estimates. However, regional consistency of the heritability measures across study designs was high (Pearson's correlation coefficient = 0.73, P = 2.6 × 10-13 ). They further show enhancement of the association signal of two previously discovered genetic loci with subcortical volume by using only the most heritable voxels. Conclusion Gray matter voxel-wise heritability can be reliably estimated with different methods. Combining heritability estimates from multiple studies is feasible to construct reliable heritability maps of gray matter voxels. Hum Brain Mapp 38:2408-2423, 2017. © 2017 Wiley Periodicals, Inc.

Published
2017
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4. A genome-wide association study identifies genetic loci associated with specific lobar brain volumes

Author

Diana van Heemst, Lisa R. Yanek, Tamara B. Harris, Fabrice Crivello, Hieab H.H. Adams, Paul A. Nyquist, Bernard Mazoyer, Najaf Amin, Pauline Maillard, Diane M. Becker, Marian Beekman, Shuo Li, Ganesh Chauhan, Charles DeCarli, Wanting Zhao, Neda Jahanshad, Rasika A. Mathias, Cornelia M. van Duijn, Manon Bernard, Derrek P. Hibar, Alexa S. Beiser, Meike W. Vernooij, Vilmundur Gudnason, Joshua C. Bis, Tomáš Paus, Edith Hofer, Lei Yu, Stéphanie Debette, Helena Schmidt, M. Kamran Ikram, P. Eline Slagboom, Erik B. van den Akker, Lenore J. Launer, Stefan Boehringer, Kent D. Taylor, Maria J. Knol, Wiro J. Niessen, Kenneth Rice, Zdenka Pausova, Gennady V. Roshchupkin, Sven J. van der Lee, Philip L. De Jager, Ching-Yu Cheng, Sudha Seshadri, Qiong Yang, Konstantinos Arfanakis, Yasaman Saba, Jeroen van der Grond, W. T. Longstreth, Albert V. Smith, Claudia L. Satizabal, Oscar L. Lopez, Bruce M. Psaty, Christopher Chen, Philippe Amouyel, Josh W. Cheung, M. Arfan Ikram, Tien Yin Wong, Reinhold Schmidt, David A. Bennett, Saima Hilal, Paul M. Thompson, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine, University of Washington [Seattle], Keck School of Medicine [Los Angeles], University of Southern California (USC), National University of Singapore (NUS), Rush University Medical Center [Chicago], Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Los Angeles Biomedical Research Institute (LA BioMed), School of Public Health [Boston], Boston University [Boston] (BU), Columbia University Medical Center (CUMC), Columbia University [New York], University of Glasgow, Leiden University Medical Center (LUMC), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidemiology, Radiology & Nuclear Medicine, Medical Informatics, Neurology, Clinical Genetics, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Universiteit Leiden

Subjects
Pathology, Heredity, Neurology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Medicine (miscellaneous), Genome-wide association study, Genome-wide association studies, Taugasjúkdómar, 0302 clinical medicine, Parietal Lobe, 2.1 Biological and endogenous factors, Developmental, Aetiology, lcsh:QH301-705.5, 0303 health sciences, Parietal lobe, Gene Expression Regulation, Developmental, Organ Size, Magnetic Resonance Imaging, Temporal Lobe, Frontal Lobe, 3. Good health, Phenotype, Mental Health, Neurological, symbols, Occipital Lobe, Erfðarannsóknir, General Agricultural and Biological Sciences, medicine.medical_specialty, Genotype, 1.1 Normal biological development and functioning, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Temporal lobe, 03 medical and health sciences, symbols.namesake, Underpinning research, Genetics, medicine, Humans, Gene, 030304 developmental biology, Genetic association, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Human Genome, Heilinn, Neurosciences, Genetic Variation, United Kingdom, Brain Disorders, Gene Expression Regulation, lcsh:Biology (General), Genetic Loci, Mendelian inheritance, Occipital lobe, Biomarkers, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein)., Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes., 23Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA. 24Research Unit-Genetic Epidemiology, Gottfried Schatz Research Centre for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria. 25Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260, USA. 26Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA. 27Department of Radiology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. 28Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto M4G 1R8, Canada. 29Departments of Psychology and Psychiatry, University of Toronto, Toronto M5S 1A1, Canada.

Published
2019
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5. Evaluation of the Performance of AmpliSeq and SureSelect Exome Sequencing Libraries for Ion Proton

Author

Piyush Gampawar, Yasaman Saba, Ulrike Werner, Reinhold Schmidt, Bertram Müller-Myhsok, and Helena Schmidt

Subjects
0301 basic medicine, validation, AmpliSeq, lcsh:QH426-470, Library preparation, Concordance, ion proton sequencer, Computational biology, Biology, SureSelect, Predictive value, lcsh:Genetics, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Genetics, Methods, Molecular Medicine, Exome, exome sequencing, library preparation, Genetics (clinical), Exome sequencing
Abstract

Library preparation for whole-exome sequencing is a critical step serving the enrichment of the regions of interest. For Ion Proton, there are only two exome library preparation methods available, AmpliSeq and SureSelect. Although of major interest, a comparison of the two methods is hitherto missing in the literature. Here, we systematically evaluate the performance of AmpliSeq and SureSelect and present an improved variant calling pipeline. We used 12 in-house DNA samples with genome-wide and exome microarray data and a commercially available reference DNA (NA12878) for evaluation. Both methods had a high concordance (>97%) with microarray genotypes and, when validating against NA12878, a sensitivity and positive predictive values of >93% and >80%, respectively. Application of our variant calling pipeline decreased the number of false positive variants dramatically by 90% and resulted in positive predictive value of 97%. This improvement is highly relevant in research as well as clinical setting.

Published
2019
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6. Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

Author

Charles DeCarli, Vilmundur Gudnason, Debra A. Fleischman, Henning Tiemeier, Rebecca F. Gottesman, William S. Kremen, Xueqiu Jian, Henry Brodaty, Maria del C. Valdés Hernández, Markus Loeffler, Reinhold Schmidt, Shahzad Ahmad, Paul A. Nyquist, Oscar L. Lopez, Anbupalam Thalamuthu, Helena Schmidt, Peter R. Schofield, Tonya White, Edith Hofer, Philip L. De Jager, David Ames, Qiong Yang, Ole A. Andreassen, Cora E. Lewis, Matthias Nauck, David S. Knopman, Anders M. Dale, Sven J. van der Lee, Jeroen van der Grond, Konstantinos Arfanakis, Margaret J. Wright, Jingyun Yang, John B.J. Kwok, Hieab H.H. Adams, Matthew S. Panizzon, Meike W. Vernooij, Yasaman Saba, David A. Bennett, Cornelia M. van Duijn, Tamara B. Harris, Pauline Maillard, Frauke Beyer, M. Arfan Ikram, Jerome I. Rotter, Ryan L. Muetzel, Tomáš Paus, Pamela J. Schreiner, Zdenka Pausova, Katharina Wittfeld, Diane M. Becker, Bruce M. Psaty, Alexander Teumer, Wei Wen, A. Veronica Witte, Karen A. Mather, Hanan El Marroun, William T. Longstreth, Perminder S. Sachdev, Mark E. Bastin, Nathan A. Gillespie, Kenneth Rice, Stella Trompet, Lisa R. Yanek, David J. Stott, Alexa S. Beiser, R. Nick Bryan, Alexander Neumann, Natalie A. Royle, Myriam Fornage, Manon Bernard, Dina Vojinovic, Najaf Amin, Ian J. Deary, Arno Villringer, Georg Homuth, Nicola J. Armstrong, Stephen Sidney, Sudha Seshadri, Joanna M. Wardlaw, Thomas H. Mosley, Hans J. Grabe, Michelle Luciano, Lenore J. Launer, J. Wouter Jukema, Robin Bülow, Markus Scholz, André G. Uitterlinden, Albert V. Smith, Shuo Li, Claudia L. Satizabal, Joshua C. Bis, Epidemiology, Radiology & Nuclear Medicine, Child and Adolescent Psychiatry / Psychology, Clinical Psychology, Internal Medicine, Psychiatry, Neurology, Faculty of Medicine (UI), Læknadeild (HÍ), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands (HÍ), and University of Iceland (UI)

Subjects
0301 basic medicine, Genetics of the nervous system, Cytoskeleton organization, General Physics and Astronomy, Genome-wide association study, Mental disorders, Genome-wide association studies, Genome, Lateral ventricles, 0302 clinical medicine, Lateral Ventricles, Ventricle (lateral), lcsh:Science, Genetics, anatomy & histology [Lateral Ventricles], education.field_of_study, Enlargement, Multidisciplinary, Brain, Organ Size, Middle Aged, Schizophrenia, ddc:500, Science, Population, Elderly people, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Erfðafræði, Humans, Genomes, education, Aged, Genetic association, genetics [Organ Size], Genome, Human, Heilinn, Brain morphometry, Litningarannsóknir, Rannsóknir, General Chemistry, medicine.disease, 030104 developmental biology, Heritable quantitative trait, lcsh:Q, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein) Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = −0.59, p-value = 3.14 × 10−6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology., See Supplementary Note 2 for information on funding sources.

Published
2018
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7. Genetic analysis of over one million people identifies 535 novel loci for blood pressure

Author

Lorenz Risch, Anne-Claire Vergnaud, Nguyen Quang Tri, Rona J. Strawbridge, Alan F. Wright, Francesco Cucca, Evan Tzanis, Caterina Barbieri, Jaakko Tuomilehto, Louise V. Wain, Jonathan Marten, James F. Wilson, Christopher Newton-Cheh, Reedik Mägi, Olli T. Raitakari, Peter W.F. Wilson, Joris Deelen, Morris Brown, Anna Morgan, Nabi Shah, Weihua Zhang, Ganesh Chauhan, Gail Davies, Peter S. Braund, Bram P. Prins, Alison Pattie, Marcus Dörr, Zoltán Kutalik, Marco Brumat, Franco Giulianini, Rainer Rettig, Uwe Völker, Georgios Ntritsos, Teresa Nutile, Todd L. Edwards, Albertine J. Oldehinkel, Christopher J. O'Donnell, Jaume Marrugat, Evangelos Evangelou, Nilesh J. Samani, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Francis S. Collins, Tim D. Spector, Simon Thom, Sarah E. Harris, Heather J. Cordell, Helen R. Warren, Cinzia Sala, Peter P. Pramstaller, Seppo Koskinen, Paul F. O'Reilly, Aravinda Chakravarti, Joshua C. Bis, Archie Campbell, Bernard Keavney, Sébastien Thériault, Gonneke Willemsen, Lynda M. Rose, Massimiliano Cocca, Jennifer E. Huffman, Meixia Ren, Massimo Mangino, Markus Perola, Joanna M. M. Howson, David Mosen-Ansorena, Harriëtte Riese, Martin Farrall, Albert V. Smith, Lenore J. Launer, Marina Ciullo, Antti-Pekka Sarin, Veikko Salomaa, Ilaria Gandin, Kent D. Taylor, Peter S. Sever, Markku Laakso, André G. Uitterlinden, Yan V. Sun, Raymond Noordam, Renée de Mutsert, Alan L. James, Jing Hua Zhao, Stefan Enroth, Andrew D. Morris, David S. Siscovick, Andrew D. Johnson, Igor Rudan, Tõnu Esko, Jun Ding, David P. Strachan, Martin D. Tobin, Christopher P. Nelson, Daniela Toniolo, J. Wouter Jukema, Vilmundur Gudnason, Borbala Mifsud, Marty Larson, Andrew A. Hicks, Adriana M. Hung, Antonietta Robino, Ruifang Li-Gao, Paul Elliott, Anne U. Jackson, Michela Traglia, Martin H. de Borst, Germaine C. Verwoert, Rheinhold Schmidt, Fabiola M Del Greco, Åsa Johansson, Anders Hamsten, Csaba P. Kovesdy, Mark J. Caulfield, Cumhur Y Demirkale, John M. C. Connell, Jian'an Luan, K. Witkowska, Georg Ehret, Cecilia M. Lindgren, Oscar H. Franco, Yongmei Liu, Ioanna Tzoulaki, Eric Boerwinkle, Catharina A. Hartman, Muralidharan Sargurupremraj, Claudia Langenberg, J. Michael Gaziano, Peter K. Joshi, Cornelia M. van Duijn, Maris Laan, Nick Shrine, Peter J. van der Most, Michael Boehnke, Leo-Pekka Lyytikäinen, Samuli Ripatti, Ben A. Oostra, Robert A. Scott, Lingchan Lu, Edward G. Lakatta, Yasaman Saba, Daniel Levy, Li Lin, Harold Schneider, Alex S. F. Doney, Michael R. Barnes, Najaf Amin, Hugh Watkins, Paul M. Ridker, Janina S Reid, Ayush Giri, Sekar Kathiresan, Lorna M. Lopez, Mike A. Nalls, Marina Evangelou, Erik Ingelsson, Lili Milani, Alice Stanton, Ozren Polasek, Sara M. Willems, Colin N. A. Palmer, Stéphanie Debette, Dan E. Arking, Helena Schmidt, Paul Knekt, John M. Starr, Yong Qian, Cristina Menni, Yuri Milaneschi, Christophe Tzourio, Tamara B. Harris, Kristin L. Ayers, Peter Vollenweider, Paolo Gasparini, Dennis O. Mook-Kanamori, Rodney J. Scott, Sandosh Padmanabhan, Anubha Mahajan, Peter Almgren, Jacklyn N. Hellwege, Teemu J. Niiranen, Mika Kähönen, Shih-Jen Hwang, Elizabeth G. Holliday, Edith Hofer, Priyanka Nandakumar, Peter J. Munson, Rick Jansen, Andrew P. Morris, Walter Palmas, Ilja M. Nolte, Siim Sõber, Thibaud Boutin, Ahmad Vaez, Albert Hofman, He Gao, Brenda W.J.H. Penninx, Neil Poulter, Alan J. Gow, Caroline Hayward, Nicholas J. Wareham, Elin Org, Philip S. Tsao, Claudia P. Cabrera, Aki S. Havulinna, Dragana Vuckovic, Kelly Cho, Jie Yao, Lars Lind, Jerome I. Rotter, David J. Stott, Ivana Kolcic, Wei-Yu Lin, Tatijana Zemunik, Tineka Blake, Kenneth Rice, Veronique Vitart, Alanna C. Morrison, Kay-Tee Khaw, Marjo-Riitta Järvelin, Guillaume Paré, Jouke-Jan Hottenga, Giorgia Girotto, Chiara Batini, Niki Dimou, Stella Trompet, John Danesh, Annette Peters, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Morris A. Swertz, Jaspal S. Kooner, Niek Verweij, Ibrahim Karaman, Murielle Bochud, Christian Gieger, Ruth J. F. Loos, Daniella Ruggiero, Arno Palotie, David Conen, Raha Pazoki, Denis C. Shields, Rossella Sorice, Philippe Amouyel, Gonçalo R. Abecasis, Andres Metspalu, John Attia, Bruce M. Psaty, Sarah H. Wild, Patricia B. Munroe, Daniel I. Chasman, Ollie Melander, John C. Chambers, Roby Joehanes, Eleftheria Zeggini, Johan Sundström, Chrysovalanto Mamasoula, Benjamin Lehne, Kati Kristiansson, Christopher Oldmeadow, Eco J. C. de Geus, A. Mesut Erzurumluoglu, Anuj Goel, Adam S. Butterworth, Digna R. Velez Edwards, Xiuqing Guo, Antti Jula, Praveen Surendran, Terho Lehtimäki, Mattias Frånberg, Teresa Ferreira, Ian J. Deary, David C. Liewald, Pim van der Harst, Erwin P. Bottinger, Roberto Elosua, and Fu Liang Ng

Subjects
Genetics, 0303 health sciences, Diastole, Disease, 030204 cardiovascular system & hematology, Biology, Precision medicine, Genetic analysis, 3. Good health, Pulse pressure, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, Disease prevention, 030304 developmental biology, Genetic association
Abstract

High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.

Published
2017
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8. Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Author

Arvin Saremi, Tomas Axelsson, Kristel R. van Eijk, Tonya White, Elena Shumskaya, Christine Macare, Christopher Chen, Neeltje E.M. van Haren, K Hegenscheid, Ingrid Melle, Benjamin S. Aribisala, Clyde Francks, Lisa R. Yanek, Konstantinos Arfanakis, Lars Nyberg, Nina Romanczuk-Seiferth, Clifford R. Jack, Thomas H. Wassink, Norman Delanty, Oscar L. Lopez, Jennifer S. Richards, Philippe Amouyel, William T. Longstreth, Michael W. Weiner, Maria J. Knol, Ralph Burkhardt, Ching-Yu Cheng, Wolfgang Hoffmann, Norbert Hosten, Alexander Teumer, Simone Reppermund, Markus M. Nöthen, Tien Yin Wong, Maria del C. Valdés Hernández, Bernd Kraemer, Murali Sargurupremraj, Amelia A. Assareh, Jessika E. Sussmann, Gabriel Cuellar-Partida, Ian J. Deary, Ganesh Chauhan, Christopher R.K. Ching, Arno Villringer, Dalia Kasperaviciute, Han G. Brunner, Srdjan Djurovic, Lachlan T. Strike, Albert V. Smith, Lars T. Westlye, Paul A. Nyquist, Bertram Müller-Myhsok, Phil Lee, Qiong Yang, Herve Lemaitre, Andreas Meyer-Lindenberg, Vidar M. Steen, Marc M. Bohlken, Rachel M. Brouwer, Charles DeCarli, Mar Matarin, Fabrice Crivello, Henry Völzke, Manuel Mattheisen, Bruno Vellas, Loes M. Olde Loohuis, Sudha Seshadri, Claudia L. Satizabal, Sebastian Mohnke, David C. Liewald, Li Shen, Kwangsik Nho, Simon E. Fisher, Deborah Janowitz, Wiro J. Niessen, Matthew J. Huentelman, Sylvane Desrivières, Ole A. Andreassen, Evan Fletcher, Christiane Wolf, Vilmundur Gudnason, Alejandro Arias-Vasquez, Charles C. White, Joshua C. Bis, Pauline Maillard, Ingrid Agartz, Oliver Grimm, Matthias Nauck, Andrew M. McIntosh, Iryna O. Fedko, Gianpiero L. Cavalleri, Andreas Heinz, Tulio Guadalupe, Andrew D. Johnson, Daan van Rooij, Thomas W. Mühleisen, Jessica A. Turner, Marieke Klein, Jia Yu Koh, Avram J. Holmes, Saud Alhusaini, Douglas N. Greve, Roberto Roiz-Santiañez, Nic J.A. van der Wee, Irina Filippi, Hans van Bokhoven, Miguel E. Rentería, Andrew J. Saykin, Marjolein M.J. van Donkelaar, Dan J. Stein, Randy L. Gollub, Sanjay M. Sisodiya, Honghuang Lin, Aaron Goldman, Patrizia Mecocci, Thomas Espeseth, Barbara Franke, Unn K. Haukvik, Theo G.M. van Erp, Venkata S. Mattay, Jonathan C Ipser, Catharina A. Hartman, Florian Holsboer, Saskia P. Hagenaars, Benedicto Crespo-Facorro, Manon Bernard, Jerome I. Rotter, Louis N. Vinke, Nastassja Koen, Vince D. Calhoun, Anders M. Dale, Dennis van der Meer, Jordan W. Smoller, Debra A. Fleischman, Janita Bralten, Hannah J. Jones, Lavinia Athanasiu, Hilleke E. Hulshoff Pol, Brenda W.J.H. Penninx, Peter R. Schofield, Roel A. Ophoff, J Wardlaw, Sven J. van der Lee, Katie L. McMahon, Esther Walton, Nicholas G. Martin, Gunter Schumann, Katharina Wittfeld, Perminder S. Sachdev, André G. Uitterlinden, Christophe Tzourio, Pieter J. Hoekstra, Roberto Toro, Henry Brodaty, Marcella Rietschel, David Ames, George Davey Smith, G. Bruce Pike, Alexa S. Beiser, Zdenka Pausova, Simon Lovestone, Robert C. Green, Greig I. de Zubicaray, Stephen M. Lawrie, Mark E. Bastin, Marco P. Boks, M. Mallar Chakravarty, Magda Tsolaki, Myriam Fornage, Nanda Rommelse, Andre F. Marquand, Anbupalam Thalamuthu, Helena Schmidt, Jason L. Stein, Bruce M. Psaty, Jan K. Buitelaar, Jean-Luc Martinot, Kazima B. Bulayeva, Henrik Walter, Xueqiu Jian, Yasaman Saba, Saima Hilal, Paul M. Thompson, Tamara B. Harris, Jaap Oosterlaan, Marie-José van Tol, Joshua L. Roffman, Bernard Mazoyer, Shuo Li, Nhat Trung Doan, Qiang Chen, John B.J. Kwok, Najaf Amin, Diana Tordesillas-Gutiérrez, Eco J. C. de Geus, Meike W. Vernooij, Andrew J. Schork, Susanne Erk, Daniel R. Weinberger, Grant W. Montgomery, Jean Shin, James T. Becker, Martine Hoogman, Philip L. De Jager, Dirk J. Heslenfeld, Derrek P. Hibar, Narelle K. Hansell, Andrew Simmons, Micael Andersson, Lucija Abramovic, Dorret I. Boomsma, Allison Stevens, Wei Wen, A. Veronica Witte, Owen Carmichael, Jayandra J. Himali, Asta Håberg, Hieab H.H. Adams, Nynke A. Groenewold, Sven Cichon, Wiepke Cahn, Lianne Schmaal, Shannon L. Risacher, Erik G. Jönsson, Shahrzad Kharabian Masouleh, Oliver Gruber, Tianye Jia, Hilkka Soininen, M. Kamran Ikram, Markus Loeffler, Philipp G. Sämann, Sungeun Kim, Jingyun Yang, Iwona Kłoszewska, Ryota Kanai, Christopher D. Whelan, Massimo Pandolfo, Dick J. Veltman, Diane M. Becker, Anouk den Braber, Hans J. Grabe, Neda Jahanshad, Yanhui Hu, Anita L. DeStefano, Beng-Choon Ho, Stephanie Le Hellard, Cornelia M. van Duijn, Georg Homuth, Tomáš Paus, Stéphanie Debette, Nicola J. Armstrong, Jouke-Jan Hottenga, Eric Westman, Tom V. Lee, Sarah E. Medland, Randy L. Buckner, Benno Pütz, Edith Hofer, Steven G. Potkin, Albert Hofman, Dennis van 't Ent, Sudheer Giddaluru, Tatiana Foroud, Guillén Fernández, John D. Eicher, Gareth E. Davies, Thomas H. Mosley, Michelle Luciano, Lenore J. Launer, Joshua W. Cheung, Markus Scholz, D. Höhn, Thomas Wolfers, Reinhold Schmidt, Arthur W. Toga, René S. Kahn, Nazanin Karbalai, Yuri Milaneschi, Margaret J. Wright, Martina Papmeyer, David A. Bennett, M. Arfan Ikram, Stefan Ehrlich, Marcel P. Zwiers, Karen A. Mather, and Joshua M. Shulman

Subjects
Candidate gene, Globus pallidus, nervous system, Putamen, Thalamus, Caudate nucleus, Synaptic signaling, Nucleus accumbens, Biology, Bioinformatics, Neuroscience, Genetic architecture
Abstract

Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2017
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9. Ninety-nine independent genetic loci influencing general cognitive function include genes associated with brain health and structure (N = 280,360)

Author

Nancy L. Pedersen, John M. Starr, Kjetil Sundet, Qiong Yang, Nicole A. Kochan, Beverly Gwen Windham, Ida K. Karlsson, Daniel E. Gustavson, Jerome I. Rotter, Antony Payton, M. Arfan Ikram, Alison D. Murray, Edith Hofer, Ozren Polasek, Markus Leber, Will Longstreth, Stephanie Le Hellard, Peter W. Schofield, Raha Pazoki, Janie Corley, Max Lam, Deborah K. Attix, Hieab H.H. Adams, Tobias Luck, Ian J. Deary, Panos Roussos, Amelia A. Assareh, Katja Petrovic, Dwight Dickinson, Elizabeth T. Cirulli, Thomas Espeseth, Richard J. Rose, Annette L. Fitzpatrick, Robert M. Bilder, Rodney J. Scott, Katherine E. Burdick, William S. Kremen, Christophe Tzourio, Richard E. Straub, Thomas H. Mosley, Michael Griswold, Ulman Lindenberger, Peter R. Schofield, Riccardo E. Marioni, Stéphanie Debette, Jennifer A. Smith, M. Kamran Ikram, Pamela DeRosse, Russell A. Poldrack, Teemu Palviainen, Panos Bitsios, Nikos C. Stefanis, Anu Loukola, Nikolaos Smyrnis, Todd Lencz, Michelle Luciano, Robert Karlsson, Bettina Konte, Dan Rujescu, Mika Kähönen, James F. Wilson, Steven T. Turner, David A. Bennett, Jingyun Yang, Cornelia M. van Duijn, David S. Knopman, Harry Campbell, R. F. Gottesman, Vidar M. Steen, Nicola J. Armstrong, Alfredo Ramirez, Ina Giegling, Jari Lahti, Marisa Koini, Tyrone D. Cannon, Gerardo Heiss, Ian Ford, Vilmundur Gudnason, Alex Hatzimanolis, Joshua C. Bis, Albert V. Smith, David Ames, Jan Bressler, Catriona L. K. Barnes, Emily Drabant Conley, Raymond Noordam, Ornit Chiba-Falek, Michael Gill, Simone Reppermund, Katri Räikkönen, Christopher Oldmeadow, Kent D. Taylor, Holger Wagner, Claudia L. Satizabal, Chandra A. Reynolds, Tian Liu, Daniel R. Weinberger, Neil Pendleton, Scott D. Gordon, Eric Boerwinkle, Saskia P. Hagenaars, Andrew M. McIntosh, Igor Rudan, Joey W. Trampush, John Attia, Michael Wagner, K. Hoyan Wen, Judith A. Okely, Aristotle N. Voineskos, Patricia A. Boyle, Danielle M. Dick, Anna C. Need, Markus Scholz, Luca Kleineidam, Aiden Corvin, Ingrid Melle, Margaret J. Wright, Helena Schmidt, Leo-Pekka Lyytikäinen, Natalie Terzikhan, Stuart J. Ritchie, He Gao, Anne C. Böhmer, Dan E. Arking, Narelle K. Hansell, Nicholas G. Martin, Fred W. Sabb, Nathan A. Gillespie, Evangelos Evangelou, Bruce M. Psaty, Anders Lundquist, Oscar L. Lopez, Emma Knowles, Matthew C. Keller, Henry Brodaty, Julian N. Trollor, Gary Donohoe, Ivar Reinvang, Ari Ahola-Olli, Tamara B. Harris, André G. Uitterlinden, David R. Weir, Abbas Dehghan, Sarah E. Harris, P. Eline Slagboom, Chloe Fawns-Ritchie, Paul Elliott, William Ollier, Edythe D. London, Anders M. Dale, Jaakko Kaprio, Catharine R. Gale, Karen A. Mather, Aarno Palotie, Stella G. Giakoumaki, Sven J. van der Lee, Jeannette Simino, Elisabeth Widen, Teresa Lee, Sudheer Giddaluru, Anil K. Malhotra, Philippe Amouyel, Caroline Hayward, Shuo Li, Goran Papenberg, Steffi G. Riedel-Heller, Wei Zhao, Nelson A. Freimer, Simon R. Cox, Yasaman Saba, Andrea Christoforou, Johan G. Eriksson, Eliza Congdon, David J. Porteous, Matthew A. Scult, Eero Vuoksimaa, Veronique Vitart, Derek W. Morris, Sharon L.R. Kardia, Elizabeth G. Holliday, Peter K. Joshi, Suvi P. Rovio, Astri J. Lundervold, J. Wouter Jukema, Aicha Soumare, Stella Trompet, Annette M. Hartmann, Ole A. Andreassen, Erin B. Ware, Matthias Schmid, Perminder S. Sachdev, Grant W. Montgomery, Lars Bertram, Philip L. De Jager, Olli T. Raitakari, Terho Lehtimäki, Arno Villringer, Srdjan Djurovic, David C. Liewald, Sudha Seshadri, Gail Davies, Ahmad R. Hariri, Sara Hägg, Lars Nyberg, Dimitrios Avramopoulos, Muralidharan Sargurupremraj, W. David Hill, Shu-Chen Li, Leonie Weinhold, David J. Stott, David C. Glahn, John B.J. Kwok, Ioanna Tzoulaki, Reinhold Schmidt, Najaf Amin, Lenore J. Launer, Jin Yu, Jessica D. Faul, Adele M. Taylor, Anbupalam Thalamuthu, and Alison Pattie

Subjects
Genetics, 0303 health sciences, media_common.quotation_subject, Longevity, Genetic data, Cognition, Heritability, Significant snps, Biology, Biobank, 03 medical and health sciences, 0302 clinical medicine, Trait, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Abstract

General cognitive function is a prominent human trait associated with many important life outcomes1,2, including longevity3. The substantial heritability of general cognitive function is known to be polygenic, but it has had little explication in terms of the contributing genetic variants4,5,6. Here, we combined cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N=280,360; age range = 16 to 102). We found 9,714 genome-wide significant SNPs (P−8) in 99 independent loci. Most showed clear evidence of functional importance. Among many novel genes associated with general cognitive function wereSGCZ,ATXN1,MAPT,AUTS2, andP2RY6. Within the novel genetic loci were variants associated with neurodegenerative disorders, neurodevelopmental disorders, physical and psychiatric illnesses, brain structure, and BMI. Gene-based analyses found 536 genes significantly associated with general cognitive function; many were highly expressed in the brain, and associated with neurogenesis and dendrite gene sets. Genetic association results predicted up to 4% of general cognitive function variance in independent samples. There was significant genetic overlap between general cognitive function and information processing speed, as well as many health variables including longevity.

Published
2017
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10. Correction: Corrigendum: 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

Author

Albertine J. Oldehinkel, Tõnu Esko, Antonietta Robino, Ingrid B. Borecki, Dragana Vuckovic, Zoltán Kutalik, Douglas M. Ruderfer, Daniel I. Chasman, Daniel Taliun, Henry Völzke, Daniela Ruggiero, Kurt Lohman, Adrienne Tin, Jorma Viikari, Qiong Yang, Martin H. de Borst, Oscar H. Franco, Yongmei Liu, Giorgia Girotto, Vladan Mijatovic, Nicole Probst-Hensch, John Attia, Adamo Pio d. Adamo, Peter P. Pramstaller, Iris M. Heid, Brenda W.J.H. Penninx, Jingzhong Ding, Caroline S. Fox, Edith Hofer, Man Li, Josef Coresh, Frank B. Hu, Abbas Dehghan, Christian Fuchsberger, Albert Hofman, Evelin Mihailov, Elizabeth G. Holliday, Gerjan Navis, Yingchang Lu, Christian Gieger, Murielle Bochud, Lenore J. Launer, Jean-Charles Lambert, Vilmundur Gudnason, Eric Boerwinkle, Paul M. Ridker, Peter Vollenweider, Anna Köttgen, Tamara B. Harris, Ilja M. Nolte, Medea Imboden, Mary F. Feitosa, Ruth J. F. Loos, Simon Höllerer, Massimiliano Cocca, Nina Hutri-Kähönen, Audrey Y. Chu, Karlhans Endlich, Thomas Meitinger, Sylvia Stracke, Cornelia Huth, Reiner Biffar, Cristian Pattaro, Jie Jin Wang, Omri Gottesman, Morris A. Swertz, Shih-Jen Hwang, Marie Metzger, Albert V. Smith, Ming-Huei Chen, Yong Li, Christa Meisinger, Bernhard K. Krämer, Laura Dengler, Daniela Toniolo, Olli T. Raitakari, Rossella Sorice, Bénédicte Stengel, Åsa Johansson, Andres Metspalu, Gerard Tromp, Cinzia Sala, Konstantin Strauch, Stefan Enroth, Helena Schmidt, Sylvia E. Rosas, Vincent Chouraki, Alexander Teumer, Ulf Gyllensten, Mathias Gorski, Giorgio Pistis, Holly Kramer, Gary C. Curhan, Peter J. van der Most, Catherine Helmer, Bamidele O. Tayo, Matthias Olden, Mark McEvoy, André G. Uitterlinden, Rainer Rettig, Rodney J. Scott, Mika Kähönen, Wolfgang König, Georg Homuth, Paolo Gasparini, Sanaz Sedaghat, Matthias Nauck, Carsten A. Böger, Sheila Ulivi, Reinhold E. Schmidt, Leo-Pekka Lyytikäinen, Paul Mitchell, Thor Aspelund, Felicia Gomez, Fernando Rivadeneira, Marilyn C. Cornelis, Yasaman Saba, Gudny Eiriksdottir, Ashok Kumar, Erwin P. Bottinger, Marina Ciullo, Terho Lehtimäki, Harold Snieder, Melanie Waldenberger, Uwe Völker, and Stephen Hancock

Subjects
Genetics, Multidisciplinary, Meta-analysis, Published Erratum, MEDLINE, Genome-wide association study, Computational biology, 1000 Genomes Project, Biology, Typographical error, Spelling
Abstract

Scientific Reports 7: Article number: 45040; published online: 28 April 2017; updated: 26 May 2017 The original version of this Article contained a typographical error in the spelling of the author Martin H. de Borst, which was incorrectly given as Martin de Borst. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2017
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11. Developmental dysplasia of the hip: Impact of sonographic newborn hip screening on the outcome of early treated decentered hip joints—a single center retrospective comparative cohort study based on Graf's method of hip ultrasonography

Author

Frank Fürntrath, Christian Tschauner, Roman Radl, Yasaman Saba, and Andrea Berghold

Subjects
medicine.medical_specialty, Pediatrics, Developmental dysplasia, business.industry, Single Center, Surgery, Pediatrics, Perinatology and Child Health, Clinical information, Orthopedic surgery, Original Clinical Article, medicine, Orthopedics and Sports Medicine, Ultrasonography, business, Cohort study
Abstract

Purpose/Background/Introduction The aim of this study was to retrospectively evaluate the impact of neonatal sonographic hip screening using Graf's method for the management and outcome of orthopaedic treatment of decentered hip joints with developmental dysplasia of the hip (DDH), using three decades (1978–2007) of clinical information compiled in a medical database. Methods Three representative cohorts of consecutive cases of decentered hip joints were selected according to different search criteria and inclusion and exclusion parameters: (1) cohort 1 (1978–1982; n = 80), without sonographic screening; (2) cohort 2.1 (1994–1996; n = 91), with nationwide established general sonographic screening according to the Graf-method; (3) cohort 2.2 (2003–2005; n = 91), with sonographic screening including referred cases for open reduction from non-screened populations. These three cohorts were compared for the following parameters: age at initial treatment, successful closed reduction, necessary overhead traction, necessary adductor-tenotomy, rate of open reduction, rate of avascular necrosis (AVN) and rate of secondary acetabuloplasty. Results The age at initial treatment was reduced from 5.5 months in the first cohort to 2 months in the two subsequent two cohorts and the rate of successful closed reduction increased from 88.7 to 98.9 and 95.6%, respectively. There was a statistically significant improvement in six out of seven parameters with sonographic hip screening; only the rate of secondary acetabuloplasty did not improve significantly. Conclusion Compared to the era before the institution of a sonographic hip screening programme according to the Graf-method in Austria in 1992, ultrasound screening based-treatment of decentered hip joints has become safer, shorter and simpler: “safer” means lower rate of AVN, “shorter” means less treatment time due to earlier onset and “simpler” means that the devices are now less invasive and highly standardized.

Published
2011
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