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1. Genetic risk factors underlying white matter hyperintensities and cortical atrophy

Author

Yash Patel, Jean Shin, Eeva Sliz, Ariana Tang, Aniket Mishra, Rui Xia, Edith Hofer, Hema Sekhar Reddy Rajula, Ruiqi Wang, Frauke Beyer, Katrin Horn, Max Riedl, Jing Yu, Henry Völzke, Robin Bülow, Uwe Völker, Stefan Frenzel, Katharina Wittfeld, Sandra Van der Auwera, Thomas H. Mosley, Vincent Bouteloup, Jean-Charles Lambert, Geneviève Chêne, Carole Dufouil, Christophe Tzourio, Jean-François Mangin, Rebecca F. Gottesman, Myriam Fornage, Reinhold Schmidt, Qiong Yang, Veronica Witte, Markus Scholz, Markus Loeffler, Gennady V. Roshchupkin, M. Arfan Ikram, Hans J. Grabe, Sudha Seshadri, Stephanie Debette, Tomas Paus, and Zdenka Pausova

Subjects
Science
Abstract

Abstract White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical ‘atrophy’ identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical ‘atrophy’ showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. 15 of the 20 loci regulated the expression of 54 genes in the cerebral cortex that, together with their co-expressed genes, were enriched in biological processes of axonal cytoskeleton and intracellular transport. The white matter hyperintensities-cortical thickness associations were most pronounced in cortical regions with higher expression of genes specific to excitatory neurons with long-range axons traversing through the white matter. The meta-GWAS-based polygenic risk score predicts vascular and all-cause dementia in an independent sample of 500,348 individuals. Thus, the genetics of white matter hyperintensities-related cortical atrophy involves vascular and neuronal processes and increases dementia risk.

Published
2024
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2. RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening

Author

Shrestha Ghosh, Mileena T. Nguyen, Ha Eun Choi, Maximilian Stahl, Annemarie Luise Kühn, Sandra Van der Auwera, Hans J. Grabe, Henry Völzke, Georg Homuth, Samuel A. Myers, Cory M. Hogaboam, Imre Noth, Fernando J. Martinez, Gregory A. Petsko, and Laurie H. Glimcher

Subjects
Science
Abstract

Abstract Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.

Published
2024
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3. Multi-site benchmark classification of major depressive disorder using machine learning on cortical and subcortical measures

Author

Vladimir Belov, Tracy Erwin-Grabner, Moji Aghajani, Andre Aleman, Alyssa R. Amod, Zeynep Basgoze, Francesco Benedetti, Bianca Besteher, Robin Bülow, Christopher R. K. Ching, Colm G. Connolly, Kathryn Cullen, Christopher G. Davey, Danai Dima, Annemiek Dols, Jennifer W. Evans, Cynthia H. Y. Fu, Ali Saffet Gonul, Ian H. Gotlib, Hans J. Grabe, Nynke Groenewold, J Paul Hamilton, Ben J. Harrison, Tiffany C. Ho, Benson Mwangi, Natalia Jaworska, Neda Jahanshad, Bonnie Klimes-Dougan, Sheri-Michelle Koopowitz, Thomas Lancaster, Meng Li, David E. J. Linden, Frank P. MacMaster, David M. A. Mehler, Elisa Melloni, Bryon A. Mueller, Amar Ojha, Mardien L. Oudega, Brenda W. J. H. Penninx, Sara Poletti, Edith Pomarol-Clotet, Maria J. Portella, Elena Pozzi, Liesbeth Reneman, Matthew D. Sacchet, Philipp G. Sämann, Anouk Schrantee, Kang Sim, Jair C. Soares, Dan J. Stein, Sophia I. Thomopoulos, Aslihan Uyar-Demir, Nic J. A. van der Wee, Steven J. A. van der Werff, Henry Völzke, Sarah Whittle, Katharina Wittfeld, Margaret J. Wright, Mon-Ju Wu, Tony T. Yang, Carlos Zarate, Dick J. Veltman, Lianne Schmaal, Paul M. Thompson, Roberto Goya-Maldonado, and the ENIGMA Major Depressive Disorder working group

Subjects
Medicine, Science
Abstract

Abstract Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.

Published
2024
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4. An explorative cross-sectional analysis of mental health shame and help-seeking intentions in different lifestyles

Author

Claudia Helmert, Toni Fleischer, Sven Speerforck, Christine Ulke, Laura Altweck, Stefanie Hahm, Holger Muehlan, Silke Schmidt, Hans J. Grabe, Henry Völzke, and Georg Schomerus

Subjects
Medicine, Science
Abstract

Abstract To identify und support particular target groups for mental health prevention, we explore the links between shame and help-seeking intentions concerning mental health in different lifestyles (based on socioeconomic status as well as health-related behaviors). Lifestyles were operationalized by nine confirmatory, homogenous clusters of the sample. These clusters are based on individuals’ similarities in sociodemographic aspects and health behavior. Analyses included t tests, Chi-square, ANOVA, regressions investigating in sociodemographic characteristics. Hierarchical linear models examining cross-sectional associations of shame and willingness to seek help for different lifestyles of participants of the Study of Health in Pomerania (SHIP-START-1 and SHIP-START-3, data collected 2002–2006 and 2014–2016; n = 1630). Hierarchical linear models showed small context effects for lifestyle-related associations of shame and willingness to seek help. For younger as well as male participants, lifestyles indicated different associations of shame and help-seeking intentions: Especially the lifestyles with unhealthy behaviors and high as well as low socioeconomic status resulted in higher shame being associated with low help-seeking intentions in case of mental illness. Lifestyle clusters might be a useful tool to identify marginalized groups with unhealthy behaviors, which should be addressed by interventions and prevention programs.

Published
2023
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5. DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases

Author

Matthias Wielscher, Pooja R. Mandaviya, Brigitte Kuehnel, Roby Joehanes, Rima Mustafa, Oliver Robinson, Yan Zhang, Barbara Bodinier, Esther Walton, Pashupati P. Mishra, Pascal Schlosser, Rory Wilson, Pei-Chien Tsai, Saranya Palaniswamy, Riccardo E. Marioni, Giovanni Fiorito, Giovanni Cugliari, Ville Karhunen, Mohsen Ghanbari, Bruce M. Psaty, Marie Loh, Joshua C. Bis, Benjamin Lehne, Nona Sotoodehnia, Ian J. Deary, Marc Chadeau-Hyam, Jennifer A. Brody, Alexia Cardona, Elizabeth Selvin, Alicia K. Smith, Andrew H. Miller, Mylin A. Torres, Eirini Marouli, Xin Gào, Joyce B. J. van Meurs, Johanna Graf-Schindler, Wolfgang Rathmann, Wolfgang Koenig, Annette Peters, Wolfgang Weninger, Matthias Farlik, Tao Zhang, Wei Chen, Yujing Xia, Alexander Teumer, Matthias Nauck, Hans J. Grabe, Macus Doerr, Terho Lehtimäki, Weihua Guan, Lili Milani, Toshiko Tanaka, Krista Fisher, Lindsay L. Waite, Silva Kasela, Paolo Vineis, Niek Verweij, Pim van der Harst, Licia Iacoviello, Carlotta Sacerdote, Salvatore Panico, Vittorio Krogh, Rosario Tumino, Evangelia Tzala, Giuseppe Matullo, Mikko A. Hurme, Olli T. Raitakari, Elena Colicino, Andrea A. Baccarelli, Mika Kähönen, Karl-Heinz Herzig, Shengxu Li, BIOS consortium, Karen N. Conneely, Jaspal S. Kooner, Anna Köttgen, Bastiaan T. Heijmans, Panos Deloukas, Caroline Relton, Ken K. Ong, Jordana T. Bell, Eric Boerwinkle, Paul Elliott, Hermann Brenner, Marian Beekman, Daniel Levy, Melanie Waldenberger, John C. Chambers, Abbas Dehghan, and Marjo-Riitta Järvelin

Subjects
Science
Abstract

Chronic inflammation, marked by C-reactive protein, has been associated with changes in methylation, but the causal relationship is unclear. Here, the authors perform a Epigenome-wide association meta-analysis for C-reactive protein levels and find that these methylation changes are likely the consequence of inflammation and could contribute to disease.

Published
2022
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6. The relation between childhood adversity and adult obesity in a population-based study in women and men

Author

Toni Fleischer, Christine Ulke, Manfred Beutel, Harald Binder, Elmar Brähler, Hamimatunnisa Johar, Seryan Atasoy, Johannes Kruse, Daniëlle Otten, Ana N. Tibubos, Daniela Zöller, Sven Speerforck, Hans J. Grabe, Karl-Heinz Ladwig, and Georg Schomerus

Subjects
Medicine, Science
Abstract

Abstract Childhood maltreatment has been shown to relate to adult obesity. In this epidemiological study, we investigate the association between childhood maltreatment and waist-to-height-ratio (WHtR) in a sample of the German adult population, comprising of N = 2936 participants. WHtR, an indicator for risk of obesity, was the primary outcome. Childhood maltreatment was assessed by the Childhood Trauma Screener (CTS), which assesses emotional and physical neglect, abuse as well as sexual abuse. Cohort-data were harmonized and analyzed within DataSHIELD. We used multivariable regression models to estimate the association of childhood maltreatment and WHtR at different levels of adjustments for potential confounders. Overall childhood maltreatment was associated with a higher WHtR in both sexes (women: p = 0.004, men: p

Published
2021
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7. Associated factors of white matter hyperintensity volume: a machine-learning approach

Author

Sergio Grosu, Susanne Rospleszcz, Felix Hartmann, Mohamad Habes, Fabian Bamberg, Christopher L. Schlett, Franziska Galie, Roberto Lorbeer, Sigrid Auweter, Sonja Selder, Robin Buelow, Margit Heier, Wolfgang Rathmann, Katharina Mueller-Peltzer, Karl-Heinz Ladwig, Hans J. Grabe, Annette Peters, Birgit B. Ertl-Wagner, and Sophia Stoecklein

Subjects
Medicine, Science
Abstract

Abstract To identify the most important parameters associated with cerebral white matter hyperintensities (WMH), in consideration of potential collinearity, we used a data-driven machine-learning approach. We analysed two independent cohorts (KORA and SHIP). WMH volumes were derived from cMRI-images (FLAIR). 90 (KORA) and 34 (SHIP) potential determinants of WMH including measures of diabetes, blood-pressure, medication-intake, sociodemographics, life-style factors, somatic/depressive-symptoms and sleep were collected. Elastic net regression was used to identify relevant predictor covariates associated with WMH volume. The ten most frequently selected variables in KORA were subsequently examined for robustness in SHIP. The final KORA sample consisted of 370 participants (58% male; age 55.7 ± 9.1 years), the SHIP sample comprised 854 participants (38% male; age 53.9 ± 9.3 years). The most often selected and highly replicable parameters associated with WMH volume were in descending order age, hypertension, components of the social environment (i.e. widowed, living alone) and prediabetes. A systematic machine-learning based analysis of two independent, population-based cohorts showed, that besides age and hypertension, prediabetes and components of the social environment might play important roles in the development of WMH. Our results enable personal risk assessment for the development of WMH and inform prevention strategies tailored to the individual patient.

Published
2021
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8. Cerebral small vessel disease genomics and its implications across the lifespan

Author

Muralidharan Sargurupremraj, Hideaki Suzuki, Xueqiu Jian, Chloé Sarnowski, Tavia E. Evans, Joshua C. Bis, Gudny Eiriksdottir, Saori Sakaue, Natalie Terzikhan, Mohamad Habes, Wei Zhao, Nicola J. Armstrong, Edith Hofer, Lisa R. Yanek, Saskia P. Hagenaars, Rajan B. Kumar, Erik B. van den Akker, Rebekah E. McWhirter, Stella Trompet, Aniket Mishra, Yasaman Saba, Claudia L. Satizabal, Gregory Beaudet, Laurent Petit, Ami Tsuchida, Laure Zago, Sabrina Schilling, Sigurdur Sigurdsson, Rebecca F. Gottesman, Cora E. Lewis, Neelum T. Aggarwal, Oscar L. Lopez, Jennifer A. Smith, Maria C. Valdés Hernández, Jeroen van der Grond, Margaret J. Wright, Maria J. Knol, Marcus Dörr, Russell J. Thomson, Constance Bordes, Quentin Le Grand, Marie-Gabrielle Duperron, Albert V. Smith, David S. Knopman, Pamela J. Schreiner, Denis A. Evans, Jerome I. Rotter, Alexa S. Beiser, Susana Muñoz Maniega, Marian Beekman, Julian Trollor, David J. Stott, Meike W. Vernooij, Katharina Wittfeld, Wiro J. Niessen, Aicha Soumaré, Eric Boerwinkle, Stephen Sidney, Stephen T. Turner, Gail Davies, Anbupalam Thalamuthu, Uwe Völker, Mark A. van Buchem, R. Nick Bryan, Josée Dupuis, Mark E. Bastin, David Ames, Alexander Teumer, Philippe Amouyel, John B. Kwok, Robin Bülow, Ian J. Deary, Peter R. Schofield, Henry Brodaty, Jiyang Jiang, Yasuharu Tabara, Kazuya Setoh, Susumu Miyamoto, Kazumichi Yoshida, Manabu Nagata, Yoichiro Kamatani, Fumihiko Matsuda, Bruce M. Psaty, David A. Bennett, Philip L. De Jager, Thomas H. Mosley, Perminder S. Sachdev, Reinhold Schmidt, Helen R. Warren, Evangelos Evangelou, David-Alexandre Trégouët, International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium (IHGC), Mohammad A. Ikram, Wei Wen, Charles DeCarli, Velandai K. Srikanth, J. Wouter Jukema, Eline P. Slagboom, Sharon L. R. Kardia, Yukinori Okada, Bernard Mazoyer, Joanna M. Wardlaw, Paul A. Nyquist, Karen A. Mather, Hans J. Grabe, Helena Schmidt, Cornelia M. Van Duijn, Vilmundur Gudnason, William T. Longstreth, Lenore J. Launer, Mark Lathrop, Sudha Seshadri, Christophe Tzourio, Hieab H. Adams, Paul M. Matthews, Myriam Fornage, and Stéphanie Debette

Subjects
Science
Abstract

White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

Published
2020
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9. Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults

Author

Edith Hofer, Gennady V. Roshchupkin, Hieab H. H. Adams, Maria J. Knol, Honghuang Lin, Shuo Li, Habil Zare, Shahzad Ahmad, Nicola J. Armstrong, Claudia L. Satizabal, Manon Bernard, Joshua C. Bis, Nathan A. Gillespie, Michelle Luciano, Aniket Mishra, Markus Scholz, Alexander Teumer, Rui Xia, Xueqiu Jian, Thomas H. Mosley, Yasaman Saba, Lukas Pirpamer, Stephan Seiler, James T. Becker, Owen Carmichael, Jerome I. Rotter, Bruce M. Psaty, Oscar L. Lopez, Najaf Amin, Sven J. van der Lee, Qiong Yang, Jayandra J. Himali, Pauline Maillard, Alexa S. Beiser, Charles DeCarli, Sherif Karama, Lindsay Lewis, Mat Harris, Mark E. Bastin, Ian J. Deary, A. Veronica Witte, Frauke Beyer, Markus Loeffler, Karen A. Mather, Peter R. Schofield, Anbupalam Thalamuthu, John B. Kwok, Margaret J. Wright, David Ames, Julian Trollor, Jiyang Jiang, Henry Brodaty, Wei Wen, Meike W. Vernooij, Albert Hofman, André G. Uitterlinden, Wiro J. Niessen, Katharina Wittfeld, Robin Bülow, Uwe Völker, Zdenka Pausova, G. Bruce Pike, Sophie Maingault, Fabrice Crivello, Christophe Tzourio, Philippe Amouyel, Bernard Mazoyer, Michael C. Neale, Carol E. Franz, Michael J. Lyons, Matthew S. Panizzon, Ole A. Andreassen, Anders M. Dale, Mark Logue, Katrina L. Grasby, Neda Jahanshad, Jodie N. Painter, Lucía Colodro-Conde, Janita Bralten, Derrek P. Hibar, Penelope A. Lind, Fabrizio Pizzagalli, Jason L. Stein, Paul M. Thompson, Sarah E. Medland, ENIGMA consortium, Perminder S. Sachdev, William S. Kremen, Joanna M. Wardlaw, Arno Villringer, Cornelia M. van Duijn, Hans J. Grabe, William T. Longstreth, Myriam Fornage, Tomas Paus, Stephanie Debette, M. Arfan Ikram, Helena Schmidt, Reinhold Schmidt, and Sudha Seshadri

Subjects
Science
Abstract

Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.

Published
2020
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10. Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration

Author

Raymond Noordam, Maxime M. Bos, Heming Wang, Thomas W. Winkler, Amy R. Bentley, Tuomas O. Kilpeläinen, Paul S. de Vries, Yun Ju Sung, Karen Schwander, Brian E. Cade, Alisa Manning, Hugues Aschard, Michael R. Brown, Han Chen, Nora Franceschini, Solomon K. Musani, Melissa Richard, Dina Vojinovic, Stella Aslibekyan, Traci M. Bartz, Lisa de las Fuentes, Mary Feitosa, Andrea R. Horimoto, Marjan Ilkov, Minjung Kho, Aldi Kraja, Changwei Li, Elise Lim, Yongmei Liu, Dennis O. Mook-Kanamori, Tuomo Rankinen, Salman M. Tajuddin, Ashley van der Spek, Zhe Wang, Jonathan Marten, Vincent Laville, Maris Alver, Evangelos Evangelou, Maria E. Graff, Meian He, Brigitte Kühnel, Leo-Pekka Lyytikäinen, Pedro Marques-Vidal, Ilja M. Nolte, Nicholette D. Palmer, Rainer Rauramaa, Xiao-Ou Shu, Harold Snieder, Stefan Weiss, Wanqing Wen, Lisa R. Yanek, Correa Adolfo, Christie Ballantyne, Larry Bielak, Nienke R. Biermasz, Eric Boerwinkle, Niki Dimou, Gudny Eiriksdottir, Chuan Gao, Sina A. Gharib, Daniel J. Gottlieb, José Haba-Rubio, Tamara B. Harris, Sami Heikkinen, Raphaël Heinzer, James E. Hixson, Georg Homuth, M. Arfan Ikram, Pirjo Komulainen, Jose E. Krieger, Jiwon Lee, Jingmin Liu, Kurt K. Lohman, Annemarie I. Luik, Reedik Mägi, Lisa W. Martin, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Mike A. Nalls, Jeff O’Connell, Annette Peters, Patricia Peyser, Olli T. Raitakari, Alex P. Reiner, Patrick C. N. Rensen, Treva K. Rice, Stephen S. Rich, Till Roenneberg, Jerome I. Rotter, Pamela J. Schreiner, James Shikany, Stephen S. Sidney, Mario Sims, Colleen M. Sitlani, Tamar Sofer, Konstantin Strauch, Morris A. Swertz, Kent D. Taylor, André G. Uitterlinden, Cornelia M. van Duijn, Henry Völzke, Melanie Waldenberger, Robert B. Wallance, Ko Willems van Dijk, Caizheng Yu, Alan B. Zonderman, Diane M. Becker, Paul Elliott, Tõnu Esko, Christian Gieger, Hans J. Grabe, Timo A. Lakka, Terho Lehtimäki, Kari E. North, Brenda W. J. H. Penninx, Peter Vollenweider, Lynne E. Wagenknecht, Tangchun Wu, Yong-Bing Xiang, Wei Zheng, Donna K. Arnett, Claude Bouchard, Michele K. Evans, Vilmundur Gudnason, Sharon Kardia, Tanika N. Kelly, Stephen B. Kritchevsky, Ruth J. F. Loos, Alexandre C. Pereira, Mike Province, Bruce M. Psaty, Charles Rotimi, Xiaofeng Zhu, Najaf Amin, L. Adrienne Cupples, Myriam Fornage, Ervin F. Fox, Xiuqing Guo, W. James Gauderman, Kenneth Rice, Charles Kooperberg, Patricia B. Munroe, Ching-Ti Liu, Alanna C. Morrison, Dabeeru C. Rao, Diana van Heemst, and Susan Redline

Subjects
Science
Abstract

Sleep duration is associated with an adverse lipid profile. Here, the authors perform genome-wide gene-by-sleep interaction analysis and find 49 previously unreported lipid loci when considering short or long total sleep time.

Published
2019
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11. Novel genetic loci associated with hippocampal volume

Author

Derrek P. Hibar, Hieab H. H. Adams, Neda Jahanshad, Ganesh Chauhan, Jason L. Stein, Edith Hofer, Miguel E. Renteria, Joshua C. Bis, Alejandro Arias-Vasquez, M. Kamran Ikram, Sylvane Desrivières, Meike W. Vernooij, Lucija Abramovic, Saud Alhusaini, Najaf Amin, Micael Andersson, Konstantinos Arfanakis, Benjamin S. Aribisala, Nicola J. Armstrong, Lavinia Athanasiu, Tomas Axelsson, Ashley H. Beecham, Alexa Beiser, Manon Bernard, Susan H. Blanton, Marc M. Bohlken, Marco P. Boks, Janita Bralten, Adam M. Brickman, Owen Carmichael, M. Mallar Chakravarty, Qiang Chen, Christopher R. K. Ching, Vincent Chouraki, Gabriel Cuellar-Partida, Fabrice Crivello, Anouk Den Braber, Nhat Trung Doan, Stefan Ehrlich, Sudheer Giddaluru, Aaron L. Goldman, Rebecca F. Gottesman, Oliver Grimm, Michael E. Griswold, Tulio Guadalupe, Boris A. Gutman, Johanna Hass, Unn K. Haukvik, David Hoehn, Avram J. Holmes, Martine Hoogman, Deborah Janowitz, Tianye Jia, Kjetil N. Jørgensen, Nazanin Karbalai, Dalia Kasperaviciute, Sungeun Kim, Marieke Klein, Bernd Kraemer, Phil H. Lee, David C. M. Liewald, Lorna M. Lopez, Michelle Luciano, Christine Macare, Andre F. Marquand, Mar Matarin, Karen A. Mather, Manuel Mattheisen, David R. McKay, Yuri Milaneschi, Susana Muñoz Maniega, Kwangsik Nho, Allison C. Nugent, Paul Nyquist, Loes M. Olde Loohuis, Jaap Oosterlaan, Martina Papmeyer, Lukas Pirpamer, Benno Pütz, Adaikalavan Ramasamy, Jennifer S. Richards, Shannon L. Risacher, Roberto Roiz-Santiañez, Nanda Rommelse, Stefan Ropele, Emma J. Rose, Natalie A. Royle, Tatjana Rundek, Philipp G. Sämann, Arvin Saremi, Claudia L. Satizabal, Lianne Schmaal, Andrew J. Schork, Li Shen, Jean Shin, Elena Shumskaya, Albert V. Smith, Emma Sprooten, Lachlan T. Strike, Alexander Teumer, Diana Tordesillas-Gutierrez, Roberto Toro, Daniah Trabzuni, Stella Trompet, Dhananjay Vaidya, Jeroen Van der Grond, Sven J. Van der Lee, Dennis Van der Meer, Marjolein M. J. Van Donkelaar, Kristel R. Van Eijk, Theo G. M. Van Erp, Daan Van Rooij, Esther Walton, Lars T. Westlye, Christopher D. Whelan, Beverly G. Windham, Anderson M. Winkler, Katharina Wittfeld, Girma Woldehawariat, Christiane Wolf, Thomas Wolfers, Lisa R. Yanek, Jingyun Yang, Alex Zijdenbos, Marcel P. Zwiers, Ingrid Agartz, Laura Almasy, David Ames, Philippe Amouyel, Ole A. Andreassen, Sampath Arepalli, Amelia A. Assareh, Sandra Barral, Mark E. Bastin, Diane M. Becker, James T. Becker, David A. Bennett, John Blangero, Hans van Bokhoven, Dorret I. Boomsma, Henry Brodaty, Rachel M. Brouwer, Han G. Brunner, Randy L. Buckner, Jan K. Buitelaar, Kazima B. Bulayeva, Wiepke Cahn, Vince D. Calhoun, Dara M. Cannon, Gianpiero L. Cavalleri, Ching-Yu Cheng, Sven Cichon, Mark R. Cookson, Aiden Corvin, Benedicto Crespo-Facorro, Joanne E. Curran, Michael Czisch, Anders M. Dale, Gareth E. Davies, Anton J. M. De Craen, Eco J. C. De Geus, Philip L. De Jager, Greig I. De Zubicaray, Ian J. Deary, Stéphanie Debette, Charles DeCarli, Norman Delanty, Chantal Depondt, Anita DeStefano, Allissa Dillman, Srdjan Djurovic, Gary Donohoe, Wayne C. Drevets, Ravi Duggirala, Thomas D. Dyer, Christian Enzinger, Susanne Erk, Thomas Espeseth, Iryna O. Fedko, Guillén Fernández, Luigi Ferrucci, Simon E. Fisher, Debra A. Fleischman, Ian Ford, Myriam Fornage, Tatiana M. Foroud, Peter T. Fox, Clyde Francks, Masaki Fukunaga, J. Raphael Gibbs, David C. Glahn, Randy L. Gollub, Harald H. H. Göring, Robert C. Green, Oliver Gruber, Vilmundur Gudnason, Sebastian Guelfi, Asta K. Håberg, Narelle K. Hansell, John Hardy, Catharina A. Hartman, Ryota Hashimoto, Katrin Hegenscheid, Andreas Heinz, Stephanie Le Hellard, Dena G. Hernandez, Dirk J. Heslenfeld, Beng-Choon Ho, Pieter J. Hoekstra, Wolfgang Hoffmann, Albert Hofman, Florian Holsboer, Georg Homuth, Norbert Hosten, Jouke-Jan Hottenga, Matthew Huentelman, Hilleke E. Hulshoff Pol, Masashi Ikeda, Clifford R. Jack Jr, Mark Jenkinson, Robert Johnson, Erik G. Jönsson, J. Wouter Jukema, René S. Kahn, Ryota Kanai, Iwona Kloszewska, David S. Knopman, Peter Kochunov, John B. Kwok, Stephen M. Lawrie, Hervé Lemaître, Xinmin Liu, Dan L. Longo, Oscar L. Lopez, Simon Lovestone, Oliver Martinez, Jean-Luc Martinot, Venkata S. Mattay, Colm McDonald, Andrew M. McIntosh, Francis J. McMahon, Katie L. McMahon, Patrizia Mecocci, Ingrid Melle, Andreas Meyer-Lindenberg, Sebastian Mohnke, Grant W. Montgomery, Derek W. Morris, Thomas H. Mosley, Thomas W. Mühleisen, Bertram Müller-Myhsok, Michael A. Nalls, Matthias Nauck, Thomas E. Nichols, Wiro J. Niessen, Markus M. Nöthen, Lars Nyberg, Kazutaka Ohi, Rene L. Olvera, Roel A. Ophoff, Massimo Pandolfo, Tomas Paus, Zdenka Pausova, Brenda W. J. H. Penninx, G. Bruce Pike, Steven G. Potkin, Bruce M. Psaty, Simone Reppermund, Marcella Rietschel, Joshua L. Roffman, Nina Romanczuk-Seiferth, Jerome I. Rotter, Mina Ryten, Ralph L. Sacco, Perminder S. Sachdev, Andrew J. Saykin, Reinhold Schmidt, Helena Schmidt, Peter R. Schofield, Sigurdur Sigursson, Andrew Simmons, Andrew Singleton, Sanjay M. Sisodiya, Colin Smith, Jordan W. Smoller, Hilkka Soininen, Vidar M. Steen, David J. Stott, Jessika E. Sussmann, Anbupalam Thalamuthu, Arthur W. Toga, Bryan J. Traynor, Juan Troncoso, Magda Tsolaki, Christophe Tzourio, Andre G. Uitterlinden, Maria C. Valdés Hernández, Marcel Van der Brug, Aad van der Lugt, Nic J. A. van der Wee, Neeltje E. M. Van Haren, Dennis van ’t Ent, Marie-Jose Van Tol, Badri N. Vardarajan, Bruno Vellas, Dick J. Veltman, Henry Völzke, Henrik Walter, Joanna M. Wardlaw, Thomas H. Wassink, Michael E. Weale, Daniel R. Weinberger, Michael W. Weiner, Wei Wen, Eric Westman, Tonya White, Tien Y. Wong, Clinton B. Wright, Ronald H. Zielke, Alan B. Zonderman, Nicholas G. Martin, Cornelia M. Van Duijn, Margaret J. Wright, W. T. Longstreth, Gunter Schumann, Hans J. Grabe, Barbara Franke, Lenore J. Launer, Sarah E. Medland, Sudha Seshadri, Paul M. Thompson, and M. Arfan Ikram

Subjects
Science
Abstract

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

Published
2017
Full Text
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12. Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration

Author

Sina A. Gharib, Kenneth Rice, Donna K. Arnett, Tõnu Esko, Annemarie I. Luik, Niki Dimou, Dabeeru C. Rao, Pamela J. Schreiner, Melissa A. Richard, Reedik Mägi, Nicholette D. Palmer, Stefan Weiss, Han Chen, Solomon K. Musani, W. James Gauderman, Christian Gieger, Kari E. North, Salman M. Tajuddin, Diana van Heemst, Rainer Rauramaa, Stephen B. Kritchevsky, Henry Völzke, Minjung Kho, Michele K. Evans, Ruth J. F. Loos, Correa Adolfo, Pedro Marques-Vidal, Diane M. Becker, Claude Bouchard, José Haba-Rubio, Georg Homuth, Kurt Lohman, Nora Franceschini, Caizheng Yu, Peter Vollenweider, Ervin F. Fox, Thomas Meitinger, Karen Schwander, Heming Wang, Morris A. Swertz, Aldi T. Kraja, José Eduardo Krieger, Xiuqing Guo, Tangchun Wu, Raymond Noordam, Yongmei Liu, Michael R. Brown, Patrick C.N. Rensen, Annette Peters, Jingmin Liu, Tuomo Rankinen, Robert B. Wallance, Timo A. Lakka, Stephen S. Rich, Yun Ju Sung, Meian He, Till Roenneberg, Wanqing Wen, Dennis O. Mook-Kanamori, M. A. Province, Evangelos Evangelou, L. Adrienne Cupples, Maxime M Bos, Paul S. de Vries, Hans J. Grabe, Lisa R. Yanek, Jiwon Lee, Mario Sims, Bruce M. Psaty, Treva Rice, Tanika N. Kelly, Brenda W.J.H. Penninx, Brigitte Kühnel, Maria E. Graff, Alexandre C. Pereira, Daniel J. Gottlieb, Charles N. Rotimi, Lynne E. Wagenknecht, Ashley van der Spek, Lisa W. Martin, Jeffrey R. O'Connell, Changwei Li, James E. Hixson, Chuan Gao, Alisa K. Manning, Sharon L.R. Kardia, Stella Aslibekyan, Andres Metspalu, Sami Heikkinen, Maris Alver, Xiao-Ou Shu, Amy R. Bentley, Susan Redline, Konstantin Strauch, Tamara B. Harris, Yuri Milaneschi, L.F. Bielak, Marjan Ilkov, Myriam Fornage, Ilja M. Nolte, André G. Uitterlinden, Dina Vojinovic, Hugues Aschard, Paul Elliott, Kent D. Taylor, Najaf Amin, James M. Shikany, Yong-Bing Xiang, Jerome I. Rotter, Vilmundur Gudnason, Cornelia M. van Duijn, Ko Willems van Dijk, Andrea R. V. R. Horimoto, Jonathan Marten, Olli T. Raitakari, Vincent Laville, Pirjo Komulainen, Zhe Wang, Traci M. Bartz, Mary F. Feitosa, Mike A. Nalls, Eric Boerwinkle, Alanna C. Morrison, Melanie Waldenberger, Alexander P. Reiner, Christie M. Ballantyne, Wei Zheng, Raphael Heinzer, M. Arfan Ikram, Colleen M. Sitlani, Lisa de las Fuentes, Patricia B. Munroe, Patricia A. Peyser, Brian E. Cade, Tamar Sofer, Xiaofeng Zhu, Nienke R. Biermasz, Harold Snieder, Elise Lim, Tuomas O. Kilpeläinen, Ching-Ti Liu, Terho Lehtimäki, Thomas W. Winkler, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Stephen Sidney, Alan B. Zonderman, Charles Kooperberg, Leiden University Medical Center (LUMC), Universiteit Leiden, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Universität Regensburg (UR), National Institutes of Health [Bethesda] (NIH), University of Copenhagen = Københavns Universitet (UCPH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), The University of Texas Health Science Center at Houston (UTHealth), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Massachusetts General Hospital [Boston], Harvard T.H. Chan School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), University of Mississippi Medical Center (UMMC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Alabama at Birmingham [ Birmingham] (UAB), University of Washington [Seattle], Universidade de São Paulo Medical School (FMUSP), Icelandic Heart Association [Kopavogur, Iceland] (IHA), University of Michigan [Ann Arbor], University of Michigan System, University of Georgia [USA], School of Public Health [Boston], Boston University [Boston] (BU), Wake Forest University, Pennington Biomedical Research Center, Louisiana State University (LSU), University of Edinburgh, University of Tartu, Imperial College London, University of Ioannina, Huazhong University of Science and Technology [Wuhan] (HUST), Helmholtz Zentrum München = German Research Center for Environmental Health, Fimlab Laboratories [Tampere, Finland], University of Tampere [Finland], Lausanne University Hospital, University of Groningen [Groningen], This project was supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF–6110-00183) and the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848 and NNF15CC0018486). Diana van Heemst was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). Susan Redline was supported in part by NIH R35HL135818 and HL11338., European Project: 602757,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,HUMAN(2013), Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, University of Copenhagen = Københavns Universitet (KU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Helmholtz-Zentrum München (HZM), Van Duijn, CM, Wang, Heming [0000-0002-1486-7495], Bentley, Amy R [0000-0002-0827-9101], Schwander, Karen [0000-0002-0193-4134], Manning, Alisa [0000-0003-0247-902X], Aschard, Hugues [0000-0002-7554-6783], Richard, Melissa [0000-0003-0129-9860], de Las Fuentes, Lisa [0000-0002-4689-325X], Feitosa, Mary [0000-0002-0933-2410], van der Spek, Ashley [0000-0001-7136-0159], Wang, Zhe [0000-0002-8046-4969], Marten, Jonathan [0000-0001-6916-2014], Laville, Vincent [0000-0003-4946-698X], Evangelou, Evangelos [0000-0002-5488-2999], He, Meian [0000-0002-2096-921X], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Marques-Vidal, Pedro [0000-0002-4548-8500], Nolte, Ilja M [0000-0001-5047-4077], Palmer, Nicholette D [0000-0001-8883-2511], Snieder, Harold [0000-0003-1949-2298], Weiss, Stefan [0000-0002-3553-4315], Yanek, Lisa R [0000-0001-7117-1075], Adolfo, Correa [0000-0002-9501-600X], Dimou, Niki [0000-0003-1678-9328], Heikkinen, Sami [0000-0002-6083-2402], Ikram, M Arfan [0000-0003-0372-8585], Krieger, Jose E [0000-0001-5464-1792], Lee, Jiwon [0000-0002-4079-7494], Liu, Jingmin [0000-0003-0001-6013], Martin, Lisa W [0000-0003-4352-0914], Metspalu, Andres [0000-0002-3718-796X], Rensen, Patrick CN [0000-0002-8455-4988], Rich, Stephen S [0000-0003-3872-7793], Rotter, Jerome I [0000-0001-7191-1723], Sofer, Tamar [0000-0001-8520-8860], Taylor, Kent D [0000-0002-2756-4370], Uitterlinden, André G [0000-0002-7276-3387], van Dijk, Ko Willems [0000-0002-2172-7394], Elliott, Paul [0000-0002-7511-5684], Esko, Tõnu [0000-0003-1982-6569], Grabe, Hans J [0000-0003-3684-4208], Zheng, Wei [0000-0003-1226-070X], Bouchard, Claude [0000-0002-0048-491X], Gudnason, Vilmundur [0000-0001-5696-0084], Loos, Ruth JF [0000-0002-8532-5087], Cupples, L Adrienne [0000-0003-0273-7965], Munroe, Patricia B [0000-0002-4176-2947], Liu, Ching-Ti [0000-0002-0703-0742], Apollo - University of Cambridge Repository, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Home Office, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), and UK DRI Ltd

Subjects
Male, 0301 basic medicine, Epidemiology, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Svefnrannsóknir, 0302 clinical medicine, MESH: Aged, 80 and over, Polymorphism (computer science), lcsh:Science, MESH: Phylogeny, Phylogeny, Aged, 80 and over, Genetics, MESH: Aged, [STAT.AP]Statistics [stat]/Applications [stat.AP], Multidisciplinary, MESH: Middle Aged, medicine.diagnostic_test, MESH: Polymorphism, Single Nucleotide, Chromosome Mapping, Middle Aged, Explained variation, Lipids, Sleep in non-human animals, Blóðfita, ddc, 3. Good health, MESH: Young Adult, Female, lipids (amino acids, peptides, and proteins), Erfðarannsóknir, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, Adolescent, MESH: Sleep, Science, Biology, Polymorphism, Single Nucleotide, MESH: Genetic Loci, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Phylogenetics, Svefn, medicine, Humans, SNP, Dyslipidaemias, Aged, MESH: Adolescent, MESH: Humans, Faraldsfræði, PCSK9, MESH: Adult, General Chemistry, MESH: Lipids, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Sleep, Lipid profile, MESH: Chromosome Mapping, MESH: Female, 030217 neurology & neurosurgery
Abstract

Publisher's version (útgefin grein)., Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles., This project was supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF–6110-00183) and the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848 and NNF15CC0018486). Diana van Heemst was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). Susan Redline was supported in part by NIH R35HL135818 and HL11338. Study-specific acknowledgements can be found in the Supplementary Notes 2 and 4. The data on coronary artery disease have been contributed by the Myocardial Infarction Genetics and CARDIoGRAM investigators, and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG.

Published
2019

13. Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder

Author

Stephan Ruhrmann, Edna Grünblatt, Paresh D. Patel, Hyun Ji Noh, Jeremy Johnson, S. Evelyn Stewart, Steven A. Rasmussen, Colm O'Dushlaine, Michael A. Jenike, Michele Koltookian, Michael Wagner, Danielle C. Cath, Gerard van Grootheest, James A. Knowles, Jason Flannick, Diana Djurfeldt, Hans J. Grabe, Guoping Feng, Michele T. Pato, Diane P. Genereux, Ruqi Tang, Elinor K. Karlsson, Ross Swofford, Carol A. Mathews, Susanne Walitza, Christina M. Hultman, Gregory L. Hanna, Kerstin Lindblad-Toh, Christian Rück, Carlos N. Pato, Erik Andersson, Daniel P. Howrigan, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Tang, Ruqi, Feng, Guoping, and Karlsson, Elinor

Subjects
0301 basic medicine, Obsessive-Compulsive Disorder, General Physics and Astronomy, genetics [Carrier Proteins], Bioinformatics, Synapse, Cohort Studies, 0302 clinical medicine, Postsynaptic potential, Transcription (biology), Calcium-binding protein, metabolism [Membrane Transport Proteins], lcsh:Science, Neural Cell Adhesion Molecules, genetics [Nerve Tissue Proteins], CTTNBP2 protein, human, Genetics, Multidisciplinary, genetics [Membrane Transport Proteins], metabolism [Proteins], metabolism [Obsessive-Compulsive Disorder], humanities, genetics [Synapses], Medical genetics, ddc:500, Medical Genetics, Signal Transduction, medicine.medical_specialty, Cell Adhesion Molecules, Neuronal, Science, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, behavioral disciplines and activities, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, metabolism [Cell Adhesion Molecules, Neuronal], mental disorders, medicine, Humans, NRXN1 protein, human, Gene, Behavioural genetics, Medicinsk genetik, genetics [Obsessive-Compulsive Disorder], metabolism [Nerve Tissue Proteins], Calcium-Binding Proteins, Membrane Transport Proteins, Proteins, genetics [Cell Adhesion Molecules, Neuronal], metabolism [Synapses], General Chemistry, genetics [Proteins], 030104 developmental biology, Synapses, lcsh:Q, Neural cell adhesion molecule, Carrier Proteins, 030217 neurology & neurosurgery, metabolism [Carrier Proteins], REEP3 protein, human
Abstract

Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit. We sequenced coding and regulatory elements for 608 genes potentially involved in obsessive-compulsive disorder in human, dog, and mouse. Using a new method that prioritizes likely functional variants, we compared 592 cases to 560 controls and found four strongly associated genes, validated in a larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains. CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants, of which at least six (35%) alter transcription factor-DNA binding in neuroblastoma cells. NRXN1 achieves genome-wide significance (p = 6.37 × 10−11) when we include 33,370 population-matched controls. Our findings suggest synaptic adhesion as a key component in compulsive behaviors, and show that targeted sequencing plus functional annotation can identify potentially causative variants, even when genomic data are limited., Nature Communications, 8, ISSN:2041-1723

Published
2017

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