Author: "Laura Crisponi" - Searchworks@Jio Institute Digital Library Search Results

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83 results on '"Laura Crisponi"'

1. Hodgkin Lymphoma after Disseminated Mycobacterium genavense Infection, Germany

Author: Janina Trauth, Thomas Discher, Moritz Fritzenwanker, Can Imirzalioglu, Tobias Arnold, Dagmar Steiner, Elvira Richter, Laura Crisponi, Bodo Grimbacher, and Susanne Herold
Subjects: Hodgkin lymphoma, Mycobacterium genavense, nontuberculous Mycobacterium, cervical lymphadenopathy, zoonoses, Germany, Medicine, Infectious and parasitic diseases, RC109-216
Abstract: Mycobacterium genavense infection, a rare nontuberculous mycobacteria infection, occurs in heavily immunocompromised patients (i.e., those with advanced HIV disease, genetic disorders, or acquired immunologic disorders and those undergoing immunosuppressive therapy). We report a case of disseminated M. genavense infection preceding Hodgkin lymphoma in a patient without obvious risk factors for this infection.
Published: 2022
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2. Editorial: Female Infertility: Genetics of Reproductive Ageing, Menopause and Primary Ovarian Insufficiency

Author: Mara Marongiu, Laura Crisponi, Manuela Uda, and Emanuele Pelosi
Subjects: female infertility, age-related decline in fertility, reproductive aging, hypothalamic-pituitary-ovarian axis, primary ovarian insufficiency (POI), ovarian biology, Genetics, QH426-470
Published: 2022
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3. Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report

Author: Rita Maria Alves, Paolo Uva, Marielza F. Veiga, Manuela Oppo, Fabiana C. R. Zschaber, Giampiero Porcu, Henrique P. Porto, Ivana Persico, Stefano Onano, Gianmauro Cuccuru, Rossano Atzeni, Lauro C. N. Vieira, Marcos V. A. Pires, Francesco Cucca, Maria Betânia P. Toralles, Andrea Angius, and Laura Crisponi
Subjects: Whole exome sequencing, KBG syndrome, ANKRD11 gene, Generalized epilepsy with febrile seizures (GEFS+), SCN9A gene, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract: Abstract Background KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. Case presentation Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. Conclusions This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.
Published: 2019
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4. Crisponi syndrome/cold-induced sweating syndrome type 2: Reprogramming of CS/CISS2 individual derived fibroblasts into three clones of one iPSC line

Author: Insa Buers, Lara Schöning, Niki Tomas Loges, Yvonne Nitschke, Inga Marlena Höben, Albrecht Röpke, Laura Crisponi, Heymut Omran, and Frank Rutsch
Subjects: Biology (General), QH301-705.5
Abstract: Crisponi syndrome/cold-induced sweating syndrome type 2 (CS/CISS2) is a rare disease with severe dysfunctions of thermoregulatory processes. CS/CISS2 individuals suffer from recurrent episodes of hyperthermia in the neonatal period and paradoxical sweating at cold ambient temperatures in adolescence. Variants in CLCF1 (cardiotrophin-like-cytokine 1) cause CS/CISS2. Here, we summarize the generation of three clones of one stem cell line (iPSC) of a CS/CISS2 individual carrying the CLCF1 variant c.321C>G on both alleles. These patient derived iPSC clones show a normal karyotype, several pluripotency markers, and the ability to differentiate into the three germ layers.
Published: 2020
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5. Generation of induced pluripotent stem cell lines from a Crisponi/Cold induced sweating syndrome type 1 individual

Author: Lara Schöning, Niki Tomas Loges, Yvonne Nitschke, Inga Marlena Höben, Albrecht Röpke, Laura Crisponi, Heymut Omran, Frank Rutsch, and Insa Buers
Subjects: Biology (General), QH301-705.5
Abstract: Cytokine receptor like factor 1 (CRLF1) is the gene implicated, when mutated, in Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1). Here, we report the establishment of induced pluripotent stem cell lines (iPSCs) from fibroblasts of a Turkish CS/CISS1 individual with a homozygous variant in CRLF1 (c.708_709delinsT; p.[Pro238Argfs*6]). This variant is the most frequent variant associated to CS/CISS1 in the Turkish population. These patient derived iPSC lines show all pluripotency markers, a normal karyotype and the ability to differentiate into the three germ layers.
Published: 2020
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6. CRLF1 and CLCF1 in Development, Health and Disease

Author: Laura Crisponi, Insa Buers, and Frank Rutsch
Subjects: CRLF1, CLCF1, type I cytokine receptor, development, Crisponi/cold-induced sweating syndrome, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Cytokines and their receptors have a vital function in regulating various processes such as immune function, inflammation, haematopoiesis, cell growth and differentiation. The interaction between a cytokine and its specific receptor triggers intracellular signalling cascades that lead to altered gene expression in the target cell and consequent changes in its proliferation, differentiation, or activation. In this review, we highlight the role of the soluble type I cytokine receptor CRLF1 (cytokine receptor-like factor-1) and the Interleukin (IL)-6 cytokine CLCF1 (cardiotrophin-like cytokine factor 1) during development in physiological and pathological conditions with particular emphasis on Crisponi/cold-induced sweating syndrome (CS/CISS) and discuss new insights, challenges and possibilities arising from recent studies.
Published: 2022
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7. A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy.

Author: Tommaso Pippucci, Antonia Parmeggiani, Flavia Palombo, Alessandra Maresca, Andrea Angius, Laura Crisponi, Francesco Cucca, Rocco Liguori, Maria Lucia Valentino, Marco Seri, and Valerio Carelli
Subjects: Medicine, Science
Abstract: Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding α2δ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished α2δ-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental.
Published: 2013
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8. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author: Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S Pankow, Hae-Won Uh, Ying Wu, Aurelian Bidulescu, Laura J Rasmussen-Torvik, Celia M T Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K Manning, Ching-Ti Liu, Jaspal Kooner, Vincent E Mooser, Peter Vollenweider, Karen A Kapur, John Chambers, Nicholas J Wareham, Claudia Langenberg, Rune Frants, Ko Willems-Vandijk, Ben A Oostra, Sara M Willems, Claudia Lamina, Thomas W Winkler, Bruce M Psaty, Russell P Tracy, Jennifer Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P Pramstaller, David M Evans, Beate St Pourcain, Naveed Sattar, Andrew R Wood, Stefania Bandinelli, Olga D Carlson, Josephine M Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja-Liisa Nuotio, Britt-Marie Loo, Tamara Harris, Melissa Garcia, Alka Kanaya, Margot Haun, Norman Klopp, H-Erich Wichmann, Panos Deloukas, Efi Katsareli, David J Couper, Bruce B Duncan, Margreet Kloppenburg, Linda S Adair, Judith B Borja, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, James G Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M Teslovich, Matthew A Allison, Susan Redline, Sarah G Buxbaum, Karen L Mohlke, Ingrid Meulenbelt, Christie M Ballantyne, George V Dedoussis, Frank B Hu, Yongmei Liu, Bernhard Paulweber, Timothy D Spector, P Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli Raitakari, Jose C Florez, Veikko Salomaa, Johan G Eriksson, Timothy M Frayling, Andrew A Hicks, Terho Lehtimäki, George Davey Smith, David S Siscovick, Florian Kronenberg, Cornelia van Duijn, Ruth J F Loos, Dawn M Waterworth, James B Meigs, Josee Dupuis, J Brent Richards, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Oliver M Hofmann, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Andrew D Morris, Colin N A Palmer, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Oluf Pedersen, Inês Barroso, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Paul Elliott, Denis Rybin, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Taina Lajunen, Alex Doney, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurðsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Ingrid B Borecki, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Procardis Consortium, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, Brenda W J H Penninx, Dorret I Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Leena Peltonen, Vincent Mooser, Robert Sladek, MAGIC investigators, GLGC Consortium, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Daniel I Chasman, Christopher T Johansen, Sigrid W Fouchier, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Mary F Feitosa, Marju Orho-Melander, Olle Melander, Xiaohui Li, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, John B Whitfield, John R Thompson, Ida Surakka, Tim D Spector, Johannes H Smit, Juha Sinisalo, James Scott, Juha Saharinen, Chiara Sabatti, Lynda M Rose, Robert Roberts, Mark Rieder, Alex N Parker, Guillaume Pare, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Gavin Lucas, Robert Luben, Marja-Liisa Lokki, Guillaume Lettre, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Inke R König, Kay-Tee Khaw, Lee M Kaplan, Åsa Johansson, A Cecile J W Janssens, Wilmar Igl, G Kees Hovingh, Christian Hengstenberg, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Leif C Groop, Elena Gonzalez, Nelson B Freimer, Jeanette Erdmann, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Ulf de Faire, Gabriel Crawford, Yii-der I Chen, Mark J Caulfield, S Matthijs Boekholdt, Themistocles L Assimes, Thomas Quertermous, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Herman A Taylor, Stacey B Gabriel, Hilma Holm, Vilmundur Gudnason, Ronald M Krauss, Jose M Ordovas, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, and Sekar Kathiresan
Subjects: Genetics, QH426-470
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p
Published: 2012
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9. A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation.

Author: Silvia Naitza, Eleonora Porcu, Maristella Steri, Dennis D Taub, Antonella Mulas, Xiang Xiao, James Strait, Mariano Dei, Sandra Lai, Fabio Busonero, Andrea Maschio, Gianluca Usala, Magdalena Zoledziewska, Carlo Sidore, Ilenia Zara, Maristella Pitzalis, Alessia Loi, Francesca Virdis, Roberta Piras, Francesca Deidda, Michael B Whalen, Laura Crisponi, Antonio Concas, Carlo Podda, Sergio Uzzau, Paul Scheet, Dan L Longo, Edward Lakatta, Gonçalo R Abecasis, Antonio Cao, David Schlessinger, Manuela Uda, Serena Sanna, and Francesco Cucca
Subjects: Genetics, QH426-470
Abstract: Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.
Published: 2012
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10. A genome-wide association search for type 2 diabetes genes in African Americans.

Author: Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, Matthew E Talbert, Joshua P Lewis, DIAGRAM Consortium, MAGIC Investigators, Assiamira Ferrara, Lingyi Lu, Julie T Ziegler, Michele M Sale, Jasmin Divers, Daniel Shriner, Adebowale Adeyemo, Charles N Rotimi, Maggie C Y Ng, Carl D Langefeld, Barry I Freedman, Donald W Bowden, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M Hofmann, Josée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, John R B Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Karen L Mohlke, Andrew D Morris, Colin N A Palmer, Peter P Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J Wareham, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Frank B Hu, James B Meigs, James S Pankow, Oluf Pedersen, H-Erich Wichmann, Inês Barroso, Jose C Florez, Timothy M Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Peter Henneman, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Josephine M Egan, Taina Lajunen, Alex Doney, Stavroula Kanoni, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Rune Frants, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Luigi Ferrucci, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, and Robert Sladek
Subjects: Medicine, Science
Abstract: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P
Published: 2012
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11. SUMOylation of the Forkhead transcription factor FOXL2 promotes its stabilization/activation through transient recruitment to PML bodies.

Author: Adrien Georges, Bérénice A Benayoun, Mara Marongiu, Aurélie Dipietromaria, David L'Hôte, Anne-Laure Todeschini, Jana Auer, Laura Crisponi, and Reiner A Veitia
Subjects: Medicine, Science
Abstract: BACKGROUND: FOXL2 is a transcription factor essential for ovarian development and maintenance. It is mutated in the genetic condition called Blepharophimosis Ptosis Epicantus inversus Syndrome (BPES) and in cases of isolated premature ovarian failure. We and others have previously shown that FOXL2 undergoes several post-translational modifications. METHODS AND PRINCIPAL FINDINGS: Here, using cells in culture, we show that interference with FOXL2 SUMOylation leads to a robust inhibition of its transactivation ability, which correlates with a decreased stability. Interestingly, FOXL2 SUMOylation promotes its transient recruitment to subnuclear structures that we demonstrate to be PML (Promyelocytic Leukemia) Nuclear Bodies. Since PML bodies are known to be sites where post-translational modifications of nuclear factors take place, we used tandem mass spectrometry to identify new post-translational modifications of FOXL2. Specifically, we detected four phosphorylated, one sulfated and three acetylated sites. CONCLUSIONS: By analogy with other transcription factors, we propose that PML Nuclear Bodies might transiently recruit FOXL2 to the vicinity of locally concentrated enzymes that could be involved in the post-translational maturation of FOXL2. FOXL2 acetylation, sulfation, phosphorylation as well as other modifications yet to be discovered might alter the transactivation capacity of FOXL2 and/or its stability, thus modulating its global intracellular activity.
Published: 2011
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12. The forkhead transcription factor Foxl2 is sumoylated in both human and mouse: sumoylation affects its stability, localization, and activity.

Author: Mara Marongiu, Manila Deiana, Alessandra Meloni, Loredana Marcia, Alessandro Puddu, Antonio Cao, David Schlessinger, and Laura Crisponi
Subjects: Medicine, Science
Abstract: The FOXL2 forkhead transcription factor is expressed in ovarian granulosa cells, and mutated FOXL2 causes the blepharophimosis, ptosis and epicanthus inversus syndrome (BPES) and predisposes to premature ovarian failure. Inactivation of Foxl2 in mice demonstrated its indispensability for female gonadal sex determination and ovary development and revealed its antagonism of Sox9, the effector of male testis development. To help to define the regulatory activities of FOXL2, we looked for interacting proteins. Based on yeast two-hybrid screening, we found that FOXL2 interacts with PIAS1 and UBC9, both parts of the sumoylation machinery. We showed that human FOXL2 is sumoylated in transfected cell lines, and that endogenous mouse Foxl2 is comparably sumoylated. This modification changes its cellular localization, stability and transcriptional activity. It is intriguing that similar sumoylation and regulatory consequences have also been reported for SOX9, the male counterpart of FOXL2 in somatic gonadal tissues.
Published: 2010
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13. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.

Author: Siguang Li, Serena Sanna, Andrea Maschio, Fabio Busonero, Gianluca Usala, Antonella Mulas, Sandra Lai, Mariano Dei, Marco Orrù, Giuseppe Albai, Stefania Bandinelli, David Schlessinger, Edward Lakatta, Angelo Scuteri, Samer S Najjar, Jack Guralnik, Silvia Naitza, Laura Crisponi, Antonio Cao, Gonçalo Abecasis, Luigi Ferrucci, Manuela Uda, Wei-Min Chen, and Ramaiah Nagaraja
Subjects: Genetics, QH426-470
Abstract: High serum uric acid levels elevate pro-inflammatory-state gout crystal arthropathy and place individuals at high risk for cardiovascular morbidity and mortality. Genome-wide scans in the genetically isolated Sardinian population identified variants associated with serum uric acid levels as a quantitative trait. They mapped within GLUT9, a Chromosome 4 glucose transporter gene predominantly expressed in liver and kidney. SNP rs6855911 showed the strongest association (p = 1.84 x 10(-16)), along with eight others (p = 7.75 x 10(-16) to 6.05 x 10(-11)). Individuals homozygous for the rare allele of rs6855911 (minor allele frequency = 0.26) had 0.6 mg/dl less uric acid than those homozygous for the common allele; the results were replicated in an unrelated cohort from Tuscany. Our results suggest that polymorphisms in GLUT9 could affect glucose metabolism and uric acid synthesis and/or renal reabsorption, influencing serum uric acid levels over a wide range of values.
Published: 2007
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14. GenIA: The Genetic Immunology Advisor Database – A Resource made for and by the IEI Community

Author: Xiao Peng, Andres Caballero G. de Oteyza, Michele Proietti, and Laura Crisponi
Subjects: Immunology, Immunology and Allergy
Published: 2023

15. Editorial: Female Infertility: Genetics of Reproductive Ageing, Menopause and Primary Ovarian Insufficiency

Author: Mara Marongiu, Laura Crisponi, Manuela Uda, and Emanuele Pelosi
Subjects: Genetics, Molecular Medicine, Genetics (clinical)
Published: 2021

16. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
Subjects: Gerontology, Aging, Far East, Endocrinology, Diabetes and Metabolism, Menopause, Premature, Genome-wide association study, VARIANTS, Primary Ovarian Insufficiency, Inbred C57BL, Bioinformatics, DISEASE, Healthy Aging, genetics of ovarian aging, Fragile X Mental Retardation Protein, Mice, Endocrinology, Medicine, EARLY MENOPAUSE, media_common, RISK, Multidisciplinary, Asia, Eastern, Reproduction, Longevity, Middle Aged, Europe, MENDELIAN RANDOMIZATION, Medical genetics, Female, ICEP, Menopause, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Fertility, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Inbred C57BL, Ovary, Uterus, Type 2, medicine.medical_specialty, media_common.quotation_subject, MEDLINE, Biology, Premature ovarian insufficiency, Article, genome-wide meta-analysis, SDG 3 - Good Health and Well-being, GERMLINE, Diabetes Mellitus, Genetic predisposition, Ovarian reserve, Premature, business.industry, Human genetics, CHROMOSOME SYNAPSIS, DNA-DAMAGE, Ageing, EXPRESSION ANALYSIS, business, MEIOTIC CELL-CYCLE
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.
Published: 2021

17. Exome sequencing in Crisponi/cold‐induced sweating syndrome–like individuals reveals unpredicted alternative diagnoses

Author: Gudrun Aubertin, Frank Rutsch, Gianmauro Cuccuru, Laura Crisponi, Insa Buers, Manuela Oppo, Paolo Uva, Eva-Lena Stattin, Andrew E. Fry, Ivana Persico, Gurdip Hulait, Andrea Angius, María Palomares-Bralo, Fernando Santos-Simarro, Göran Annerén, Margot I. Van Allen, Francesco Muntoni, Giangiorgio Crisponi, Stefano Onano, and Francesco Cucca
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Scoliosis, 030105 genetics & heredity, Bioinformatics, Genetic analysis, Death, Sudden, 03 medical and health sciences, Exome Sequencing, Genetics, medicine, Humans, Hyperhidrosis, Genetics (clinical), Exome sequencing, Genetic heterogeneity, business.industry, Facies, Infant, medicine.disease, Phenotype, Hypotonia, Pedigree, 030104 developmental biology, Medical genetics, Female, Trismus, CLCF1, medicine.symptom, business, Hand Deformities, Congenital
Abstract: Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.
Published: 2019

18. Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report

Author: Rossano Atzeni, Henrique P. Porto, Lauro C. N. Vieira, Manuela Oppo, Maria Betânia Pereira Toralles, Andrea Angius, Marielza Veiga, Rita Maria Alves, Fabiana C. R. Zschaber, Stefano Onano, Gianmauro Cuccuru, Paolo Uva, Laura Crisponi, Marcos V. A. Pires, Giampiero Porcu, Francesco Cucca, and Ivana Persico
Subjects: 0301 basic medicine, Proband, Case Report, 030105 genetics & heredity, Gene mutation, ANKRD11 gene, Genetics (clinical), Exome sequencing, Genetics, NAV1.7 Voltage-Gated Sodium Channel, Electroencephalography, Pedigree, 3. Good health, KBG syndrome, Generalized epilepsy with febrile seizures (GEFS+), Phenotype, Epilepsy, Generalized, Female, Brazil, Heterozygote, lcsh:Internal medicine, Adolescent, lcsh:QH426-470, Locus (genetics), Biology, Seizures, Febrile, 03 medical and health sciences, Dravet syndrome, Intellectual Disability, Exome Sequencing, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Allele, Generalized epilepsy, lcsh:RC31-1245, Alleles, Genetic Association Studies, Bone Diseases, Developmental, Tooth Abnormalities, Whole exome sequencing, Facies, SCN9A gene, medicine.disease, Human genetics, Repressor Proteins, lcsh:Genetics, 030104 developmental biology, Genetic Loci, Mutation
Abstract: Background KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. Case presentation Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. Conclusions This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.
Published: 2019

19. Crisponi/Cold Induced Sweating Syndrome Type 1 With a Private Cytokine Receptor Like Factor 1 (CRLF1) Mutation in an Indian Family

Author: Laura Crisponi, Ivana Persico, Anirban Mandal, Anju Seth, and Puneet Kaur Sahi
Subjects: medicine.medical_specialty, Cytokine Receptor-Like Factor 1, business.industry, Maternal and child health, Facies, Cold-induced sweating syndrome, Sweating, Death, Sudden, Pediatrics, Perinatology and Child Health, Mutation (genetic algorithm), Immunology, Pediatric surgery, Mutation, Medicine, Humans, Hyperhidrosis, Trismus, Receptors, Cytokine, business, Hand Deformities, Congenital
Published: 2020

20. Generation of induced pluripotent stem cell lines from a Crisponi/Cold induced sweating syndrome type 1 individual

Author: Inga M. Höben, Frank Rutsch, Heymut Omran, Albrecht Röpke, Lara Schöning, Laura Crisponi, Insa Buers, Yvonne Nitschke, and Niki T. Loges
Subjects: 0301 basic medicine, Turkish population, Induced Pluripotent Stem Cells, Sweating, Germ layer, Crisponi syndrome, Biology, 03 medical and health sciences, 0302 clinical medicine, Humans, Hyperhidrosis, Induced pluripotent stem cell, Gene, lcsh:QH301-705.5, Cytokine Receptor-Like Factor 1, Facies, Karyotype, Cold-induced sweating syndrome, Cell Biology, General Medicine, 030104 developmental biology, lcsh:Biology (General), Cancer research, Hand Deformities, Congenital, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Cytokine receptor like factor 1 (CRLF1) is the gene implicated, when mutated, in Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1). Here, we report the establishment of induced pluripotent stem cell lines (iPSCs) from fibroblasts of a Turkish CS/CISS1 individual with a homozygous variant in CRLF1 (c.708_709delinsT; p.[Pro238Argfs*6]). This variant is the most frequent variant associated to CS/CISS1 in the Turkish population. These patient derived iPSC lines show all pluripotency markers, a normal karyotype and the ability to differentiate into the three germ layers.
Published: 2020

21. Crisponi syndrome/cold-induced sweating syndrome type 2: Reprogramming of CS/CISS2 individual derived fibroblasts into three clones of one iPSC line

Author: Lara Schöning, Laura Crisponi, Insa Buers, Inga M. Höben, Heymut Omran, Frank Rutsch, Niki T. Loges, Yvonne Nitschke, and Albrecht Röpke
Subjects: 0301 basic medicine, Hyperthermia, Adolescent, Period (gene), Induced Pluripotent Stem Cells, Germ layer, Crisponi syndrome, Biology, 03 medical and health sciences, Death, Sudden, 0302 clinical medicine, medicine, Humans, Hyperhidrosis, Allele, Receptors, Cytokine, lcsh:QH301-705.5, Infant, Newborn, Facies, Karyotype, Cell Biology, General Medicine, Fibroblasts, medicine.disease, Cellular Reprogramming, Clone Cells, 030104 developmental biology, lcsh:Biology (General), Immunology, CLCF1, Trismus, Reprogramming, Hand Deformities, Congenital, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Crisponi syndrome/cold-induced sweating syndrome type 2 (CS/CISS2) is a rare disease with severe dysfunctions of thermoregulatory processes. CS/CISS2 individuals suffer from recurrent episodes of hyperthermia in the neonatal period and paradoxical sweating at cold ambient temperatures in adolescence. Variants in CLCF1 (cardiotrophin-like-cytokine 1) cause CS/CISS2. Here, we summarize the generation of three clones of one stem cell line (iPSC) of a CS/CISS2 individual carrying the CLCF1 variant c.321C>G on both alleles. These patient derived iPSC clones show a normal karyotype, several pluripotency markers, and the ability to differentiate into the three germ layers.
Published: 2020

22. Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts

Author: Gülen Eda Utine, Laura Crisponi, Insa Buers, Lara Schöning, Giangiorgio Crisponi, Bilge Bayraktar-Tanyeri, Yvonne Nitschke, Puneet Kaur Sahi, Maja Di Rocco, Angela Loi, Giuseppe Zampino, Frank Rutsch, and Ivana Persico
Subjects: 0301 basic medicine, Disease, 030105 genetics & heredity, Crisponi syndrome, Bioinformatics, Sudden death, Diagnosis, Differential, MAGEL2, 03 medical and health sciences, Camptodactyly, Craniosynostoses, Death, Sudden, Intellectual Disability, Retinitis pigmentosa, Genetics, medicine, Humans, Hyperhidrosis, Receptors, Cytokine, Genetics (clinical), NALCN, business.industry, Differential diagnosis, pathogenesis and treatment concepts-, CLINICAL GENETICS, cilt.97, ss.209-221, 2020 [Buers I., Persico I., Schoening L., Nitschke Y., Di Rocco M., Loi A., Sahi P. K. , ÜTİNE G. E. , Bayraktar-Tanyeri B., Zampino G., et al., -Crisponi/cold-induced sweating syndrome], Facies, medicine.disease, Hypotonia, Cold-induced sweating, 030104 developmental biology, Scoliosis, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Cytokines, Ciliary neurotrophic factor receptor, Trismus, CLCF1, KLHL7, CRLF1, SCN2A, Differential diagnosis, medicine.symptom, KLHL7, business, Hand Deformities, Congenital, CLCF1, Retinitis Pigmentosa, Ciliary Neurotrophic Factor Receptor alpha Subunit
Abstract: Crisponi/cold-induced sweating syndrome (CS/CISS) is an autosomal recessive disease characterized by hyperthermia, camptodactyly, feeding and respiratory difficulties often leading to sudden death in the neonatal period. The affected individuals who survived the first critical years of life, develop cold-induced sweating and scoliosis in early childhood. The disease is caused by variants in the CRLF1 or in the CLCF1 gene. Both proteins form a heterodimeric complex that acts on cells expressing the ciliary neurotrophic factor receptor (CNTFR). CS/CISS belongs to the family of "CNTFR-related disorders" showing a similar clinical phenotype. Recently, variants in other genes, including KLHL7, NALCN, MAGEL2 and SCN2A, previously linked to other diseases, have been associated with a CS/CISS-like phenotype. Therefore, retinitis pigmentosa and Bohring-Optiz syndrome-like (KLHL7), Congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome (NALCN), Chitayat-Hall/Schaaf-Yang syndrome (MAGEL2), and early infantile epileptic encephalopathy-11 syndrome (SCN2A) all share an overlapping phenotype with CS/CISS, especially in the neonatal period. This review aims to summarize the existing literature on CS/CISS, focusing on the current state of differential diagnosis, pathogenesis and treatment concepts in order to achieve an accurate and rapid diagnosis. This will improve patient management and enable specific treatments for the affected individuals.
Published: 2020

23. Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome

Author: Laura Crisponi, Paolo Uva, M Asunis, Giorgio Fotia, D Pruna, S Cossu, Francesco Cucca, Ivana Persico, Gianmauro Cuccuru, M Oppo, Rossano Atzeni, Stefano Onano, and Andrea Angius
Subjects: 0301 basic medicine, Proband, Pediatrics, medicine.medical_specialty, Sleep disorder, Psychomotor retardation, business.industry, medicine.disease, Hypotonia, Cachexia, 03 medical and health sciences, Epilepsy, 030104 developmental biology, Genetics, Medicine, medicine.symptom, Allele, business, Genetics (clinical), Exome sequencing
Abstract: Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. It is caused by mutations in the NALCN gene that encodes a voltage-independent, cation channel permeable to NM, K+ and Ca2+ and forms a channel complex with UNCSO and UNC79. So far, only 4 homozygous mutations have been found in 11 cases belonging to 4 independent consanguineous families. We studied a Sardinian family with 2 siblings presenting dysmorphic facies, hypotonia, psychomotor retardation, epilepsy, absent speech, sleep disturbance, hyperkinetic movement disorder, cachexia and chronic constipation. Polymorphic generalized seizures started at 4 and 6 years, respectively. Anti-epileptic drugs (AEDs) therapy was efficient for female proband's epilepsy, but the male still has weekly seizures. Whole exome sequencing identified 2 novel truncating mutations in NALCN allowing to assess the clinical phenotype to IHPRF1. This is the fifth family reported worldwide, and these are the first European cases with IHPRF1 syndrome with biallelic truncating mutations of NALCN.
Published: 2018

24. Author response for 'Crisponi/cold‐induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts'

Author: Laura Crisponi, Giuseppe Zampino, Insa Buers, Bilge Bayraktar-Tanyeri, Gülen Eda Utine, Yvonne Nitschke, Angela Loi, Lara Schöning, Ivana Persico, Giangiorgio Crisponi, Frank Rutsch, Maja Di Rocco, and Puneet Kaur Sahi
Subjects: Pathogenesis, medicine.medical_specialty, business.industry, Medicine, Cold-induced sweating syndrome, Differential diagnosis, business, Dermatology
Published: 2019

25. Confirmation of a new phenotype in an individual with a variant in the last part of exon 30 of CREBBP

Author: Valentina Pes, Manuela Oppo, Stefano Sotgiu, Chiara Perria, Rossano Atzeni, Gianmauro Cuccuru, Andrea Angius, Paolo Uva, Gigliola Serra, Laura Crisponi, Stefano Onano, Stefania Olla, Ivana Persico, Francesco Cucca, Raoul C.M. Hennekam, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), and Paediatric Genetics
Subjects: Male, 0301 basic medicine, Adolescent, 030105 genetics & heredity, Biology, medicine.disease_cause, 03 medical and health sciences, Exon, Genetics, medicine, Humans, Missense mutation, CREB-binding protein, EP300, Genetic Association Studies, Genetics (clinical), Exome sequencing, Rubinstein-Taybi Syndrome, Mutation, Rubinstein–Taybi syndrome, Exons, Prognosis, medicine.disease, CREB-Binding Protein, Phenotype, Pedigree, 030104 developmental biology, biology.protein, Female
Abstract: We report here a novel de novo missense variant affecting the last amino acid of exon 30 of CREBBP [NM_004380, c.5170G>A; p.(Glu1724Lys)] in a 17-year-old boy presenting mild intellectual disability and dysmorphisms but not resembling the phenotype of classical Rubinstein–Taybi syndrome. The patient showed a marked overweight from early infancy on and had cortical heterotopias. Recently, 22 individuals have been reported with missense mutations in the last part of exon 30 and the beginning of exon 31 of CREBBP, showing this new phenotype. This additional case further delineates the genotype–phenotype correlations within the molecular and phenotypic spectrum of variants in CREBBP and EP300.
Published: 2019

26. Novel action of FOXL2 as mediator of Col1a2 gene autoregulation

Author: Laura Crisponi, Andrea Angius, Francesca Crobu, Loredana Marcia, Roberto Cusano, Mara Marongiu, Francesco Cucca, Manila Deiana, Andrea Sbardellati, David Schlessinger, Isadora Asunis, Giorgio Fotia, Angela Loi, and Alessandra Meloni
Subjects: Forkhead Box Protein L2, 0301 basic medicine, Chromatin Immunoprecipitation, medicine.medical_specialty, Response element, Collagen Type I, Article, Cell Line, Extracellular matrix, Mice, 03 medical and health sciences, 0302 clinical medicine, Mediator, Laminin, Internal medicine, Consensus Sequence, medicine, Transcriptional regulation, Animals, Promoter Regions, Genetic, Molecular Biology, Transcription factor, Oligonucleotide Array Sequence Analysis, biology, Ovary, Gene Expression Regulation, Developmental, Forkhead Transcription Factors, Cell Biology, Extracellular Matrix, Cell biology, Mice, Inbred C57BL, Fibronectin, 030104 developmental biology, Endocrinology, 030220 oncology & carcinogenesis, biology.protein, Female, Folliculogenesis, Protein Binding, Developmental Biology
Abstract: FOXL2 belongs to the evolutionarily conserved forkhead box (FOX) superfamily and is a master transcription factor in a spectrum of developmental pathways, including ovarian and eyelid development and bone, cartilage and uterine maturation. To analyse its action, we searched for proteins that interact with FOXL2. We found that FOXL2 interacts with specific C-terminal propeptides of several fibrillary collagens. Because these propeptides can participate in feedback regulation of collagen biosynthesis, we inferred that FOXL2 could thereby affect the transcription of the cognate collagen genes. Focusing on COL1A2, we found that FOXL2 indeed affects collagen synthesis, by binding to a DNA response element located about 65Kb upstream of this gene. According to our hypothesis we found that in Foxl2(-/-) mouse ovaries, Col1a2 was elevated from birth to adulthood. The extracellular matrix (ECM) compartmentalizes the ovary during folliculogenesis, (with type I, type III and type IV collagens as primary components), and ECM composition changes during the reproductive lifespan. In Foxl2(-/-) mouse ovaries, in addition to up-regulation of Col1a2, Col3a1, Col4a1 and fibronectin were also upregulated, while laminin expression was reduced. Thus, by regulating levels of extracellular matrix components, FOXL2 may contribute to both ovarian histogenesis and the fibrosis attendant on depletion of the follicle reserve during reproductive aging and menopause.
Published: 2016

27. Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome in the context of inherited lipodystrophies

Author: Ilenia Zara, Magdalena Zoledziewska, Chris Jones, Laura Crisponi, Josh Smith, Riccardo Berutti, Deborah A. Nickerson, Roberto Cusano, Serena Sanna, Manuela Oppo, Decio Cerimele, Maria A. Montesu, Francesco Cucca, Andrea Angius, M. Valentini, David S. Hanna, Rosanna Satta, Frederic Reinier, and Francesca Cottoni
Subjects: Adult, Male, medicine.medical_specialty, Lipodystrophy, POLD1, Endocrinology, Diabetes and Metabolism, Context (language use), Syndrome, Deafness, Biology, medicine.disease, Familial partial lipodystrophy, Hypoplasia, Pedigree, Congenital generalized lipodystrophy, Endocrinology, Internal medicine, medicine, Humans, Female, Mandibular Diseases, Exome sequencing, Werner syndrome
Abstract: Background Lipodystrophies are a large heterogeneous group of genetic or acquired disorders characterized by generalized or partial fat loss, usually associated with metabolic complications such as diabetes mellitus, hypertriglyceridemia and hepatic steatosis. Many efforts have been made in the last years in identifying the genetic etiologies of several lipodystrophy forms, although some remain to be elucidated. Methods We report here the clinical description of a woman with a rare severe lipodystrophic and progeroid syndrome associated with hypertriglyceridemia and diabetes whose genetic bases have been clarified through whole-exome sequencing (WES) analysis. Results This article reports the 5th MDPL (Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome) patient with the same de novo p.S605del mutation in POLD1. We provided further genetic evidence that this is a disease-causing mutation along with a plausible molecular mechanism responsible for this recurring event. Moreover we overviewed the current classification of the inherited forms of lipodystrophy, along with their underlying molecular basis. Conclusions Progress in the identification of lipodystrophy genes will help in better understanding the role of the pathways involved in the complex physiology of fat. This will lead to new targets towards develop innovative therapeutic strategies for treating the disorder and its metabolic complications, as well as more common forms of adipose tissue redistribution as observed in the metabolic syndrome and type 2 diabetes.
Published: 2015

28. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Author: Bjarni J. Vilhjálmsson, Jian Yang, Hilary K. Finucane, Alexander Gusev, Sara Lindström, Stephan Ripke, Giulio Genovese, Po-Ru Loh, Gaurav Bhatia, Ron Do, Tristan Hayeck, Hong-Hee Won, Sekar Kathiresan, Michele Pato, Carlos Pato, Rulla Tamimi, Eli Stahl, Noah Zaitlen, Bogdan Pasaniuc, Gillian Belbin, Eimear E. Kenny, Mikkel H. Schierup, Philip De Jager, Nikolaos A. Patsopoulos, Steve McCarroll, Mark Daly, Shaun Purcell, Daniel Chasman, Benjamin Neale, Michael Goddard, Peter M. Visscher, Peter Kraft, Nick Patterson, Alkes L. Price, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Lynn E. DeLisi, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Lyudmila Georgieva, Elliot S. Gershon, Ina Giegling, Paola Giusti-Rodrguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Jakob Grove, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julia, Rene S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, Brian J. Kelly, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kahler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lnnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Preben B. Mortensen, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Mller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietilinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Sderman, Srinivas Thirumalai, Draga Toncheva, Paul A. Tooney, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Jing Qin Wu, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tonu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jonsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Bryan J. Mowry, Markus M. Nthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St. Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O’Donovan, David J. Hunter, Muriel Adank, Habibul Ahsan, Kristiina Aittomäki, Laura Baglietto, Sonja Berndt, Carl Blomquist, Federico Canzian, Jenny Chang-Claude, Stephen J. Chanock, Laura Crisponi, Kamila Czene, Norbert Dahmen, Isabel dos Santos Silva, Douglas Easton, A. Heather Eliassen, Jonine Figueroa, Olivia Fletcher, Montserrat Garcia-Closas, Mia M. Gaudet, Lorna Gibson, Christopher A. Haiman, Per Hall, Aditi Hazra, Rebecca Hein, Brian E. Henderson, Albert Hofman, John L. Hopper, Astrid Irwanto, Mattias Johansson, Rudolf Kaaks, Muhammad G. Kibriya, Peter Lichtner, Eiliv Lund, Enes Makalic, Alfons Meindl, Hanne Meijers-Heijboer, Bertram Müller-Myhsok, Taru A. Muranen, Heli Nevanlinna, Petra H. Peeters, Julian Peto, Ross L. Prentice, Nazneen Rahman, María José Sánchez, Daniel F. Schmidt, Rita K. Schmutzler, Melissa C. Southey, Ruth Travis, Clare Turnbull, Andre G. Uitterlinden, Rob B. van der Luijt, Quinten Waisfisz, Zhaoming Wang, Alice S. Whittemore, Rose Yang, Wei Zheng, ANS - Amsterdam Neuroscience, Adult Psychiatry, Other departments, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, Grove, Jakob, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Vilhjalmsson, Bjarni J, Yang, Jian, Finucane, Hilary K, Gusev, Alexander, Lee, SH, Price, Alkes L, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Study, Psychosis Endophenotype International Consortium, Wellcome Trust Case Control Consortium, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Human genetics, NCA - Brain mechanisms in health and disease, CCA - Oncogenesis, CCA - Quality of life, CCA - Cancer biology and immunology, Psychiatry, Department of Technology and Operations Management, Department of Organisation and Personnel Management, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Cell biology, and Internal Medicine
Subjects: Multifactorial Inheritance, Linkage disequilibrium, Complex disease, heritability, Bioinformatics, Medical and Health Sciences, Linkage Disequilibrium, 0302 clinical medicine, Theoretical, External reference, Models, Statistics, GWAS, Genetics(clinical), Genetics (clinical), Mathematics, Genetics & Heredity, Schizophrenia Working Group of the Psychiatric Genomics Consortium, 0303 health sciences, Single Nucleotide, Biological Sciences, Serious Mental Illness, Prognosis, Thresholding, Regression, Mental Health, Phenotype, polygenic risk scores, Mixed model, Multiple Sclerosis, Genotype, Quantitative Trait Loci, polygenic risk score, schizophrenia, GWAS, Discovery, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetics, Humans, p-value, Pruning (decision trees), Polymorphism, Genome-Wide Association Study, Schizophrenia, Models, Theoretical, 030304 developmental biology, genome-wide association study, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Brain Disorders, Data set, schizophrenia, Sample size determination, polygenic risk score, Polygenic risk score, 030217 neurology & neurosurgery, linkage disequilibrium
Abstract: Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R-2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. Refereed/Peer-reviewed
Published: 2015

29. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Author: Emmi Tikkanen, Pascal Guénel, Rico Rueedi, Hamdi Mbarek, Gerardo Heiss, Hilary K. Finucane, Jing Hua Zhao, Peter K. Joshi, Mark I. McCarthy, Frank B. Hu, Stephen J. Chanock, Manjeet K. Bolla, Sandosh Padmanabhan, Vilmundur Gudnason, Chunyan He, Aarno Palotie, Reedik Mägi, Joe Dennis, Nicholas G. Martin, Behrooz Z. Alizadeh, Elisabeth Widen, Caroline Hayward, Penelope A. Lind, Magdalena Zoledziewska, Ayellet V. Segrè, Fergus J. Couch, Massimo Mangino, Melissa C. Southey, Immaculata De Vivo, Yongmei Liu, Ute Hamann, Angela Cox, Maartje J. Hooning, Iffat Rahman, Mitul Shah, Eric Boerwinkle, Matthias W. Beckmann, Catharina A. Hartman, Tanguy Corre, Kathryn L. Lunetta, Thérèse Truong, Anna Marie Mulligan, Caterina Barbieri, Robert Winqvist, Lili Milani, Cristina Menni, Frits R. Rosendaal, Pau Navarro, Christian Gieger, Ken K. Ong, Stig E. Bojesen, Susan M. Ring, Marjanka K. Schmidt, George McMahon, Deborah J. Thompson, Robert Karlsson, Nicholas J. Timpson, M. Arfan Ikram, Alexander Teumer, Jingmei Li, Christa Meisinger, Diana L. Cousminer, Doris Stöckl, Heli Nevanlinna, Teresa Nutile, Tim D. Spector, Eva Albrecht, Murielle Bochud, Linda Broer, Felix R. Day, Sven Bergmann, Renée de Mutsert, Nicholas J. Wareham, Marjo-Riitta Järvelin, Marzyeh Amini, Elisabeth Altmaier, Isabel dos-Santos-Silva, Peter Vollenweider, Douglas F. Easton, Tamara B. Harris, Ellen A. Nohr, Paul D.P. Pharoah, David J. Porteous, Jenny A. Visser, Ilja M. Nolte, Genevieve Lachance, Thomas Meitinger, Archie Campbell, Thomas Brüning, Graham G. Giles, Johan G. Eriksson, Nancy L. Pedersen, George Davey Smith, Gonneke Willemsen, Joanne M. Murabito, Francesco Cucca, Daniel I. Chasman, Eleonora Porcu, Nora Franceschini, Thibaud Boutin, Ulla Sovio, Roger L. Milne, Annette Peters, Lisette Stolk, Paul M. Ridker, Claudia Langenberg, Patrick Sulem, Toshiko Tanaka, Marike Gabrielson, Judith S. Brand, Unnur Thorsteindottir, Alison M. Dunning, Marina Ciullo, Julie E. Buring, Harold Snieder, Lude Franke, Meir J. Stampfer, Po-Ru Loh, Julian Peto, Ellen W. Demerath, Sheila Ulivi, Ivana Kolcic, Maristella Steri, Jouke J. Hottenga, Amanda B. Spurdle, Tõnu Esko, Katherine S. Pollard, Eulalia Catamo, Anneli Pouta, Kyriaki Michailidou, Dieter Flesch-Janys, James F. Wilson, Kamila Czene, Sean Whalen, Diether Lambrechts, Abhishek Sarkar, Laura Crisponi, Jonathan Tyrer, Antonietta Robino, Sara Lindström, Harald Grallert, Stefania Lenarduzzi, Peter Kraft, Patrik K. E. Magnusson, Lavinia Paternoster, Digna R. Velez Edwards, Mike A. Nalls, Per Hall, Joyce Y. Tung, Cinzia Sala, Lindsay Fernández-Rhodes, Ayush Giri, Hiltrud Brauch, André G. Uitterlinden, Alkes L. Price, Tracy A. O'Mara, Lynda M. Rose, John L. Hopper, David A. Hinds, Katherine S. Ruth, Arto Mannermaa, Uwe Völker, Rossella Sorice, Zoltán Kutalik, Debbie A Lawlor, Georgia Chenevix-Trench, Anna Murray, Albertine J. Oldehinkel, Bruce H. R. Wolffenbuttel, Hae Kyung Im, Dale R. Nyholt, Lenore J. Launer, Andres Metspalu, Irene L. Andrulis, Konstantin Strauch, Albert V. Smith, Daniela Toniolo, Eco J. C. de Geus, Jenny Chang-Claude, Marek Zygmunt, Dorret I. Boomsma, Harry Campbell, Peter Devilee, Henry Völzke, Daniela Ruggiero, Dennis O. Mook-Kanamori, John R. B. Perry, Javier Benitez, Grant W. Montgomery, David J. Hunter, David Karasik, Luigi Ferrucci, Emily Hallberg, Stefania Bandinelli, Hermann Brenner, Raymond Noordam, Sarah E. Medland, Peter A. Fasching, Qin Wang, Ilaria Gandin, Manolis Kellis, Hannes Helgason, Igor Rudan, Paolo Radice, Michela Traglia, Jian'an Luan, Robert A. Scott, Brumat Marco, Veronique Vitart, Kari Stefansson, Katharina E. Schraut, Ko Willems van Dijk, Ozren Polasek, Daniel F. Gudbjartsson, Natalia Perjakova, Joop S.E. Laven, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Art and Culture, History, Antiquity, Day, Felix R., Thompson, Deborah J., Helgason, Hanne, Chasman, Daniel I., Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S., Whalen, Sean, Sarkar, Abhishek K., Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, CATERINA MARIA, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J., Karlsson, Robert, Kolcic, Ivana, Loh, Po Ru, Lunetta, Kathryn L., Mangino, Massimo, Brumat, Marco, Mcmahon, George, Medland, Sarah E., Nolte, Ilja M., Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M., Schraut, Katharina E., Segrã¨, Ayellet V., Smith, Albert V., Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L., Bandinelli, Stefania, Beckmann, Matthias W., Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brã¼ning, Thoma, Buring, Julie E., Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix Trench, Georgia, Corre, Tanguy, Couch, Fergus J., Cousminer, Diana L., Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, De Geus, Eco J. C. N., De Mutsert, Renã©e, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos Santos Silva, Isabel, Dunning, Alison M., Eriksson, Johan G., Fasching, Peter A., FernÃ¡ndez Rhodes, Lindsay, Ferrucci, Luigi, Flesch Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Guã©nel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B., Hartman, Catharina A., Heiss, Gerardo, Hooning, Maartje J., Hopper, John L., Hu, Frank, Hunter, David J., Ikram, M. Arfan, Im, Hae Kyung, Jã¤rvelin, Marjo Riitta, Joshi, Peter K., Karasik, David, Kellis, Manoli, Kutalik, Zoltan, Lachance, Genevieve, Lambrechts, Diether, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lenarduzzi, Stefania, Li, Jingmei, Lind, Penelope A., Lindstrom, Sara, Liu, Yongmei, Luan, Jian'An, Mã¤gi, Reedik, Mannermaa, Arto, Mbarek, Hamdi, Mccarthy, Mark I., Meisinger, Christa, Meitinger, Thoma, Menni, Cristina, Metspalu, Andre, Michailidou, Kyriaki, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mulligan, Anna M., Nalls, Mike A., Navarro, Pau, Nevanlinna, Heli, Nyholt, Dale R., Oldehinkel, Albertine J., O'Mara, Tracy A., Padmanabhan, Sandosh, Palotie, Aarno, Pedersen, Nancy, Peters, Annette, Peto, Julian, Pharoah, Paul D. P., Pouta, Anneli, Radice, Paolo, Rahman, Iffat, Ring, Susan M., Robino, Antonietta, Rosendaal, Frits R., Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Schmidt, Marjanka K., Scott, Robert A., Shah, Mitul, Sorice, Rossella, Southey, Melissa C., Sovio, Ulla, Stampfer, Meir, Steri, Maristella, Strauch, Konstantin, Tanaka, Toshiko, Tikkanen, Emmi, Timpson, Nicholas J., Traglia, Michela, Truong, Thã©rã¨se, Tyrer, Jonathan P., Uitterlinden, AndrÃ© G., Edwards, Digna R. Velez, Vitart, Veronique, Vã¶lker, Uwe, Vollenweider, Peter, Wang, Qin, Widen, Elisabeth, Van Dijk, Ko Willem, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R., Zhao, Jing Hua, Zoledziewska, Magdalena, Zygmunt, Marek, Alizadeh, Behrooz Z., Boomsma, Dorret I., Ciullo, Marina, Cucca, Francesco, Esko, Tãµnu, Franceschini, Nora, Gieger, Christian, Gudnason, Vilmundur, Hayward, Caroline, Kraft, Peter, Lawlor, Debbie A., Magnusson, Patrik K. E., Martin, Nicholas G., Mook Kanamori, Dennis O., Nohr, Ellen A., Polasek, Ozren, Porteous, David, Price, Alkes L., Ridker, Paul M., Snieder, Harold, Spector, Tim D., Stã¶ckl, Dori, Toniolo, Daniela, Ulivi, Sheila, Visser, Jenny A., Vã¶lzke, Henry, Wareham, Nicholas J., Wilson, James F., LifeLines Cohort, Study, Interact, Consortium, Kconfab/aocs, Investigator, Endometrial Cancer Association, Consortium, Ovarian Cancer Association, Consortium, Practical, Consortium, Spurdle, Amanda B., Thorsteindottir, Unnur, Pollard, Katherine S., Easton, Douglas F., Tung, Joyce Y., Chang Claude, Jenny, Hinds, David, Murray, Anna, Murabito, Joanne M., Stefansson, Kari, Ong, Ken K., Perry, John R. B., Internal Medicine, Erasmus MC other, Medical Oncology, Epidemiology, Obstetrics & Gynecology, Day, Felix [0000-0003-3789-7651], Thompson, Deborah [0000-0003-1465-5799], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Pharoah, Paul [0000-0001-8494-732X], Sovio, Ulla [0000-0002-0799-1105], Tyrer, Jonathan [0000-0003-3724-4757], Zhao, Jing Hua [0000-0003-4930-3582], Wareham, Nicholas [0000-0003-1422-2993], Easton, Douglas [0000-0003-2444-3247], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Massachusetts Institute of Technology. Department of Mathematics, and Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Subjects: 0301 basic medicine, Male, Netherlands Twin Register (NTR), Ovarian Cancer Association Consortium, LOCI, Genome-wide association study, cancer risk, Menarche/genetics, Bioinformatics, GWAS, menarche, puberty, Body Mass Index, Risk Factors, Neoplasms, Databases, Genetic, WIDE ASSOCIATION, Endometrial Cancer Association Consortium, Ribonucleoproteins/genetics, 2. Zero hunger, Genetics, Age Factors, Genetics GWAS menarche, reproductive disorders, Neoplasms/genetics, 3. Good health, Ribonucleoproteins, Menarche, MENDELIAN RANDOMIZATION, Intercellular Signaling Peptides and Proteins, GROWTH, Female, TRAITS, Population variance, Intercellular Signaling Peptides and Proteins/genetics, Adolescent, Ubiquitin-Protein Ligases, kConFab/AOCS Investigators, Quantitative Trait Loci, Quantitative trait locus, Biology, METABOLISM, INHERITANCE, Polymorphism, Single Nucleotide, PRACTICAL consortium, 03 medical and health sciences, Genomic Imprinting, SDG 3 - Good Health and Well-being, Mendelian randomization, REGRESSION, medicine, Journal Article, Humans, cancer, Genetic Predisposition to Disease, 1000 Genomes Project, Membrane Proteins/genetics, METAANALYSIS, Puberty, Calcium-Binding Proteins, Membrane Proteins, Cancer, InterAct Consortium, Heritability, medicine.disease, BODY-MASS INDEX, 030104 developmental biology, genome-wide association studies, Puberty/genetics, LifeLines Cohort Study, Genome-Wide Association Study
Abstract: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P
Published: 2017

30. A new case series of Crisponi syndrome in a Turkish family and review of the literature

Author: Bilge Bayraktar-Tanyeri, Ivana Persico, Suleyman Bayraktar, Mervenur Hepokur, and Laura Crisponi
Subjects: 0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, Turkey, DNA Mutational Analysis, Consanguinity, 030105 genetics & heredity, Crisponi syndrome, medicine.disease_cause, Pathology and Forensic Medicine, Frameshift mutation, 03 medical and health sciences, Exon, Camptodactyly, Death, Sudden, 0302 clinical medicine, medicine, Humans, Hyperhidrosis, Receptors, Cytokine, Child, Gene, Genetics (clinical), Mutation, Base Sequence, business.industry, Homozygote, Infant, Newborn, Facies, General Medicine, Pedigree, Pediatrics, Perinatology and Child Health, Trismus, Anatomy, Differential diagnosis, medicine.symptom, business, Hand Deformities, Congenital, 030217 neurology & neurosurgery
Abstract: Crisponi syndrome/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder with a complex phenotype, reported in the neonatal period for CS and in the evolutive one for CISS. The syndrome usually manifests at birth. The aim of this study was to report on three new patients with CS and review the Turkish patients. We report here on three patients from two related families harboring a homozygous mutation in the cytokine receptor-like factor-1 (CRLF1) gene. DNA samples of the three patients and their parents were subjected to a mutational analysis of the CRLF1 gene at the Institute of Biomedical and Genetic Research - National Research Council, Cagliari (Italy). Direct sequencing of the nine coding exons and surrounding intronic regions of CRLF1 was performed using specific primers. All three patients were found to be homozygotes for the mutation c.708_709delinsT, which leads to a frameshift in the second fibronectin type III domain (p.Pro238Argfs*6). CS should be considered in the differential diagnosis of newborns with muscle contractions, feeding and swallowing difficulties, dysmorphic facial findings, camptodactyly, and hypertermia. Neonatologists must be aware of this syndrome that, although very rare worldwide, has a higher prevalence in Turkey.
Published: 2016

31. Genomic analyses for age at menarche identify 389 independent signals and indicate BMI-independent effects of puberty timing on cancer susceptibility

Author: Nora Franceschini, Rico Rueedi, Gerardo Heiss, Behrooz Z. Alizadeh, Marike Gabrielson, Henry Völzke, Daniela Ruggiero, Judith S. Brand, Stig E. Bojesen, Iffat Rahman, Fergus J. Couch, Patrick Sulem, Harold Snieder, Jenny Chang-Claude, Caterina Barbieri, Ute Hamann, Hinds D, Pascal Guénel, Amanda B. Spurdle, Paul M. Ridker, Ulla Sovio, Roger L. Milne, Hamdi Mbarek, H Brenner, Hilary K. Finucane, Maristella Steri, Lude Franke, Emmi Tikkanen, Ivana Kolcic, Vitart, Ken K. Ong, Alison M. Dunning, Aarno Palotie, Caroline Hayward, Jouke J. Hottenga, Abhishek Sarkar, Stefania Lenarduzzi, Nicholas G. Martin, Katharina E. Schraut, Eva Albrecht, Hiltrud Brauch, Lisette Stolk, Joop S.E. Laven, Penelope A. Lind, Ilaria Gandin, Patrik K. E. Magnusson, Ellen A. Nohr, Tanguy Corre, Jing Hua Zhao, N J Timpson, Jenny A. Visser, Harald Grallert, P. A. Fasching, Susan M. Ring, Stöckl D, Grant W. Montgomery, Marzyeh Amini, Velez Edwards Dr, Thomas Meitinger, Qinghua Wang, David Karasik, Daniel I. Chasman, Nicholas J. Wareham, Alexander Teumer, Mellissa C. Southey, Kathryn L. Lunetta, S. E. Medland, Dieter Flesch-Janys, Maartje J. Hooning, Lili Milani, D Lambrechts, Ozren Polasek, Po-Ru Loh, James F. Wilson, Campbell A, Julian Peto, Ellen W. Demerath, Christian Gieger, de Geus Ej, Cox A, Javier Benítez, Mitul Shah, Eric Boerwinkle, Matthias W. Beckmann, Thorsteindottir U, Julie E. Buring, De Vivo I, Hannes Helgason, Paolo Radice, Tracy A. O'Mara, L. J. Launer, D. F. Gudbjartsson, Frits R. Rosendaal, C.A. Hartman, Stefania Bandinelli, Felix R. Day, Lynda M. Rose, van Dijk Kw, Natalia Perjakova, Anneli Pouta, Igor Rudan, Sven Bergmann, Kamila Czene, Georgia Chenevix-Trench, Pau Navarro, Sean Whalen, Heli Nevanlinna, Teresa Nutile, Diana L. Cousminer, Albert V. Smith, Massimo Mangino, Uwe Völker, Michela Traglia, Lindsay Fernández-Rhodes, Ayush Giri, Linda Broer, Albertine J. Oldehinkel, Isabel dos-Santos-Silva, Peter Vollenweider, Jian'an Luan, Nancy L. Pedersen, Irene L. Andrulis, Reedik Mägi, Robert Winqvist, Gonneke Willemsen, John L. Hopper, Gudnason, Marjanka K. Schmidt, David G. Hunter, Robert A. Scott, T.B. Harris, Joanne M. Murabito, David J. Porteous, Harry Campbell, Eleonora Porcu, D.I. Boomsma, Thibaud Boutin, M. A. Ikram, Doug Easton, Magdalena Zoledziewska, Meir J. Stampfer, Katherine S. Pollard, Eulalia Catamo, Tõnu Esko, M-R Jarvelin, Laura Crisponi, Claudia Langenberg, Marek Zygmunt, Antonietta Robino, Emily Hallberg, Manjeet K. Bolla, Ruth Ks, Bruce H W Wolffenbuttel, Lavinia Paternoster, Tyrer Jp, P. Kraft, George Davey-Smith, Robert Karlsson, Graham G. Giles, Jingmei Li, Pharoah Pd, Segrè Av, Marina Ciullo, Perry, Brumat Marco, Peter K. Joshi, Chunyan He, Sara Lindström, Joe Dennis, Thérèse Truong, Yongmei Liu, Anna Marie Mulligan, Mike A. Nalls, Cinzia Sala, K. Stefansson, Murray A, Debbie A Lawlor, Tung Jy, Deborah J. Thompson, Dennis O. Mook-Kanamori, Daniela Toniolo, Luigi Ferrucci, Peter Devilee, S. Chanock, Cristina Menni, George McMahon, Murielle Bochud, A. Metspalu, Tomohiro Tanaka, E. Widen, Hae Kyung Im, Dale R. Nyholt, Ilja M. Nolte, Thomas Brüning, Christina Meisinger, Annette Peters, Kyriaki Michailidou, Per Hall, Rossella Sorice, Genevieve Lachance, Johan G. Eriksson, Francesco Cucca, A.G. Uitterlinden, Z. Kutalik, Mark I. McCarthy, Frank B. Hu, Konstantin Strauch, Tim D. Spector, Elisabeth Altmaier, S. Ulivi, Alkes L. Price, Arto Mannermaa, Raymond Noordam, and de Mutsert R
Subjects: Genetics, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Genotype, Menarche, Trait, Cancer susceptibility, Genomics, Biology, 030304 developmental biology
Abstract: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Here, we analyse 1000-Genome reference panel imputed genotype data on up to ~370,000 women and identify 389 independent signals (all P−8) for age at menarche, a notable milestone in female pubertal development. In Icelandic data from deCODE, these signals explain ~7.4% of the population variance in age at menarche, corresponding to one quarter of the estimated heritability. We implicate over 250 genes via coding variation or associated gene expression, and demonstrate enrichment across genes active in neural tissues. We identify multiple rare variants near the imprinted genes MKRN3 and DLK1 that exhibit large effects on menarche only when paternally inherited. Disproportionate effects of variants on early or late puberty timing are observed: single variant and heritability estimates are larger for early than late puberty timing in females. The opposite pattern is seen in males, with larger estimates for late than early puberty timing. Mendelian randomization analyses indicate causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women, and prostate cancer in men. In aggregate, our findings reveal new complexity in the genetic regulation of puberty timing and support new causal links with adult cancer risks.
Published: 2016
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32. Neuroticism, Depressive Symptoms, and Serum BDNF

Author: Alessandra Cannas, Angelina R. Sutin, Maria Grazia Piras, Osorio Meirelles, Monia Lobina, Laura Crisponi, Antonio Terracciano, Alan B. Zonderman, David Schlessinger, Manuela Uda, and Antonella Mulas
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Neurotic Disorders, Population, Article, Revised NEO Personality Inventory, Young Adult, Sex Factors, Internal medicine, medicine, Humans, education, Applied Psychology, Depression (differential diagnoses), Aged, Aged, 80 and over, Brain-derived neurotrophic factor, education.field_of_study, Depression, Brain-Derived Neurotrophic Factor, Age Factors, Middle Aged, Center for Epidemiologic Studies Depression Scale, Neuroticism, Psychiatry and Mental health, Endocrinology, nervous system, Acute Disease, Cohort, Antidepressant, Female, Psychology, Clinical psychology
Abstract: Animal models and clinical studies suggest that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of depression. We test whether serum and plasma levels of BDNF are associated with trait neuroticism and its facets and with state measures of depressive symptoms.In a community-based cohort (N = 2099), we measured serum and plasma BDNF concentrations and administered the Revised NEO Personality Inventory and the Center for Epidemiological Studies Depression Scale. Covariates included age, sex, cigarette smoking, obesity, and antidepressant use.Serum BDNF concentrations were inversely related to neuroticism (r = -0.074, p.001), in particular the depression facet (r = -0.08, p.001). Lower BDNF concentrations were also associated with severe depressive symptoms (Center for Epidemiological Studies Depression Scale ≥ 28; odds ratio = 0.906; 95% confidence interval = 0.851-0.965). The association of serum BDNF with neuroticism was independent of depressive symptoms, indicating that serum BDNF might represent a biological correlate of neuroticism and not just of transient depressive states. Plasma BDNF was not associated with measures of depression.Our study suggests that lower serum BDNF is associated with both a dispositional vulnerability to depression and acute depressive states in the general population.
Published: 2011

33. Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders

Author: Francesca Chiappe, Per Erik Waaler, Alessandra Meloni, Mara Marongiu, Yusra Zalloum, Hanan Hamamy, Laura Crisponi, Giuseppe Zampino, Frank Rutsch, Jana Herholz, Manila Deiana, Carmen Roche Herrero, and Giangiorgio Crisponi
Subjects: Male, medicine.medical_specialty, Adolescent, Fever, DNA Mutational Analysis, Scoliosis, Biology, Crisponi syndrome, Article, Death, Sudden, Terminology as Topic, Chlorocebus aethiops, Genotype, Genetics, medicine, Animals, Humans, Hyperhidrosis, Secretion, Amino Acid Sequence, Receptors, Cytokine, Allele, Child, Genetics (clinical), Clinical pathology, Facies, Infant, Cold-induced sweating, medicine.disease, Phenotype, Child, Preschool, COS Cells, Immunology, Female, Trismus, Hand Deformities, Congenital, Sequence Alignment, Muscle Contraction
Abstract: Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) are disorders caused by mutations in CRLF1. The two syndromes share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia, associated with death in most cases in the first years of life. To evaluate a potential genotype/phenotype correlation and whether CS and CISS1 represent two allelic diseases or manifestations at different ages of the same disorder, we carried out a detailed clinical analysis of 19 patients carrying mutations in CRLF1. We studied the functional significance of the mutations found in CRLF1, providing evidence that phenotypic severity of the two disorders mainly depends on altered kinetics of secretion of the mutated CRLF1 protein. On the basis of these findings, we believe that the two syndromes, CS and CISS1, represent manifestations of the same disorder, with different degrees of severity. We suggest renaming the two genetic entities CS and CISS1 with the broader term of Sohar–Crisponi syndrome.
Published: 2011

34. Successful treatment of cold-induced sweating in Crisponi syndrome and its possible mechanism of action

Author: Birendra Nath Mallick, Frank Rutsch, Jana Herholz, and Laura Crisponi
Subjects: medicine.medical_specialty, business.industry, Treatment outcome, Follow up studies, MEDLINE, Cold-induced sweating, Pharmacology, Crisponi syndrome, Developmental Neuroscience, Pediatrics, Perinatology and Child Health, medicine, New delhi, Neurology (clinical), Psychiatry, business
Abstract: Jana Herholz, Laura Crisponi, Birendra N Mallick, Frank Rutsch 1 Department of General Pediatics, M nster University Children's Hospital, M nster, Germany. 2 Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari, Italy. 3 School of Life Sciences, Jawaharlal Nehru University, New Delhi, India. Correspondence to: rutschf@ukmuenster.de doi: 10.1111/j.1469-8749.2010.03630.x
Published: 2010

35. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author: Kenneth Rice, Amy J. Swift, Veronique Vitart, Lu Qi, Kaisa Silander, Olivier Le Bacquer, Laura Crisponi, David S. Siscovick, Bo Isomaa, Anne U. Jackson, Anke Tönjes, Richard N. Bergman, Rosa Maria Roccasecca, Luigi Ferrucci, Narisu Narisu, Kari Stefansson, Holly E. Syddall, Giuseppe Paolisso, Kim L. Ward, Paul Elliott, Scott M. Grundy, Paul Johnson, Jerome I. Rotter, Philippe Froguel, James B. Meigs, George Davey Smith, Andrew T. Hattersley, Leena Peltonen, Eric J.G. Sijbrands, Serena Sanna, María TeresaMartínez-Larrad, David Altshuler, Harald Grallert, Caroline S. Fox, Nita G. Forouhi, Dorret I. Boomsma, Harry Campbell, Jean Tichet, Angelo Scuteri, Aroon D. Hingorani, Daniel S. Pearson, Meena Kumari, Silvia Naitza, Shah Ebrahim, Manjinder S. Sandhu, Jose C. Florez, Cyrus Cooper, David M. Nathan, Joseph Hung, Fredrik Karpe, Ozren Polasek, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Abbas Dehghan, Udo Seedorf, Beverley M. Shields, Antti Jula, Pau Navarro, Josephine M. Egan, Rune R. Frants, Leif Groop, Gunnar Sigursson, Seppo Koskinen, Vincent Mooser, François Pattou, Jing Hua Zhao, Irene Pichler, John F. Peden, Göran Hallmans, Toshiko Tanaka, Ruth J. F. Loos, Peter Kovacs, Andrew D. Morris, Cécile Lecoeur, Jeffrey R. O'Connell, Massimo Mangino, Nicole Vogelzangs, Rhian Gwilliam, Gordon H. Williams, Carina Zabena, Naomi Hammond, Amélie Bonnefond, Björn Zethelius, Joachim Spranger, Nancy L. Pedersen, Christopher J. Groves, Nicholas J. Timpson, George Dedoussis, Veikko Salomaa, Peter Henneman, Andrew Walley, Serge Hercberg, Ian N. M. Day, Simon Heath, Matt Neville, Alex S. F. Doney, Robert Clarke, Olov Rolandsson, Panos Deloukas, Eric Boerwinkle, Y. AnteroKesaniemi, Mike Sampson, Gerard Waeber, Sven Bergmann, Ben A. Oostra, Manuel Serrano-Ríos, Mandy van Hoek, Christine Cavalcanti-Proença, Anna L. Gloyn, Ulla Sovio, Andrew P. Morris, Anneli Pouta, Amanda J. Bennett, Paul Scheet, Peter Schwarz, Jaakko Tuomilehto, Hugh Watkins, Johanna Kuusisto, Denis Rybin, Anna LiisaHartikainen, Maria GraziaFranzosi, Unnur Thorsteinsdottir, Rafn Benediktsson, Alan F. Wright, Colin N. Apalmer, Anuj Goel, Yavuz Ariyurek, Lars Lind, Robert Sladek, Stefan R. Bornstein, Reedik Mägi, Laila Simpson, Tim D. Spector, Paul W. Franks, Nicholas L. Smith, John R. B. Perry, Peter Vollenweider, Suzannah Bumpstead, Ruth E. Pakyz, Christa Meisinger, Alan R. Shuldiner, Josée Dupuis, Man Li, Eric J. Brunner, Francis S. Collins, Torben Hansen, James F. Wilson, Guangju Zhai, Igor Rudan, Nicole L. Glazer, Marco Orrù, Pierre Meneton, Knut Borch-Johnsen, Eleanor Wheeler, Gonçalo R. Abecasis, Mark I. McCarthy, Jouke JanHottenga, Inga Prokopenko, Ping An, Jérôme Delplanque, Albert Hofman, Andrew B. Singleton, Gabe Crawford, Thomas A. Buchanan, Avan Aihie Sayer, Richard M. Watanabe, David Schlessinger, A C Fedson, André G. Uitterlinden, Frank B. Hu, Jaqueline C. MWitteman, Dhiraj Varma, Ingrid B. Borecki, Sutapa Mukherjee, Murielle Bochud, Barbara Thorand, Christian Gieger, Lori L. Bonnycastle, Stephen J. Sharp, Markus Perola, Caroline Hayward, Kristin Ardlie, J. Graessler, Robert W. Mahley, Toby Johnson, Jian'an Luan, Joshua C. Randall, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Valgerdur Steinthorsdottir, Yurii S. Aulchenko, G. Mark Lathrop, Christian Dina, Eleftheria Zeggini, Cecilia M. Lindgren, Stavroula Kanoni, Timothy M. Frayling, Dawn M. Waterworth, Marika Kaakinen, Timo T. Valle, Diana Zelenika, Yii Der IdaChen, Angela Silveira, Nigel W. Rayner, Aimo Ruokonen, Yun Li, Cristian Pattaro, Annelli Sandbæk, Richa Saxena, Danielle Posthuma, Steven A. McCarroll, Niels Grarup, Samy Hadjadj, Pilar Galan, Xijing Han, Lyle J. Palmer, Ulf Gyllensten, Peter P. Pramstaller, Manuela Uda, Jarred B. McAteer, Brenda W.J.H. Penninx, Debbie A Lawlor, Torben Jørgensen, Beatrice Knight, Yvonne Böttcher, Claudia Langenberg, Nicole Soranzo, Ghislain Rocheleau, Erik Ingelsson, Mario A. Morken, Michael Roden, Felicity Payne, David R. Hillman, Michael Marmot, Karen L. Mohlke, Heather M. Stringham, Bruce M. Psaty, Gudmar Thorleifsson, Yoav Ben-Shlomo, Inês Barroso, W. H. Linda Kao, James S. Pankow, Valeriya Lyssenko, Nicholas J. Wareham, Tiinamaija Tuomi, Ann ChristineSyvänen, Braxton D. Mitchell, Alisa K. Manning, Mika Kivimäki, Peter Wagner, Praveen Sethupathy, G. BragiWalters, Jaakko Kaprio, Kijoung Song, Marjo Riitta-Järvelin, Michael A. Province, Andrew A. Hicks, Marilyn C. Cornelis, Sarah H. Wild, David Meyre, Guillaume Charpentier, Patrik K. E. Magnusson, David Melzer, Jennie Hui, Peter Shrader, Michael Stumvoll, Mark O. Goodarzi, Michael R. Erdos, Oluf Pedersen, Andreas Pfeiffer, Augustine Kong, Christian Herder, Laura J. Scott, John W. GYarnell, Kirsten Ohm Kyvik, Beverley Balkau, Antje Fischer-Rosinsky, Gonneke Willemsen, Thomas Illig, Neelam Hassanali, Markku Laakso, Michael Boehnke, John Beilby, Christopher S. Franklin, Fernando Rivadeneira, M. Carola Zillikens, Michael N. Weedon, Antonio Cao, Mark E. Cooper, Simon C. Potter, Eco J. C. de Geus, H.-Erich Wichmann, Amanda F. Elliott, Lachlan J. McOin, Sophie Visvikis-Siest, Thomas Sparsø, Laura J. McCulloch, Taina K. Lajunen, Peter S. Chines, Nabila Bouatia-Naji, Medical Research Council (MRC), Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, Ophthalmology, Epidemiology, Clinical Genetics, Dermatology, Internal Medicine, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Anders Hamsten on behalf of Procardis Consortium, MAGIC investigators, Human genetics, Psychiatry, EMGO - Mental health, NCA - Attention & Cognition, and NCA - Anxiety & Depression
Subjects: Blood Glucose, Netherlands Twin Register (NTR), Candidate gene, Genome-wide association study, Type 2 diabetes, CIRCADIAN CLOCK, TRIGLYCERIDE LEVELS, 0302 clinical medicine, Delta-5 Fatty Acid Desaturase, Databases, Genetic, Homeostasis, GENETICS & HEREDITY, Anders Hamsten on behalf of Procardis Consortium, Child, Genetics, PLASMA-GLUCOSE, 0303 health sciences, Glucokinase regulatory protein, COMMON VARIANTS, 11 Medical And Health Sciences, Fasting, MAGIC investigators, 3. Good health, MODEL ASSESSMENT, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, ESSENTIAL COMPONENTS, Adolescent, DNA Copy Number Variations, Alleles, Blood Glucose/genetics, Blood Glucose/metabolism, DNA Copy Number Variations/genetics, Diabetes Mellitus, Type 2/genetics, Fasting/blood, Gene Expression Regulation, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis/genetics, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Quantitative Trait, Heritable, Reproducibility of Results, Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, DIAGRAM Consortium, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, Fasting glucose, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal medicine, genome wide association study, glucose, diabetes type 2, medicine, GIANT Consortium, Allele, GENOME-WIDE ASSOCIATION, Global BPgen Consortium, 030304 developmental biology, Glycemic, Science & Technology, genome-wide association beta-cell dysfunction plasma-glucose insulin-secretion triglyceride levels essential components model assessment common variants circadian clock disease risk, DISEASE RISK, 06 Biological Sciences, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, Genetic Loci, biology.protein, BETA-CELL DYSFUNCTION, Developmental Biology
Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46, 186 nondiabetic participants. Follow-up of 25 loci in up to 76, 558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Published: 2010
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36. Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia

Author: Gonçalo R. Abecasis, Antonella Mulas, Gianluca Usala, Mara Marongiu, Maria Grazia Piras, Marco Masala, Manuela Uda, Silvia Naitza, David Schlessinger, Mariano Dei, Laura Crisponi, Serena Sanna, Lucia Perseu, Renzo Galanello, Fabio Busonero, Andrea Maschio, Alan R. Shuldiner, Antonio Cao, Patrick F. McArdle, and Sandra Lai
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Genotype, Bilirubin, Genome-wide association study, Locus (genetics), Organic Anion Transporters, Sodium-Independent, Biology, Solute Carrier Organic Anion Transporter Family Member 1B3, chemistry.chemical_compound, Internal medicine, Genetics, medicine, Humans, Molecular Biology, Genetics (clinical), Chromosome 12, Aged, Hyperbilirubinemia, Unconjugated hyperbilirubinemia, Aged, 80 and over, Association Studies Articles, Genetic Variation, General Medicine, Middle Aged, Glucuronic acid, Endocrinology, Italy, chemistry, Biochemistry, Old Order Amish, Female, Hemoglobin, Genome-Wide Association Study
Abstract: Bilirubin, resulting largely from the turnover of hemoglobin, is found in the plasma in two main forms: unconjugated or conjugated with glucuronic acid. Unconjugated bilirubin is transported into hepatocytes. There, it is glucuronidated by UGT1A1 and secreted into the bile canaliculi. We report a genome wide association scan in 4300 Sardinian individuals for total serum bilirubin levels. In addition to the two known loci previously involved in the regulation of bilirubin levels, UGT1A1 (P = 6.2 x 10(-62)) and G6PD (P = 2.5 x 10(-8)), we observed a strong association on chromosome 12 within the SLCO1B3 gene (P = 3.9 x 10(-9)). Our findings were replicated in an independent sample of 1860 Sardinians and in 832 subjects from the Old Order Amish (combined P5 x 10(-14)). We also show that SLC01B3 variants contribute to idiopathic mild unconjugated hyperbilirubinemia. Thus, SLC01B3 appears to be involved in the regulation of serum bilirubin levels in healthy individuals and in some bilirubin-related disorders that are only partially explained by other known gene variants.
Published: 2009

37. Crisponi syndrome in an Indian patient: A rare differential diagnosis for neonatal tetanus

Author: Atanu Kumar Jana, Niranjan Thomas, Manish Kumar, Laura Crisponi, Giangiorgio Crisponi, Alessandra Meloni, and Sumita Danda
Subjects: Male, Pediatrics, medicine.medical_specialty, Tetanus, Base Sequence, business.industry, Infant, Newborn, India, Syndrome, Crisponi syndrome, Craniofacial Abnormalities, Diagnosis, Differential, Neonatal tetanus, Immunology, Genetics, Humans, Medicine, Base sequence, Receptors, Cytokine, Differential diagnosis, business, Genetics (clinical), DNA Primers
Published: 2008

38. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia

Author: Renzo Galanello, Fabio Busonero, G. Abecasis, Paolo Moi, Silvia Naitza, Maria Grazia Piras, Natascia Sestu, Mariano Dei, Ramaiah Nagaraja, Sandra Lai, Vijay G. Sankaran, Stuart H. Orkin, Giuseppe Albai, Carla Sollaino, Antonio Cao, Guillaume Lettre, Wei-Min Chen, Manuela Uda, Maria Dolores Cipollina, Serena Sanna, Gianluca Usala, David Schlessinger, Antonella Mulas, Isadora Asunis, Joel N. Hirschhorn, Manila Deiana, Andrea Maschio, Laura Crisponi, Stefania Satta, and Lucia Perseu
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Hereditary persistence of fetal hemoglobin, Genetic Linkage, Thalassemia, Genome-wide association study, KLF1, Biology, Polymorphism, Single Nucleotide, HBG2, Cohort Studies, Gene Frequency, hemic and lymphatic diseases, Fetal hemoglobin, medicine, Humans, Fetal Hemoglobin, Aged, Aged, 80 and over, Genetics, Multidisciplinary, Genome, Human, Genetic heterogeneity, beta-Thalassemia, Nuclear Proteins, Biological Sciences, Middle Aged, medicine.disease, Sickle cell anemia, Repressor Proteins, Phenotype, Italy, Immunology, Female, Carrier Proteins
Abstract: β-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought of as simple Mendelian diseases. The reasons for this are not well understood, although the level of fetal hemoglobin (HbF) is one well characterized ameliorating factor in both of these conditions. To better understand the genetic basis of this heterogeneity, we carried out genome-wide scans with 362,129 common SNPs on 4,305 Sardinians to look for genetic linkage and association with HbF levels, as well as other red blood cell-related traits. Among major variants affecting HbF levels, SNP rs11886868 in the BCL11A gene was strongly associated with this trait ( P < 10 −35 ). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening for β-thalassemia, and patients with attenuated forms of β-thalassemia vs. those with thalassemia major. We also show that the same BCL11A variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the β-thalassemia phenotype, and it is likely they could help ameliorate other hemoglobin disorders. We expect our findings will help to characterize the molecular mechanisms of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for β-thalassemia and sickle cell anemia.
Published: 2008

39. Transcriptional Control of Ovarian Development in Somatic Cells

Author: Antonino Forabosco, Maria Colombino, Chris Ottolenghi, Laura Crisponi, Manuela Uda, Antonio Cao, and David Schlessinger
Subjects: Time Factors, Transcription, Genetic, Somatic cell, Endocrinology, Diabetes and Metabolism, Granulosa cell, Morphogenesis, Cell Communication, Biology, Mice, Oogenesis, Endocrinology, Physiology (medical), Transcriptional regulation, Animals, Humans, Transcription factor, Ovum, Regulation of gene expression, Genetics, Gene Expression Profiling, Egg Proteins, Ovary, Gene Expression Regulation, Developmental, Obstetrics and Gynecology, Cell Differentiation, Gene expression profiling, Reproductive Medicine, Models, Animal, Somatic sex determination, Female
Abstract: Developmental transitions of the bipotential gonad to the embryonic ovary and thence to the follicle-filled mature ovary are expected to be coordinated by sets of transcription factors. We infer candidate lists here, focusing on somatic cell fate and function. For the mouse, developmental stages of ovary differentiation are relatively discretely phased, and provide a unique tool to investigate the intricate mechanisms that lead to the acquisition of female reproductive competence. Cross-platform gene expression profiles supplement functional studies of specific genes and comparative information about human biology. Available data suggest that: (1) peak transcription activity just precedes the two most decisive steps of early ovary differentiation (i.e., entry into meiosis and follicle formation); (2) alternating peak gene activities in oocytes and somatic cells may reflect reciprocal interactions; and (3) in addition to stable states of chromatin modification associated with morphogenesis, some features of differentiation are labile, contingent on the expression state of critical factors. Examples are the maintenance of somatic sex determination by continued Foxl2 action and the reversible maintenance of follicles in a quiescent state by nuclear Foxo3.
Published: 2007

40. FOXL2 modulates cartilage, skeletal development and IGF1-dependent growth in mice

Author: Alessandro Puddu, Loredana Marcia, Mario Lovicu, Manila Deiana, Mara Marongiu, David Schlessinger, Laura Crisponi, Antonino Forabosco, Emanuele Pelosi, Manuela Uda, Yonqing Zhang, and Angela Loi
Subjects: Forkhead Box Protein L2, Male, medicine.medical_specialty, Gonadal dysgenesis, Cartilage metabolism, Biology, Blepharophimosis, Mice, Ptosis, Internal medicine, medicine, Animals, Humans, Insulin-Like Growth Factor I, Bone Development, Cartilage, Forkhead Transcription Factors, medicine.disease, Premature ovarian failure, body regions, Forkhead box L2, Endocrinology, medicine.anatomical_structure, Urogenital Abnormalities, Skin Abnormalities, Female, medicine.symptom, Haploinsufficiency, Developmental Biology, Research Article, Signal Transduction
Abstract: Background Haploinsufficiency of the FOXL2 transcription factor in humans causes Blepharophimosis/Ptosis/Epicanthus Inversus syndrome (BPES), characterized by eyelid anomalies and premature ovarian failure. Mice lacking Foxl2 recapitulate human eyelid/forehead defects and undergo female gonadal dysgenesis. We report here that mice lacking Foxl2 also show defects in postnatal growth and embryonic bone and cartilage formation. Methods Foxl2−/− male mice at different stages of development have been characterized and compared to wild type. Body length and weight were measured and growth curves were created. Skeletons were stained with alcian blue and/or alizarin red. Bone and cartilage formation was analyzed by Von Kossa staining and immunofluorescence using anti-FOXL2 and anti-SOX9 antibodies followed by confocal microscopy. Genes differentially expressed in skull vaults were evaluated by microarray analysis. Analysis of the GH/IGF1 pathway was done evaluating the expression of several hypothalamic-pituitary-bone axis markers by RT-qPCR. Results Compared to wild-type, Foxl2 null mice are smaller and show skeletal abnormalities and defects in cartilage and bone mineralization, with down-regulation of the GH/IGF1 axis. Consistent with these effects, we find FOXL2 expressed in embryos at 9.5 dpc in neural tube epithelium, in head mesenchyme near the neural tube, and within the first branchial arch; then, starting at 12.5 dpc, expressed in cartilaginous tissue; and at PO and P7, in hypothalamus. Conclusions Our results support FOXL2 as a master transcription factor in a spectrum of developmental processes, including growth, cartilage and bone formation. Its action overlaps that of SOX9, though they are antagonistic in female vs male gonadal sex determination but conjoint in cartilage and skeletal development. Electronic supplementary material The online version of this article (doi:10.1186/s12861-015-0072-y) contains supplementary material, which is available to authorized users.
Published: 2015

41. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Author: Lynne J. Hocking, Caterina Barbieri, Jenny Chang-Claude, David Karasik, Dieter Flesch-Janys, James F. Wilson, Mark S. Goldberg, Henry Voelzke, Archie Campbell, Stig E. Bojesen, David R. Weir, Ailith Pirie, Megan L. Grove, Melissa Wellons, Georg Homuth, Corrado Masciullo, Jennifer A. Brody, Hermann Brenner, Paolo Gasparini, Andrew D. Johnson, Patrick Neven, Graham G. Giles, Peter Kraft, André G. Uitterlinden, Wei Zheng, Alkes L. Price, Anja Rudolph, Arto Mannermaa, Nicholas G. Martin, Christopher A. Haiman, Massimo Mangino, Melissa C. Southey, Daniela Ruggiero, Toshiko Tanaka, Kathryn L. Lunetta, Julie E. Buring, John R. B. Perry, Robert Winqvist, Laufey Tryggvadottir, Angela Cox, Serena Sanna, Nicola Pirastu, Anna Jakubowska, Paul D.P. Pharoah, David J. Porteous, Dragana Vuckovic, Andrea D. Coviello, Giorgia Girotto, Sara Lindstroem, Patrick Sulem, Astrid Petersmann, Xin Li, Maartje J. Hooning, Lili Milani, Sven Bergmann, Marek Zygmunt, Javier Benitez, Vilmundur Gudnason, Fernando Rivadeneira, Volker Arndt, Marina Ciullo, Caroline Hayward, Sheila Ulivi, Janet E. Olson, Hoda Anton-Culver, Maria Kabisch, Sara Margolin, Vessela N. Kristensen, Patrick F. McArdle, Tanguy Corre, Nora Franceschini, Veli-Matti Kosma, Hiltrud Brauch, Roger L. Milne, Eric Boerwinkle, Matthias W. Beckmann, Charles Kooperberg, Qin Wang, Jessica D. Faul, Stephen J. Chanock, Alexander Teumer, Mark O. Goodarzi, Unnur Thorsteinsdottir, R Maegi, Paul M. Ridker, Antonis C. Antoniou, Ozren Polasek, Daniel F. Gudbjartsson, Barbara McKnight, Melissa E. Garcia, Manjeet K. Bolla, Alanna C. Morrison, Paolo Radice, Xiuqing Guo, Lude L. Franke, Michela Traglia, Marjanka K. Schmidt, Heli Nevanlinna, Teresa Nutile, Cinzia Sala, Pascal Guénel, Jennifer E. Huffman, Stephen T. Turner, Anna Murray, Carl Blomqvist, Margaux F. Keller, Samuel E. Jones, Montserrat Garcia-Closas, Ivana Kolcic, Anne B. Newman, Jan Lubinski, Albert Hofman, Isabel dos-Santos-Silva, Hilary K. Finucane, Anne Lise Børresen-Dale, Alexander P. Reiner, Tim D. Spector, Gonneke Willemsen, John D. Eicher, Douglas F. Easton, Claudia Langenberg, Anthony J. Swerdlow, Natalia Bogdanova, Alison M. Dunning, Giorgio Pistis, Tõnu Esko, Behrooz Z. Alizadeh, Martina Mueller-Nurasyid, Eleonora Porcu, Laura M. Yerges-Armstrong, Leslie J. Raffel, Laura Crisponi, Gonçalo R. Abecasis, Jerome I. Rotter, Yii-Der Ida Chen, Antonietta Robino, Katri Pylkaes, Ken K. Ong, Thibaud Boutin, Elinor J. Sawyer, Daniel I. Chasman, Brian E. Henderson, Frank B. Hu, Leslie Bernstein, Drakoulis Yannoukakos, Tamara B. Harris, Dorret I. Boomsma, Katherine S. Ruth, Jie Yao, Keith Humphreys, Jennifer A. Smith, Elisabeth Altmaier, Ulrike Peters, Doris Stoeckl, Eva Albrecht, Tatijana Zemunik, Jenny A. Visser, Minouk J. Schoemaker, Diego Vozzi, Thilo Doerk, J. Ross Chapman, Irene L. Andrulis, Joanne M. Murabito, Alan F. Wright, Lisette Stolk, Jonathan Marten, Alice M. Arnold, Paolo Peterlongo, Harry Campbell, Natalia Pervjakova, Jingmei Li, Jennifer Kriebel, Alicia Beeghly-Fadiel, Immaculata De Vivo, Jouke-Jan Hottenga, Kari Stefansson, Cornelia M. van Duijn, Brendan Bulik-Sullivan, Evelin Mihailov, Chunyan He, Joe Dennis, Nicholas J. Wareham, Yongmei Liu, Sharon L.R. Kardia, Lynda M. Rose, Felix R. Day, Georgia Chenevix-Trench, Albert V. Smith, David J. Hunter, Sandosh Padmanabhan, Christian Gieger, Konstantin Strauch, Igor Rudan, Jacques Simard, Jian'an Luan, Robert A. Scott, Kyriaki Michailidou, Bruce M. Psaty, Per Hall, Suzette J. Bielinski, Rita K. Schmutzler, Julian Peto, Ellen W. Demerath, Ursula M. Schick, Rossella Sorice, Wei Zhao, Børge G. Nordestgaard, Andres Metspalu, Jonine D. Figueroa, Julia A. Knight, Barbara Burwinkel, Thomas Bruening, Judith Manz, Anna González-Neira, Ilaria Gandin, Ian Tomlinson, Thérèse Truong, Kent D. Taylor, Amanda E. Toland, Deborah J. Thompson, Alfons Meindl, Caroline M. Seynaeve, Benjamin M. Neale, Fergus J. Couch, Mike A. Nalls, Ute Hamann, Kamila Czene, John L. Hopper, Bruce H. R. Wolffenbuttel, Grant W. Montgomery, Hatef Darabi, Daniela Toniolo, Jinyan Huang, Peter Devilee, Cathy E. Elks, David Schlessinger, Luigi Ferrucci, Frank Schmidt, Peter A. Fasching, Diether Lambrechts, Najaf Amin, Day, Felix R, Ruth, Katherine S, Thompson, Deborah J, Lunetta, Kathryn L, Pervjakova, Natalia, Chasman, Daniel I, Stolk, Lisette, Finucane, Hilary K, Sulem, Patrick, Bulik Sullivan, Brendan, Esko, Tõnu, Johnson, Andrew D, Elks, Cathy E, Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A, Franke, Lude L, Huffman, Jennifer E, Keller, Margaux F, Mcardle, Patrick F, Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M, Schick, Ursula M, Smith, Jennifer A, Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke Jan, Mangino, Massimo, Smith, Albert V, Tanaka, Toshiko, Abecasis, Gonçalo R, Andrulis, Irene L, Anton Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Arnold, Alice M, Barbieri, CATERINA MARIA, Beckmann, Matthias W, Beeghly Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J, Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borresen Dale, Anne Lise, Boutin, Thibaud S, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thoma, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J, Chapman, J. Ro, Chen, Yii Der Ida, Chenevix Trench, Georgia, Couch, Fergus J, Coviello, Andrea D, Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dos Santos Silva, Isabel, Dunning, Alison M, Eicher, John D, Fasching, Peter A, Faul, Jessica D, Figueroa, Jonine, Flesch Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E, García Closas, Montserrat, Giles, Graham G, Girotto, Giorgia, Goldberg, Mark S, González Neira, Anna, Goodarzi, Mark O, Grove, Megan L, Gudbjartsson, Daniel F, Guénel, Pascal, Guo, Xiuqing, Haiman, Christopher A, Hall, Per, Hamann, Ute, Henderson, Brian E, Hocking, Lynne J, Hofman, Albert, Homuth, Georg, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Huang, Jinyan, Humphreys, Keith, Hunter, David J, Jakubowska, Anna, Jones, Samuel E, Kabisch, Maria, Karasik, David, Knight, Julia A, Kolcic, Ivana, Kooperberg, Charle, Kosma, Veli Matti, Kriebel, Jennifer, Kristensen, Vessela, Lambrechts, Diether, Langenberg, Claudia, Li, Jingmei, Li, Xin, Lindström, Sara, Liu, Yongmei, Luan, Jian'An, Lubinski, Jan, Mägi, Reedik, Mannermaa, Arto, Manz, Judith, Margolin, Sara, Marten, Jonathan, Martin, Nicholas G, Masciullo, Corrado, Meindl, Alfon, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L, Müller Nurasyid, Martina, Nalls, Michael, Neale, Benjamin M, Nevanlinna, Heli, Neven, Patrick, Newman, Anne B, Nordestgaard, Børge G, Olson, Janet E, Padmanabhan, Sandosh, Peterlongo, Paolo, Peters, Ulrike, Petersmann, Astrid, Peto, Julian, Pharoah, Paul D. P, Pirastu, Nicola, Pirie, Ailith, Pistis, Giorgio, Polasek, Ozren, Porteous, David, Psaty, Bruce M, Pylkäs, Katri, Radice, Paolo, Raffel, Leslie J, Rivadeneira, Fernando, Rudan, Igor, Rudolph, Anja, Ruggiero, Daniela, Sala, Cinzia F, Sanna, Serena, Sawyer, Elinor J, Schlessinger, David, Schmidt, Marjanka K, Schmidt, Frank, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Robert A, Seynaeve, Caroline M, Simard, Jacque, Sorice, Rossella, Southey, Melissa C, Stöckl, Dori, Strauch, Konstantin, Swerdlow, Anthony, Taylor, Kent D, Thorsteinsdottir, Unnur, Toland, Amanda E, Tomlinson, Ian, Truong, Thérèse, Tryggvadottir, Laufey, Turner, Stephen T, Vozzi, Diego, Wang, Qin, Wellons, Melissa, Willemsen, Gonneke, Wilson, James F, Winqvist, Robert, Wolffenbuttel, Bruce B. H. R, Wright, Alan F, Yannoukakos, Drakouli, Zemunik, Tatijana, Zheng, Wei, Zygmunt, Marek, Bergmann, Sven, Boomsma, Dorret I, Buring, Julie E, Ferrucci, Luigi, Montgomery, Grant W, Gudnason, Vilmundur, Spector, Tim D, van Duijn, Cornelia M, Alizadeh, Behrooz Z, Ciullo, Marina, Crisponi, Laura, Easton, Douglas F, Gasparini, Paolo, Gieger, Christian, Harris, Tamara B, Hayward, Caroline, Kardia, Sharon L. R, Kraft, Peter, Mcknight, Barbara, Metspalu, Andre, Morrison, Alanna C, Reiner, Alex P, Ridker, Paul M, Rotter, Jerome I, Toniolo, Daniela, Uitterlinden, André G, Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J, Weir, David R, Yerges Armstrong, Laura M, Price, Alkes L, Stefansson, Kari, Visser, Jenny A, Ong, Ken K, Chang Claude, Jenny, Murabito, Joanne M, Perry, John R. B, Murray, Anna, Internal Medicine, Epidemiology, Medical Oncology, Clinical Genetics, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, PRACTICAL Consortium, kConFab Investigators, AOCS Investigators, EPIC-InterAct Consortium, LifeLines Cohort Study, Generation, Scotland, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Life Course Epidemiology (LCE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
Subjects: Netherlands Twin Register (NTR), Aging, DNA Repair, LOCI, Genome-wide association study, BLOOD-PRESSURE, Disease, CHROMOSOMAL INSTABILITY, Bioinformatics, HOMOLOGOUS RECOMBINATION, PREMATURE OVARIAN FAILURE, Genotype, BRCA2 MUTATION CARRIERS, WIDE ASSOCIATION, Gene Regulatory Networks, NATURAL MENOPAUSE, Genetics, education.field_of_study, menopause, DDR, BODY-MASS INDEX, CELL-TYPES, BRCA1 Protein, Reproduction, BRCA1-mediated DNA repair, Age Factors, Obstetrics and Gynecology, General Medicine, Genomics, Middle Aged, 3. Good health, Menopause, Phenotype, Female, medicine.symptom, Signal Transduction, Delayed puberty, Adult, DNA repair, Population, Hypothalamus, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Lower risk, DDR, Article, Breast cancer, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Humans, Genetic Predisposition to Disease, Allele, education, Genetic association, Models, Genetic, business.industry, Genetic Variation, medicine.disease, Aging/genetics, BRCA1 Protein/genetics, Breast Neoplasms/genetics, Gene Regulatory Networks/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Genomics/methods, Hypothalamus/metabolism, Menopause/genetics, Reproduction/genetics, Signal Transduction/genetics, business, Genome-Wide Association Study
Abstract: Menopause timing has a major impact on infertility and risk of disease. Younger age at natural (nonsurgical) menopause (ANM) is associated with a higher risk of osteoporosis, cardiovascular disease, and type 2 diabetes and a lower risk of breast cancer. Late menopause is associated with a higher risk of breast cancer. It is well known that the age at which women go through menopause is partly determined by genes, but the underlying mechanisms are poorly understood. Genome-wide association studies have identified 18 common genetic variants associated with ANM. These variants explain less than 5% of the variation in ANM compared with the 21% explained by all common variants on genome-wide association study arrays. This genome-wide association study was the collaborative effort of researchers from 177 institutions worldwide. The study was designed to investigate genetic variants associated with timing of menopause among a population of approximately 70,000 women of European ancestry. A dual strategy was used to identify both common and, for the first time, low-frequency coding variants associated with ANM. The causal relationship between ANM and breast cancer was investigated using a Mendelian randomization approach. Combined analysis identified 1208 single-nucleotide polymorphisms (SNPs) of a total of approximately 2.6 million that reached the genome-wide significance threshold for association with ANM. Forty-four regions with common variants were identified; among these 44 loci were 2 rare low-frequency missense alleles of large effect. A majority of ANM SNPs were enriched in DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal relationship between delayed ANM and breast cancer risk; there was approximately 6% increase in risk per year; P = 3 × 10-14); increased risk with delayed menopause appeared to be mediated primarily by prolonged sex hormone exposure in a woman’s lifetime, not DDR mechanisms. This is the first study to confirm the link between early and late menopause and breast cancer risk using genetic information. Age at natural menopause genetic variants influence breast cancer risk primarily through variation in menopause timing. Although carrying higher numbers of ANM-increasing variants and enrichment in DDR genes are associated with a modest increase in breast cancer risk, the major mechanism for increased risk appears to be prolonged estrogen and/or progesterone exposure due to delayed menopause.
Published: 2015

42. Rare coding variants and X-linked loci associated with age at menarche

Author: Kathryn L. Lunetta, Felix R. Day, Patrick Sulem, Katherine S. Ruth, Joyce Y. Tung, David A. Hinds, Tõnu Esko, Cathy E. Elks, Elisabeth Altmaier, Chunyan He, Jennifer E. Huffman, Evelin Mihailov, Eleonora Porcu, Antonietta Robino, Lynda M. Rose, Ursula M. Schick, Lisette Stolk, Alexander Teumer, Deborah J. Thompson, Michela Traglia, Carol A. Wang, Laura M. Yerges-Armstrong, Antonis C. Antoniou, Caterina Barbieri, Andrea D. Coviello, Francesco Cucca, Ellen W. Demerath, Alison M. Dunning, Ilaria Gandin, Megan L. Grove, Daniel F. Gudbjartsson, Lynne J. Hocking, Albert Hofman, Jinyan Huang, Rebecca D. Jackson, David Karasik, Jennifer Kriebel, Ethan M. Lange, Leslie A. Lange, Claudia Langenberg, Xin Li, Jian'an Luan, Reedik Mägi, Alanna C. Morrison, Sandosh Padmanabhan, Ailith Pirie, Ozren Polasek, David Porteous, Alex P. Reiner, Fernando Rivadeneira, Igor Rudan, Cinzia F. Sala, David Schlessinger, Robert A. Scott, Doris Stöckl, Jenny A. Visser, Uwe Völker, Diego Vozzi, James G. Wilson, Marek Zygmunt, Nita G. Forouhi, Nicola D. Kerrison, Stephen J. Sharp, Matt Sims, Inês Barroso, Panos Deloukas, Mark I. McCarthy, Larraitz Arriola, Beverley Balkau, Aurelio Barricarte, Heiner Boeing, Paul W. Franks, Carlos Gonzalez, Sara Grioni, Rudolf Kaaks, Timothy J. Key, Carmen Navarro, Peter M. Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, J Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, María‐José Sánchez, Nadia Slimani, Anne Tjonneland, Rosario Tumino, Daphne L. van der A, Yvonne T. van der Schouw, Elio Riboli, Blair H. Smith, Archie Campbell, Ian J. Deary, Andrew M. McIntosh, Eric Boerwinkle, Julie E. Buring, Laura Crisponi, Douglas F. Easton, Caroline Hayward, Frank B. Hu, Simin Liu, Andres Metspalu, Craig E. Pennell, Paul M. Ridker, Konstantin Strauch, Elizabeth A. Streeten, Daniela Toniolo, André G. Uitterlinden, Sheila Ulivi, Henry Völzke, Nicholas J. Wareham, Melissa Wellons, Nora Franceschini, Daniel I. Chasman, Unnur Thorsteinsdottir, Anna Murray, Kari Stefansson, Joanne M. Murabito, Ken K. Ong, John R. B. Perry
Published: 2015
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43. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

Author: Sophie H. Van Wingerden, Wei V. Zhuang, Mladen Boban, John R. B. Perry, Joop S.E. Laven, Shah Ebrahim, Andrea D. Coviello, Barbara McKnight, Laura Crisponi, Sharon L.R. Kardia, Daniel I. Chasman, Lorna M. Lopez, George Dedoussis, Stefania Bandinelli, Nora Franceschini, Florian Ernst, A. Cecile J.W. Janssens, Yvonne T. van der Schouw, Henri Wallaschofski, Jari Lahti, Triin Laisk, Elizabeth A. Streeten, Joanne M. Murabito, Liana Ferreli, Harold Snieder, Dale R. Nyholt, Lenore J. Launer, Panagiotis Deloukas, Melissa E. Garcia, Eco J. C. de Geus, H.-Erich Wichmann, John M. Starr, Eva Albrecht, Paul M. Ridker, N. Charlotte Onland-Moret, Petra H.M. Peeters, Massimo Mangino, Jacques S. Beckmann, Stephen J. Chanock, Grant W. Montgomery, Julie E. Buring, Barbara Thorand, Diederick E. Grobbee, Irena Martinović Klarić, Constance Chen, So-Youn Shin, Ozren Polasek, Daniel F. Gudbjartsson, Patrick Sulem, Carla H. van Gils, Eleonora Porcu, Cinzia Sala, Tim D. Spector, Alexander N. Parker, Ellen W. Demerath, Guillaume Paré, Krista Fischer, Simon N. Stacey, Mara Marongiu, Lina Zgaga, Jouke-Jan Hottenga, Unnur Styrkarsdottir, Debbie A Lawlor, Douglas P. Kiel, Guangju Zhai, Kari Stefansson, Lisette Stolk, Igor Rudan, David Schlessinger, Katri R Currency Signikkönen, Z. Kutalik, Ian J. Deary, Frank J.M. Broekmans, Ulf de Faire, Vincent Mooser, Luigi Ferrucci, Maria G. Stathopoulou, Pio D'Adamo, Marek Zygmunt, Linda Broer, James F. Wilson, Lovorka Barać Lauc, Angelo Scuteri, Patrik K. E. Magnusson, Frank B. Hu, Jennifer A. Smith, Toomas Haller, Giorgio Pistis, Colette J M Wijnands-van Gent, Emil Rehnberg, Marlies Voorhuis, Anna Murray, David Melzer, Chunyan He, Tamara B. Harris, Merli Hass, Patrick F. McArdle, Valur Emilsson, Gérard Waeber, Manuela Uda, Nancy L. Pedersen, Jenny A. Visser, Behrooz Z. Alizadeh, Andres Salumets, Andrew D. Johnson, Gonneke Willemsen, Sheila Ulivi, Tmu Esko, Vilmundur Gudnason, Bart C.J.M. Fauser, Maja Barbalić, Henry Völzke, Ronald P. Stolk, Aarno Palotie, Peter Van Nierop, Thor Aspelund, Elisabeth Widen, Caroline Hayward, Johan G. Eriksson, Alan F. Wright, Marilyn C. Cornelis, Tanguy Corre, Eric Boerwinkle, Ben A. Oostra, Alice M. Arnold, Kathleen Stirrups, Yvonne V. Louwers, M. Carola Zillikens, Anne B. Newman, Jerome I. Rotter, Jianjun Liu, Per Hall, Aaron R. Folsom, David Karasik, Yan V. Sun, Albert Hofman, Gudny Eiriksdottir, Andrew B. Singleton, Victor J M Pop, Pau Navarro, Tatijana Zemunik, Andres Metspalu, Andrew S. Plump, Cornelia M. van Duijn, Dorret I. Boomsma, Harry Campbell, Nicole Soranzo, Bruce M. Psaty, Enda M. Byrne, Christian Gieger, Albert Tenesa, Nicholas G. Martin, Unnur Thorsteinsdottir, Kathryn L. Lunetta, Laufey Tryggvadottir, Serena Sanna, Kim Tsui, Ivana Kolcic, Laura M. Yerges-Armstrong, Jacqueline M. Vink, Bruce H. R. Wolffenbuttel, Daniela Toniolo, Peter M. Visscher, Rob M. van Dam, Erik Ingelsson, Sandra Lai, Corrado Masciullo, Albert V. Smith, Paolo Gasparini, Sarah E. Medland, Nicole L. Glazer, Peter Kraft, André G. Uitterlinden, David J. Hunter, Andrea Burri, Jules J. Keyzer, Susan E. Hankinson, Gail Davies, Andrew C. Heath, Biological Psychology, EMGO+ - Mental Health, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Surgery, Hematology, Clinical Genetics, Study T.L., Lisette, Stolk, John R. B., Perry, Daniel I., Chasman, Chunyan, He, Massimo, Mangino, Patrick, Sulem, Maja, Barbalic, Linda, Broer, Enda M., Byrne, Florian, Ernst, Tõnu, Esko, Nora, Franceschini, Daniel F., Gudbjartsson, Jouke Jan, Hottenga, Peter, Kraft, Patrick F., Mcardle, Eleonora, Porcu, So Youn, Shin, Albert V., Smith, Sophie van, Wingerden, Guangju, Zhai, Wei V., Zhuang, Eva, Albrecht, Behrooz Z., Alizadeh, Thor, Aspelund, Stefania, Bandinelli, Lovorka Barac, Lauc, Jacques S., Beckmann, Mladen, Boban, Eric, Boerwinkle, Frank J., Broekman, Andrea, Burri, Harry, Campbell, Stephen J., Chanock, Constance, Chen, Marilyn C., Corneli, Tanguy, Corre, Andrea D., Coviello, D'Adamo, ADAMO PIO, Gail, Davie, Ulf de, Faire, Eco J. C., de Geu, Ian J., Deary, George V. Z., Dedoussi, Panagiotis, Delouka, Shah, Ebrahim, Gudny, Eiriksdottir, Valur, Emilsson, Johan G., Eriksson, Bart C. J. M., Fauser, Liana, Ferreli, Luigi, Ferrucci, Krista, Fischer, Aaron R., Folsom, Melissa E., Garcia, Gasparini, Paolo, Christian, Gieger, Nicole, Glazer, Diederick E., Grobbee, Per, Hall, Toomas, Haller, Susan E., Hankinson, Merli, Ha, Caroline, Hayward, Andrew C., Heath, Albert, Hofman, Erik, Ingelsson, A. Cecile J. W., Janssen, Andrew D., Johnson, David, Karasik, Sharon L. R., Kardia, Jules, Keyzer, Douglas P., Kiel, Ivana, Kolcic, Zoltán, Kutalik, Jari, Lahti, Sandra, Lai, Triin, Laisk, Joop S. E., Laven, Debbie A., Lawlor, Jianjun, Liu, Lorna M., Lopez, Yvonne V., Louwer, Patrik K. E., Magnusson, Mara, Marongiu, Nicholas G., Martin, Irena Martinovic, Klaric, Corrado, Masciullo, Barbara, Mcknight, Sarah E., Medland, David, Melzer, Vincent, Mooser, Pau, Navarro, Anne B., Newman, Dale R., Nyholt, N., Charlotte Onland Moret, Aarno, Palotie, Guillaume, Paré, Alex N., Parker, Nancy L., Pedersen, Petra H. M., Peeter, Giorgio, Pisti, Andrew S., Plump, Ozren, Polasek, Victor J. M., Pop, Bruce M., Psaty, Katri, Räikkönen, Emil, Rehnberg, Jerome I., Rotter, Igor, Rudan, Cinzia, Sala, Andres, Salumet, Angelo, Scuteri, Andrew, Singleton, Jennifer A., Smith, Harold, Snieder, Nicole, Soranzo, Simon N., Stacey, John M., Starr, Maria G., Stathopoulou, Kathleen, Stirrup, Ronald P., Stolk, Unnur, Styrkarsdottir, Yan V., Sun, Albert, Tenesa, Barbara, Thorand, Daniela, Toniolo, Laufey, Tryggvadottir, Kim, Tsui, Sheila, Ulivi, Rob M., van Dam, Yvonne T., van der Schouw, Carla H., van Gil, Peter van, Nierop, Jacqueline M., Vink, Peter M., Visscher, Marlies, Voorhui, Gérard, Waeber, Henri, Wallaschofski, H., Erich Wichmann, Elisabeth, Widen, Colette J. M., Wijnands van Gent, Gonneke, Willemsen, James F., Wilson, Bruce H. R., Wolffenbuttel, Alan F., Wright, Laura M., Yerges Armstrong, Tatijana, Zemunik, Lina, Zgaga, M., Carola Zilliken, Marek, Zygmunt, The LifeLines Cohort, Study, Alice M., Arnold, Dorret I., Boomsma, Julie E., Buring, Laura, Crisponi, Ellen W., Demerath, Vilmundur, Gudnason, Tamara B., Harri, Frank B., Hu, David J., Hunter, Lenore J., Launer, Andres, Metspalu, Grant W., Montgomery, Ben A., Oostra, Paul M., Ridker, Serena, Sanna, David, Schlessinger, Tim D., Spector, Kari, Stefansson, Elizabeth A., Streeten, Unnur, Thorsteinsdottir, Manuela, Uda, André G., Uitterlinden, Cornelia M., van Duijn, Henry, Völzke, Anna, Murray, Joanne M., Murabito, Jenny A., Visser, Kathryn L., Lunetta, Faculteit Medische Wetenschappen/UMCG, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Netherlands Twin Register (NTR), Candidate gene, Menopause, dna repair, DNA Repair, PROTEIN, Genome-wide association study, DNA-Directed DNA Polymerase, medicine.disease_cause, Bioinformatics, DISEASE, PREMATURE OVARIAN FAILURE, 0302 clinical medicine, NATURAL MENOPAUSE, MUTATION, GENE-EXPRESSION, Genetics, 0303 health sciences, Mutation, 030219 obstetrics & reproductive medicine, Age Factors, 3. Good health, Premature ovarian failure, DNA Polymerase gamma, menopause, loci, genetics, Female, DNA repair, DNA Primase, Biology, Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, FOLLICLE-STIMULATING-HORMONEPREMATURE OVARIAN FAILUREGENOME-WIDE ASSOCIATIONGENE-EXPRESSIONONSETPOLYMORPHISMSMUTATIONHERITABILITYCHROMOSOMEMENARCHE, medicine, Humans, GENOME-WIDE ASSOCIATION, Gene, POLYMORPHISMS, 030304 developmental biology, Genetic association, DNA Helicases, Immunity, Proteins, medicine.disease, FOLLICLE-STIMULATING-HORMONE, DNA Repair Enzymes, Exodeoxyribonucleases, Genetic Loci, ONSET, Genome-Wide Association Study
Abstract: To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 - 10 g8). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-I °B signaling and mitochondrial dysfunction as biological processes related to timing of menopause. © 2012 Nature America, Inc. All rights reserved.
Published: 2012

44. Genome-wide association study of susceptibility loci for breast cancer in Sardinian population

Author: Mario Lovicu, Maria Teresa Ionta, Antonio Cossu, Magdalena Zoledziewska, Gonçalo R. Abecasis, Francesco Tanda, Francesco Atzori, Manuela Uda, Robert N. Hoover, Serena Sanna, Nazario Olla, Grazia Palomba, Sandra Lai, David Schlessinger, Laura Crisponi, Stephen J. Chanock, Mario Budroni, Maristella Pitzalis, Douglas F. Easton, N. Olmeo, Eleonora Porcu, Marina Pisano, Gianmauro Cuccuru, David J. Hunter, Giuseppe Palmieri, Ilenia Zara, Antonella Mulas, Mariano Dei, Angela Loi, and Kyriaki Michailidou
Subjects: Cancer Research, Genome-wide association study, Population, Genes, BRCA2, Genes, BRCA1, Single-nucleotide polymorphism, Breast Neoplasms, Penetrance, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Genotype, Genetics, medicine, Humans, Genetic Predisposition to Disease, Sardinian population, International HapMap Project, Receptor, Fibroblast Growth Factor, Type 2, BRCA1/2 mutation analysis, education, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, High Mobility Group Proteins, medicine.disease, 3. Good health, Oncology, TOX3, Italy, Genetic Loci, 030220 oncology & carcinogenesis, Case-Control Studies, Trans-Activators, Female, business, Apoptosis Regulatory Proteins, Receptors, Progesterone, Breast cancer risk, Research Article
Abstract: Background Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. Methods We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Results Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p
Published: 2014

45. Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty

Author: Toos Van Beijsterveldt, Nicholas Schork, Ruth Loos, Eleftheria Zeggini, LAURA CRISPONI, Valur Emilsson, Nicole Soranzo, Ozren Polasek, Elisabeth Thiering, Elina Hypponen, Andrew Hattersley, Craig Pennell, Alexandra Lewin, ANGELO SCUTERI, Adamo Pio D'Adamo, Antje Körner, Peter Kraft, Thor Aspelund, Timo Lakka, Johannes Kettunen, Mara Marongiu, Christel Middeldorp, Mika Kähönen, Lachlan Coin, Alina Rodriguez, Terho Lehtimäki, Kalliope Panoutsopoulou, Carol Wang, Kathryn Lunetta, George Davey Smith, Debbie A Lawlor, Jianjun Liu, Nicholas Timpson, Xavier Estivill, Tuomas Kilpeläinen, Thomas Price, Mariona Bustamante, Evangelia Stergiakouli, Struan Grant, Gerard Waeber, Lyle John Palmer, Paolo Gasparini, Katja Pahkala, André Scherag, John Holloway, Carmen Iñiguez, Paul Elliott, Albert Vernon Smith, MANUELA UDA, Harri Niinikoski, Oliver Davis, Mads Melbye, Ida Surakka, Frank Geller, Rick Jansen, Mark McCarthy, Cecilia Lindgren, Hilleke Evertje Hulshoff Pol, Nicole Warrington, Ellen Demerath, ReproGen Consortium, Early Growth Genetics (EGG) Consortium, Cousminer, Diana L, Stergiakouli, Evangelia, Berry, Diane J, Ang, Wei, Hyppönen, Elina, Widen, Elisabeth, Biological Psychology, EMGO+ - Mental Health, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hebebrand, Johannes (Beitragende*r), Hinney, Anke (Beitragende*r), Psychiatry, and EMGO - Mental health
Subjects: Male, Netherlands Twin Register (NTR), puberty, Medizin, Body Mass Index, 0302 clinical medicine, Sexual maturity, Breast, Sexual Maturation, Child, Genetics (clinical), Adiposity, 2. Zero hunger, 0303 health sciences, Genome, Articles, General Medicine, Menarche, Female, medicine.medical_specialty, Adolescent, Genotype, males, 030209 endocrinology & metabolism, Genitalia, Male, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Sex Factors, SDG 3 - Good Health and Well-being, Internal medicine, Genetics, medicine, Humans, Sex organ, Allele, Molecular Biology, Tanner scale, 030304 developmental biology, Breast development, maturation, ta1184, Puberty, ta3121, medicine.disease, Obesity, body mass, Endocrinology, Genetic Loci, Body mass index, Chromosomes, Human, Pair 16, Genome-Wide Association Study, Transcription Factors
Abstract: Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 × 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 × 10(-5)) and short adult stature (p = 7.5 × 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
Published: 2014

46. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome

Author: Manila Deiana, Francesca Chiappe, Annie Nivelon, Luigi Bisceglia, Giuseppe Pilia, Lienhardt-Roussie A, Ramaiah Nagaraja, Laura Crisponi, M Nicolino, Antonio Cao, Ristaldi Ms, Paolo Gasparini, Loi A, R. Marzella, Mariano Rocchi, Patrizia Amati, Leopoldo Zelante, David Schlessinger, Alain Verloes, Manuela Uda, S. Porcu, and Dominique Bonneau
Subjects: Adult, Forkhead Box Protein L2, Male, Female sex determination, Molecular Sequence Data, Blepharophimosis, Winged Helix, Biology, FOXL2 Gene, Mice, Forkhead Transcription Factors, Ptosis, Chromosome Segregation, Gene Duplication, Nose Diseases, Genetics, medicine, Animals, Blepharoptosis, Humans, Abnormalities, Multiple, Amino Acid Sequence, Child, Base Sequence, Sequence Homology, Amino Acid, Ovary, Eyelids, Syndrome, medicine.disease, Pedigree, DNA-Binding Proteins, Proton-Translocating ATPases, Forkhead box L2, Codon, Nonsense, Mutation, Eyelid Diseases, Female, Chromosomes, Human, Pair 3, medicine.symptom, Transcription Factor Gene, Transcription Factors
Abstract: In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.
Published: 2001

47. Analysis of Exon/Intron Structure and 400 kb of Genomic Sequence Surrounding the 5′-Promoter and 3′-Terminal Ends of the Human Glypican 3 (GPC3) Gene

Author: Laura Crisponi, Ellson Y. Chen, Giuseppe Pilia, Reid Huber, Ying Su, Hiroaki Shizuya, Antonio Cao, Chun-Nan Chen, and Richard Mazzarella
Subjects: DNA, Complementary, X Chromosome, Sequence analysis, Molecular Sequence Data, Locus (genetics), Biology, Exon, Glypicans, Gene mapping, Sequence Homology, Nucleic Acid, Genetics, Humans, Amino Acid Sequence, Promoter Regions, Genetic, Peptide sequence, Gene, Polymorphism, Single-Stranded Conformational, Base Sequence, Nucleic acid sequence, Intron, Chromosome Mapping, Exons, Molecular biology, Introns, Proteoglycans, Heparitin Sulfate, Heparan Sulfate Proteoglycans
Abstract: GPC3, the gene modified in the Simpson-Golabi-Behmel gigantism/overgrowth syndrome (SGBS), is shown to span more than 500 kb of genomic sequence, with the transcript beginning 197 bp 5' of the translational start site. The Xq26.1 region containing GPC3 as the only known gene has been extended to > 900 kb by sequence analysis of flanking BAC clones. Two GC isochores (40.6 and 42.6% GC) are observed at the 5' and 3' ends of the locus, with a large repertoire of repetitive sequences that includes an unusual cluster of four L1 elements > 92% identical over 2.8 kb. Eight exons, accounting for the full 2.4-kb GPC3 cDNA, have been sequenced along with neighboring intronic regions. PCR assays have been developed to amplify each exon and exon/intron junction sequence, to help discriminate instances of SGBS among individuals with overgrowth syndromes and to facilitate mutational analysis of lesions in the gene.
Published: 1997

48. Expanding the mutational spectrum of CRLF1 in Crisponi/CISS1 syndrome

Author: Giovanni Zanda, Gianluca Usala, Carmen Herrero Roche, Gülen Eda Utine, Osama El Assy, Enrica Paderi, Roberta Piras, Giuseppe Zampino, Esra Kılıç, Ilaria La Torraca, Leyla Tümer, Javier Guibert, Francesco Benedicenti, Çiğdem Seher Kasapkara, Lina Basel-Vanagaite, Mustafa Ali Akin, Francesca Chiappe, Elisabetta Chiodin, Selim Kurtoglu, Koray Boduroğlu, Michal Feingold-Zadok, Laura Crisponi, Insa Buers, Benjamin Kamien, Sezin Unal, Giangiorgio Crisponi, Andrea Angius, Andreas Zankl, Adnan Y. Manzur, Frank Rutsch, and Eray Esra Onal
Subjects: Male, Fever, Biology, Crisponi syndrome, Compound heterozygosity, Polymerase Chain Reaction, symbols.namesake, Death, Sudden, Databases, Genetic, Genetics, Humans, Hyperhidrosis, Receptors, Cytokine, Child, Gene, Genetics (clinical), Syndrome type, Clinical course, Facies, Genetic Variation, Child, Preschool, Mutation, Mendelian inheritance, symbols, Female, Trismus, Hand Deformities, Congenital, Ciliary Neurotrophic Factor Receptor alpha Subunit, Muscle Contraction
Abstract: Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis, and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia associated with death in most cases in the first years of life. To date, 24 distinct CRLF1 mutations have been found either in homozygosity or in compound heterozygosity in CS/CISS1 patients, with the highest prevalence in Sardinia, Turkey, and Spain. By reporting 11 novel CRLF1 mutations, here we expand the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants and present an overview of the different molecular and clinical features of all of them. To catalog all the 35 mutations, we created a CRLF1 mutations database, based on the Leiden Open (source) Variation Database (LOVD) system (). Overall, the available functional and clinical data support the fact that both syndromes actually represent manifestations of the same autosomal-recessive disorder caused by mutations in the CRLF1 gene. Therefore, we propose to rename the two overlapping entities with the broader term of Crisponi/CISS1 syndrome., Abstract Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis, and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia associated with death in most cases in the first years of life. To date, 24 distinct CRLF1 mutations have been found either in homozygosity or in compound heterozygosity in CS/CISS1 patients, with the highest prevalence in Sardinia, Turkey, and Spain. By reporting 11 novel CRLF1 mutations, here we expand the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants and present an overview of the different molecular and clinical features of all of them. To catalog all the 35 mutations, we created a CRLF1 mutations database, based on the Leiden Open (source) Variation Database (LOVD) system (https://grenada.lumc.nl/LOVD2/mendelian_genes/variants). Overall, the available functional and clinical data support the fact that both syndromes actually represent manifestations of the same autosomal-recessive disorder caused by mutations in the CRLF1 gene. Therefore, we propose to rename the two overlapping entities with the broader term of Crisponi/CISS1 syndrome. &nbsp
Published: 2013

49. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women

Author: Amelie Bonnefond, Nancy Heard-Costa, Eleftheria Zeggini, Anna Gloyn, LAURA CRISPONI, Eco De Geus, Michael Weedon, Torben Jørgensen, Jaakko Kaprio, Iva Miljkovic, Amanda Bennett, Yurii Aulchenko, Michael Stumvoll, Andrew Hattersley, Christian Dina, Sophie Visvikis-Siest, Udo Seedorf, Vilmundur Gudnason, Michael Marmot, Mika Kivimaki, Mary Feitosa, Danielle Posthuma, Claudia Langenberg, Stavroula Kanoni, Cyrus Cooper, Meena Kumari, Peter Kovacs, Debbie A Lawlor, Inga Prokopenko, Rafn Benediktsson, Stephen Kritchevsky, Philippe Froguel, Cornelia Van Duijn, Nita Forouhi, Anne B. Newman, Ko Willems van Dijk, John Carr, Reedik Mägi, Sutapa Mukherjee, Lyle John Palmer, Francois Pattou, L. Adrienne Cupples, Paul Franks, Paul Elliott, Albert Vernon Smith, MANUELA UDA, Kirsten Ohm Kyvik, Manuel Serrano Ríos, Richard Bergman, Gonneke Willemsen, Cecilia Lindgren, Igor Rudan, Human genetics, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Institute for Molecular Medicine Finland, Research Group Ripatti Samuli, Hjelt Institute (-2014), Department of Public Health, Biostatistics Helsinki, Complex Disease Genetics, Genetic Epidemiology, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, GIANT Consortium, MAGIC Consortium, GLGC Consortium, Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, AU., Wheeler, E., Glazer, NL., Bouatia-Naji, N., Gloyn, AL., Lindgren, CM., Mägi, R., Morris, AP., Randall, J., Johnson, T., Elliott, P., Rybin, D., Thorleifsson, G., Steinthorsdottir, V., Henneman, P., Grallert, H., Dehghan, A., Hottenga, JJ., Franklin, CS., Navarro, P., Song, K., Goel, A., Perry, JR., Egan, JM., Lajunen, T., Grarup, N., Sparsø, T., Doney, A., Voight, BF., Stringham, HM., Li, M., Kanoni, S., Shrader, P., Cavalcanti-Proença, C., Kumari, M., Qi, L., Timpson, NJ., Gieger, C., Zabena, C., Rocheleau, G., Ingelsson, E., An, P., O'Connell, J., Luan£££Jian'an£££ J., Elliott, A., McCarroll, SA., Payne, F., Roccasecca, RM., Pattou, F., Sethupathy, P., Ardlie, K., Ariyurek, Y., Balkau, B., Barter, P., Beilby, JP., Ben-Shlomo, Y., Benediktsson, R., Bennett, AJ., Bergmann, S., Bochud, M., Boerwinkle, E., Bonnefond, A., Bonnycastle, LL., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, SJ., Charpentier, G., Chen, YD., Chines, P., Clarke, R., Coin, LJ., Cooper, MN., Cornelis, M., Crawford, G., Crisponi, L., Day, IN., de Geus EJ., Delplanque, J., Dina, C., Erdos, MR., Fedson, AC., Fischer-Rosinsky, A., Forouhi, NG., Fox, CS., Frants, R., Franzosi, MG., Galan, P., Goodarzi, MO., Graessler, J., Groves, CJ., Grundy, S., Gwilliam, R., Gyllensten, U., Hadjadj, S., Hallmans, G., Hammond, N., Han, X., Hartikainen, AL., Hassanali, N., Hayward, C., Heath, SC., Hercberg, S., Herder, C., Hicks, AA., Hillman, DR., Hingorani, AD., Hofman, A., Hui, J., Hung, J., Isomaa, B., Johnson, PR., Jørgensen, T., Jula, A., Kaakinen, M., Kaprio, J., Kesaniemi, YA., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, KO., Lathrop, GM., Lawlor, DA., Le Bacquer, O., Lecoeur, C., Li, Y., Lyssenko, V., Mahley, R., Mangino, M., Manning, AK., Martínez-Larrad£££María Teresa£££ MT., McAteer, JB., McCulloch, LJ., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, BD., Morken, MA., Mukherjee, S., Naitza, S., Narisu, N., Neville, MJ., Oostra, BA., Orrù, M., Pakyz, R., Palmer, CN., Paolisso, G., Pattaro, C., Pearson, D., Peden, JF., Pedersen, NL., Perola, M., Pfeiffer, AF., Pichler, I., Polasek, O., Posthuma, D., Potter, SC., Pouta, A., Province, MA., Psaty, BM., Rathmann, W., Rayner, NW., Rice, K., Ripatti, S., Rivadeneira, F., Roden, M., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, AA., Scheet, P., Scott, LJ., Seedorf, U., Sharp, SJ., Shields, B., Sigurðsson, G., Sijbrands, EJ., Silveira, A., Simpson, L., Singleton, A., Smith, NL., Sovio, U., Swift, A., Syddall, H., Syvänen, AC., Tanaka, T., Thorand, B., Tichet, J., Tönjes, A., Tuomi, T., Uitterlinden, AG., van Dijk KW., van Hoek, M., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, PJ., Walley, A., Walters, GB., Ward, KL., Watkins, H., Weedon, MN., Wild, SH., Willemsen, G., Witteman, JC., Yarnell, JW., Zeggini, E., Zelenika, D., Zethelius, B., Zhai, G., Zhao, JH., Zillikens, MC., Borecki, IB., Loos, RJ., Meneton, P., Magnusson, PK., Nathan, DM., Williams, GH., Hattersley, AT., Silander, K., Salomaa, V., Smith, GD., Bornstein, SR., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, AR., Cooper, C., Dedoussis, GV., Serrano-Ríos, M., Morris, AD., Lind, L., Palmer, LJ., Hu, FB., Franks, PW., Ebrahim, S., Marmot, M., Kao, WH., Pankow, JS., Sampson, MJ., Kuusisto, J., Laakso, M., Hansen, T., Pedersen, O., Pramstaller, PP., Wichmann, HE., Illig, T., Rudan, I., Wright, AF., Stumvoll, M., Campbell, H., Wilson, JF., Hamsten, A., Bergman, RN., Buchanan, TA., Collins, FS., Mohlke, KL., Tuomilehto, J., Valle, TT., Altshuler, D., Rotter, JI., Siscovick, DS., Penninx, BW., Boomsma, ID., Deloukas, P., Spector, TD., Frayling, TM., Ferrucci, L., Kong, A., Thorsteinsdottir, U., Stefansson, K., van Duijn CM., Aulchenko, YS., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, MR., Waterworth, DM., Vollenweider, P., Peltonen, L., Mooser, V., Abecasis, RG., Wareham, NJ., Sladek, R., Froguel, P., Watanabe, RM., Meigs, JB., Groop, L., Boehnke, M., McCarthy, MI., Florez, JC., Barroso£££Inês£££ I., Feitosa, Mary [0000-0002-0933-2410], Heard-Costa, Nancy [0000-0001-9730-0306], Newman, Anne B [0000-0002-0106-1150], Miljkovic, Iva [0000-0002-3155-9777], Kritchevsky, Stephen B [0000-0003-3336-6781], Carr, J Jeffrey [0000-0002-4398-8237], Gudnason, Vilmunder [0000-0001-5696-0084], Cupples, L Adrienne [0000-0003-0273-7965], Apollo - University of Cambridge Repository, and Medical Research Council (MRC)
Subjects: Male, Netherlands Twin Register (NTR), Cancer Research, Adipose tissue, Genome-wide association study, QH426-470, FTO gene, Body Mass Index, 0302 clinical medicine, Genetics (clinical), TISSUE DISTRIBUTION, GENE-EXPRESSION, 2. Zero hunger, ATHEROSCLEROSIS MESA, 0303 health sciences, INSULIN-RESISTANCE, Sex Characteristics, MAGIC Consortium, Adult, Aged, Cytokines/genetics, European Continental Ancestry Group, Female, Genome-Wide Association Study, HapMap Project, Humans, Intra-Abdominal Fat, Lysophospholipase/genetics, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proteins/genetics, Subcutaneous Fat, Abdominal, 3142 Public health care science, environmental and occupational health, CARDIOVASCULAR-DISEASE, OBESITY, Cytokines, Medicine, Lysophospholipase, Research Article, medicine.medical_specialty, Waist, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, 030209 endocrinology & metabolism, HIP RATIO, Biology, White People, GLGC Consortium, 03 medical and health sciences, Insulin resistance, Internal medicine, GIANT Consortium, medicine, Genetics, CORONARY-HEART-DISEASE, ddc:610, Molecular Biology, PERICARDIAL FAT, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0604 Genetics, Proteins, nutritional and metabolic diseases, medicine.disease, Obesity, Endocrinology, RISK-FACTORS, Body mass index, Developmental Biology
Abstract: Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1×10E-09), previously identified in association with waist–hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9×10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6×10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits., Author Summary Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. We quantified subcutaneous and visceral fat in more than 10,000 women and men who also had genome-wide association data available. Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, near the THNSL2 gene. These findings were not observed in men. We also interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed for 7 of these loci, most notably for VAT/SAT ratio. We conclude that genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not uncovered in large-scale GWAS of anthropometric traits.
Published: 2012

50. Reproductive aging-associated common genetic variants and the risk of breast cancer

Author: Joanne M. Murabito, Lynda M. Rose, Nora Franceschini, Greta Lee Splansky, Jill Dreyfus, Ellen W. Demerath, Sanna Sanna, Lindsay Fernández-Rhodes, Julie E. Buring, David J. Hunter, Lisette Stolk, Susan E. Hankinson, Albert Hofman, Giuseppe Palmieri, Paul M. Ridker, Rikje Ruiter, Chunyan He, Kathryn L. Lunetta, Eleonora Porcu, Shih-Jen Hwang, Bruno H. Stricker, Laura Crisponi, Fernando Rivadeneira, André G. Uitterlinden, Daniel I. Chasman, Stephen J. Chanock, Erasmus School of Health Policy & Management, Epidemiology, and Internal Medicine
Subjects: Adult, medicine.medical_specialty, Adolescent, Population, Breast Neoplasms, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Risk Factors, medicine, Humans, Child, 10. No inequality, education, 030304 developmental biology, Menarche, Medicine(all), Gynecology, 0303 health sciences, education.field_of_study, business.industry, Case-control study, Odds ratio, Middle Aged, medicine.disease, 3. Good health, Menopause, Risk factors for breast cancer, Case-Control Studies, 030220 oncology & carcinogenesis, Female, business, Research Article, Demography
Abstract: Introduction A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown. Methods In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait. Results After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4th and 5th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile. Conclusions Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.
Published: 2012

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