Filter and export

Publications

959 Publications visible to you, out of a total of 959
Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically … adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Authors: Manuel A. Ferreira, Eric R. Gamazon, Fares Al-Ejeh, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Ella Asseryanis, Jacopo Azzollini, Judith Balmaña, Daniel R. Barnes, Daniel Barrowdale, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Katarzyna Białkowska, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Ake Borg, Hiltrud Brauch, Hermann Brenner, Annegien Broeks, Barbara Burwinkel, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Ian Campbell, Federico Canzian, Jonathan Carter, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Miguel de La Hoya, Joe Dennis, Peter Devilee, Orland Diez, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Bent Ejlertsen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Eitan Friedman, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Wei He, Jane Heyworth, Frans B. L. Hogervorst, Antoinette Hollestelle, Robert N. Hoover, John L. Hopper, Peter J. Hulick, Keith Humphreys, Evgeny N. Imyanitov, Claudine Isaacs, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Vijai Joseph, Beth Y. Karlan, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Michael E. Jones, Irene Konstantopoulou, Vessela N. Kristensen, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Goska Leslie, Jenny Lester, Fabienne Lesueur, Sara Lindström, Jirong Long, Jennifer T. Loud, Jan Lubiński, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Tabea Maurer, Dimitrios Mavroudis, Lesley McGuffog, Alfons Meindl, Usha Menon, Kyriaki Michailidou, Austin Miller, Marco Montagna, Fernando Moreno, Lidia Moserle, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Finn C. Nielsen, Liene Nikitina-Zake, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Ana Osorio, Janos Papp, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Ana Peixoto, Paolo Peterlongo, Paul D. P. Pharoah, Dijana Plaseska-Karanfilska, Bruce Poppe, Nadege Presneau, Paolo Radice, Johanna Rantala, Gad Rennert, Harvey A. Risch, Emmanouil Saloustros, Kristin Sanden, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Priyanka Sharma, Xiao-Ou Shu, Jacques Simard, Christian F. Singer, Penny Soucy, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Anthony J. Swerdlow, William J. Tapper, Jack A. Taylor, Manuel R. Teixeira, Mary Beth Terry, Alex Teulé, Mads Thomassen, Kathrin Thöne, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Thérèse Truong, Nadine Tung, Celine M. Vachon, Christi J. van Asperen, Ans M. W. van den Ouweland, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Qin Wang, Barbara Wappenschmidt, Jeffrey N. Weitzel, Camilla Wendt, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Peter Kraft, Antonis C. Antoniou, Wei Zheng, Douglas F. Easton, Roger L. Milne, Jonathan Beesley, Georgia Chenevix-Trench

Date Published: 1st Dec 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Genetical Statistics and Systems Biology

Abstract (Expand)

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely … understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Authors: Alexander Teumer, Yong Li, Sahar Ghasemi, Bram P. Prins, Matthias Wuttke, Tobias Hermle, Ayush Giri, Karsten B. Sieber, Chengxiang Qiu, Holger Kirsten, Adrienne Tin, Audrey Y. Chu, Nisha Bansal, Mary F. Feitosa, Lihua Wang, Jin-Fang Chai, Massimiliano Cocca, Christian Fuchsberger, Mathias Gorski, Anselm Hoppmann, Katrin Horn, Man Li, Jonathan Marten, Damia Noce, Teresa Nutile, Sanaz Sedaghat, Gardar Sveinbjornsson, Bamidele O. Tayo, Peter J. van der Most, Yizhe Xu, Zhi Yu, Lea Gerstner, Johan Ärnlöv, Stephan J. L. Bakker, Daniela Baptista, Mary L. Biggs, Eric Boerwinkle, Hermann Brenner, Ralph Burkhardt, Robert J. Carroll, Miao-Li Chee, Miao-Ling Chee, Mengmeng Chen, Ching-Yu Cheng, James P. Cook, Josef Coresh, Tanguy Corre, John Danesh, Martin H. de Borst, Alessandro de Grandi, Renée de Mutsert, Aiko P. J. de Vries, Frauke Degenhardt, Katalin Dittrich, Jasmin Divers, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Janine F. Felix, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Ron T. Gansevoort, Vilmantas Giedraitis, Martin Gögele, Franziska Grundner-Culemann, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pavel Hamet, Tamara B. Harris, Andrew A. Hicks, Hilma Holm, Valencia Hui Xian Foo, Shih-Jen Hwang, M. Arfan Ikram, Erik Ingelsson, Vincent W. V. Jaddoe, Johanna Jakobsdottir, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Chiea-Chuen Khor, Wieland Kiess, Wolfgang Koenig, Antje Körner, Peter Kovacs, Holly Kramer, Bernhard K. Krämer, Florian Kronenberg, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen-Mai Lee, Terho Lehtimäki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M. Lindgren, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Anubha Mahajan, Joseph C. Maranville, Deborah Mascalzoni, Barbara McMullen, Christa Meisinger, Thomas Meitinger, Kozeta Miliku, Dennis O. Mook-Kanamori, Martina Müller-Nurasyid, Josyf C. Mychaleckyj, Matthias Nauck, Kjell Nikus, Boting Ning, Raymond Noordam, Jeffrey O’ Connell, Isleifur Olafsson, Nicholette D. Palmer, Annette Peters, Anna I. Podgornaia, Belen Ponte, Tanja Poulain, Peter P. Pramstaller, Ton J. Rabelink, Laura M. Raffield, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Fernando Rivadeneira, Heiko Runz, Kathleen A. Ryan, Charumathi Sabanayagam, Kai-Uwe Saum, Ben Schöttker, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Konstantin Strauch, Michael Stumvoll, Benjamin B. Sun, Silke Szymczak, E-Shyong Tai, Nicholas Y. Q. Tan, Kent D. Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Hauke Thomsen, Unnur Thorsteinsdottir, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Pim van der Harst, Niek Verweij, Suzanne Vogelezang, Uwe Völker, Melanie Waldenberger, Chaolong Wang, Otis D. Wilson, Charlene Wong, Tien-Yin Wong, Qiong Yang, Masayuki Yasuda, Shreeram Akilesh, Murielle Bochud, Carsten A. Böger, Olivier Devuyst, Todd L. Edwards, Kevin Ho, Andrew P. Morris, Afshin Parsa, Sarah A. Pendergrass, Bruce M. Psaty, Jerome I. Rotter, Kari Stefansson, James G. Wilson, Katalin Susztak, Harold Snieder, Iris M. Heid, Markus Scholz, Adam S. Butterworth, Adriana M. Hung, Cristian Pattaro, Anna Köttgen

Date Published: 1st Dec 2019

Publication Type: Journal article

Telomere Length Maintenance and Its Transcriptional Regulation in Lynch Syndrome and Sporadic Colorectal Carcinoma.
HNPCC-Sys - Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome, oBIG - omics Bioinformatics for Health

Abstract (Expand)

Background: Activation of telomere maintenance mechanisms (TMMs) is a hallmark of most cancers, and is required to prevent genome instability and to establish cellular immortality through reconstitution … of capping of chromosome ends. TMM depends on the cancer type. Comparative studies linking tumor biology and TMM have potential impact for evaluating cancer onset and development. Methods: We have studied alterations of telomere length, their sequence composition and transcriptional regulation in mismatch repair deficient colorectal cancers arising in Lynch syndrome (LS-CRC) and microsatellite instable (MSI) sporadic CRC (MSI s-CRC), and for comparison, in microsatellite stable (MSS) s-CRC and in benign colon mucosa. Our study applied bioinformatics analysis of whole genome DNA and RNA sequencing data and a pathway model to study telomere length alterations and the potential effect of the "classical" telomerase (TEL-) and alternative (ALT-) TMM using transcriptomic signatures. Results: We have found progressive decrease of mean telomere length in all cancer subtypes compared with reference systems. Our results support the view that telomere attrition is an early event in tumorigenesis. TMM gets activated in all tumors studied due to concerted overexpression of a large fraction of genes with direct relation to telomere function, where only a very small fraction of them showed recurrent mutations. TEL-related transcriptional state was dominating in all CRC subtypes, showing, however, subtype-specific activation patterns; while contribution of the ALT-TMM was slightly more prominent in the hypermutated MSI s-CRC and LS-CRC. TEL-TMM is mainly activated by over-expression of DKC1 and/or TERT genes and their interaction partners, where DKC1 is more prominent in MSS than in MSI s-CRC and can serve as a transcriptomic marker of TMM activity. Conclusions: Our results suggest that transcriptional patterns are indicative for TMM pathway activation with subtle differences between TEL and ALT mechanisms in a CRC subtype-specific fashion. Sequencing data potentially provide a suited measure to study alterations of telomere length and of underlying transcriptional regulation. Further studies are needed to improve this method.

Authors: L. Nersisyan, L. Hopp, H. Loeffler-Wirth, J. Galle, M. Loeffler, A. Arakelyan, H. Binder

Date Published: 22nd Nov 2019

Publication Type: Not specified

Human Diseases: cancer

Sex-Specific Differences in Circumpapillary Retinal Nerve Fiber Layer Thickness.
LIFE Adult

Abstract (Expand)

PURPOSE: To investigate the role of sex on retinal nerve fiber layer (RNFL) thickness at 768 circumpapillary locations based on OCT findings. DESIGN: Population-based cross-sectional study. PARTICIPANTS: … We investigated 5646 eyes of 5646 healthy participants from the Leipzig Research Centre for Civilization Diseases (LIFE)-Adult Study of a predominantly white population. METHODS: All participants underwent standardized systemic assessments and ocular imaging. Circumpapillary RNFL (cRNFL) thickness was measured at 768 points equidistant from the optic nerve head using spectral-domain OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany). To control ocular magnification effects, the true scanning radius was estimated by scanning focus. Student t test was used to evaluate sex differences in cRNFL thickness globally and at each of the 768 locations. Multivariable linear regression and analysis of variance were used to evaluate individual contributions of various factors to cRNFL thickness variance. MAIN OUTCOME MEASURES: Difference in cRNFL thickness between males and females. RESULTS: Our population consisted of 54.8% females. The global cRNFL thickness was 1 mum thicker in females (P < 0.001). However, detailed analysis at each of the 768 locations revealed substantial location specificity of the sex effects, with RNFL thickness difference ranging from -9.98 to +8.00 mum. Females showed significantly thicker RNFLs in the temporal, superotemporal, nasal, inferonasal, and inferotemporal regions (43.6% of 768 locations), whereas males showed significantly thicker RNFLs in the superior region (13.2%). The results were similar after adjusting for age, body height, and scanning radius. The superotemporal and inferotemporal RNFL peaks shifted temporally in females by 2.4 degrees and 1.9 degrees , respectively. On regions with significant sex effects, sex explained more RNFL thickness variance than age, whereas the major peak locations and interpeak angle explained most of the RNFL thickness variance unexplained by sex. CONCLUSIONS: Substantial sex effects on cRNFL thickness were found at 56.8% of all 768 circumpapillary locations, with specific patterns for different sectors. Over large regions, sex was at least as important in explaining the cRNFL thickness variance as was age, which is well established to have a substantial impact on cRNFL thickness. Including sex in the cRNFL thickness norm could therefore improve glaucoma diagnosis and monitoring.

Authors: D. Li, F. G. Rauscher, E. Y. Choi, M. Wang, N. Baniasadi, K. Wirkner, T. Kirsten, J. Thiery, C. Engel, M. Loeffler, T. Elze

Date Published: 17th Nov 2019

Publication Type: Journal article

Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer (PCa). We evaluated whether PSVs in BRCA1/2 were associated with risk … of overall PCa or high grade (Gleason 8+) PCa using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with PCa, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without PCa. PSVs in the 3’ region of BRCA2 (c.7914+) were significantly associated with elevated risk of PCa compared with reference bin c.1001-c.7913 (HR=1.78, 95%CI: 1.25-2.52, p=0.001), as well as elevated risk of Gleason 8+ PCa (HR=3.11, 95%CI: 1.63-5.95, p=0.001). c.756-c.1000 was also associated with elevated PCa risk (HR=2.83, 95%CI: 1.71-4.68, p=0.00004) and elevated risk of Gleason 8+ PCa (HR=4.95, 95%CI: 2.12-11.54, p=0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive PCa.

Authors: Vivek L. Patel, Evan L. Busch, Tara M. Friebel, Angel Cronin, Goska Leslie, Lesley McGuffog, Julian Adlard, Simona Agata, Bjarni A. Agnarsson, Munaza Ahmed, Kristiina Aittomäki, Elisa Alducci, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Grazia Artioli, Brita Arver, Bernd Auber, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel R. Barnes, Alicia Barroso, Daniel Barrowdale, Muriel Belotti, Javier Benitez, Brigitte Bertelsen, Marinus J. Blok, Istvan Bodrogi, Valérie Bonadona, Bernardo Bonanni, Davide Bondavalli, Susanne E. Boonen, Julika Borde, Ake Borg, Angela R. Bradbury, Angela Brady, Carole Brewer, Joan Brunet, Bruno Buecher, Saundra S. Buys, Santiago Cabezas-Camarero, Trinidad Caldés, Almuth Caliebe, Maria A. Caligo, Mariarosaria Calvello, Ian G. Campbell, Ileana Carnevali, Estela Carrasco, Tsun L. Chan, Annie T. W. Chu, Wendy K. Chung, Kathleen B. M. Claes, Gemo Study Collaborators, Embrace Collaborators, Jackie Cook, Laura Cortesi, Fergus J. Couch, Mary B. Daly, Giuseppe Damante, Esther Darder, Rosemarie Davidson, Miguel de La Hoya, Lara Della Puppa, Joe Dennis, Orland Díez, Yuan Chun Ding, Nina Ditsch, Susan M. Domchek, Alan Donaldson, Bernd Dworniczak, Douglas F. Easton, Diana M. Eccles, Rosalind A. Eeles, Hans Ehrencrona, Bent Ejlertsen, Christoph Engel, D. Gareth Evans, Laurence Faivre, Ulrike Faust, Lídia Feliubadaló, Lenka Foretova, Florentia Fostira, George Fountzilas, Debra Frost, Vanesa García-Barberán, Pilar Garre, Marion Gauthier-Villars, Lajos Géczi, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Giuseppe Giannini, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Mark H. Greene, Angelica M. Gutierrez-Barrera, Eric Hahnen, Ute Hamann, Jan Hauke, Natalie Herold, Frans B. L. Hogervorst, Ellen Honisch, John L. Hopper, Peter J. Hulick, Kconfab Investigators, Hebon Investigators, Louise Izatt, Agnes Jager, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Thomas Dyrso Jensen, Oskar Th Johannsson, Esther M. John, Vijai Joseph, Eunyoung Kang, Karin Kast, Johanna I. Kiiski, Sung-Won Kim, Zisun Kim, Kwang-Pil Ko, Irene Konstantopoulou, Gero Kramer, Lotte Krogh, Torben A. Kruse, Ava Kwong, Mirjam Larsen, Christine Lasset, Charlotte Lautrup, Conxi Lázaro, Jihyoun Lee, Jong Won Lee, Min Hyuk Lee, Johannes Lemke, Fabienne Lesueur, Annelie Liljegren, Annika Lindblom, Patricia Llovet, Adria Lopez-Fernández, Irene Lopez-Perolio, Victor Lorca, Jennifer T. Loud, Edmond S. K. Ma, Phuong L. Mai, Siranoush Manoukian, Veronique Mari, Lynn Martin, Laura Matricardi, Noura Mebirouk, Veronica Medici, Hanne E. J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Clare Miller, Denise Molina Gomes, Marco Montagna, Thea M. Mooij, Lidia Moserle, Emmanuelle Mouret-Fourme, Anna Marie Mulligan, Katherine L. Nathanson, Marie Navratilova, Heli Nevanlinna, Dieter Niederacher, Finn C. Cilius Nielsen, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Kai-Ren Ong, Ana Osorio, Claus-Eric Ott, Domenico Palli, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Bernard Peissel, Ana Peixoto, Pedro Pérez-Segura, Paolo Peterlongo, Annabeth Høgh Petersen, Mary E. Porteous, Miguel Angel Pujana, Paolo Radice, Juliane Ramser, Johanna Rantala, Muhammad U. Rashid, Kerstin Rhiem, Piera Rizzolo, Mark E. Robson, Matti A. Rookus, Caroline Maria Rossing, Kathryn J. Ruddy, Catarina Santos, Claire Saule, Rosa Scarpitta, Rita K. Schmutzler, Hélène Schuster, Leigha Senter, Caroline M. Seynaeve, Payal D. Shah, Priyanka Sharma, Vivian Y. Shin, Valentina Silvestri, Jacques Simard, Christian F. Singer, Anne-Bine Skytte, Katie Snape, Angela R. Solano, Penny Soucy, Melissa C. Southey, Amanda B. Spurdle, Linda Steele, Doris Steinemann, Dominique Stoppa-Lyonnet, Agostina Stradella, Lone Sunde, Christian Sutter, Yen Y. Tan, Manuel R. Teixeira, Soo Hwang Teo, Mads Thomassen, Maria Grazia Tibiletti, Marc Tischkowitz, Silvia Tognazzo, Amanda E. Toland, Stefania Tommasi, Diana Torres, Angela Toss, Alison H. Trainer, Nadine Tung, Christi J. van Asperen, Frederieke H. van der Baan, Lizet E. van der Kolk, Rob B. van der Luijt, Liselotte P. van Hest, Liliana Varesco, Raymonda Varon-Mateeva, Alessandra Viel, Jeroen Vierstraete, Roberta Villa, Anna von Wachenfeldt, Philipp Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Greet Wieme, Siddhartha Yadav, Drakoulis Yannoukakos, Sook-Yee Yoon, Cristina Zanzottera, Kristin K. Zorn, Anthony V. D’Amico, Matthew L. Freedman, Mark M. Pomerantz, Georgia Chenevix-Trench, Antonis C. Antoniou, Susan L. Neuhausen, Laura Ottini, Henriette Roed Nielsen, Timothy R. Rebbeck

Date Published: 13th Nov 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Genetic architecture of subcortical brain structures in 38,851 individuals
Genetical Statistics and Systems Biology

Abstract (Expand)

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, … caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection 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.

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

Date Published: 1st Nov 2019

Publication Type: Journal article

Human brain arousal in the resting state: a genome-wide association study
Genetical Statistics and Systems Biology

Abstract (Expand)

Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, … stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p \textless 5E-8), although seven loci were suggestive (p \textless 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer’s Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.   Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p \textless 5E-8), although seven loci were suggestive (p \textless 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer’s Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders. // Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p \textless 5E-8), although seven loci were suggestive (p \textless 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer’s Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.

Authors: Philippe Jawinski, Holger Kirsten, Christian Sander, Janek Spada, Christine Ulke, Jue Huang, Ralph Burkhardt, Markus Scholz, Tilman Hensch, Ulrich Hegerl

Date Published: 1st Nov 2019

Publication Type: Journal article

Navigate

Health Atlas - Local Data Hub/Leipzig

The Health Atlas - Local Data Hub/Leipzig is an alliance of medical ontologists, medical systems biologists and clinical trials groups to design and implement a multi-functional and quality-assured atlas. It provides models, data and metadata on specific use cases from medical research fields.

Registered Repository

re3data.org Badge
Powered by
 (v.1.13.0-master)
Health Atlas | Funding and Programmes | Credits | Terms & Conditions | Privacy Policy | Imprint
Copyright © 2008 - 2021 The University of Manchester and HITS gGmbH
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig

By continuing to use this site you agree to the use of cookies