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Escott-Price, Valentina ; Bellenguez, Céline ; Wang, Li-San ; Choi, Seung-Hoan ; Harold, Denise ; Jones, Lesley ; Holmans, Peter ; Gerrish, Amy ; Vedernikov, Alexey ; Richards, Alexander ; DeStefano, Anita L. ; Lambert, Jean-Charles ; Ibrahim-Verbaas, Carla A. ; Naj, Adam C. ; Sims, Rebecca ; Jun, Gyungah ; Bis, Joshua C. ; Beecham, Gary W. ; Grenier-Boley, Benjamin ; Russo, Giancarlo ; Thornton-Wells, Tricia A. ; Denning, Nicola ; Smith, Albert V. ; Chouraki, Vincent ; Thomas, Charlene ; Ikram, M. Arfan ; Zelenika, Diana ; Vardarajan, Badri N. ; Kamatani, Yoichiro ; Lin, Chiao-Feng ; Schmidt, Helena ; Kunkle, Brian ; Dunstan, Melanie L. ; Vronskaya, Maria ; Johnson, Andrew D. ; Ruiz, Agustin ; Bihoreau, Marie-Thérèse ; Reitz, Christiane ; Pasquier, Florence ; Hollingworth, Paul ; Hanon, Olivier ; Fitzpatrick, Annette L. ; Buxbaum, Joseph D. ; Campion, Dominique ; Crane, Paul K. ; Baldwin, Clinton ; Becker, Tim ; Gudnason, Vilmundur ; Cruchaga, Carlos ; Craig, David ; Amin, Najaf ; Berr, Claudine ; Lopez, Oscar L. ; Jager, Philip L. De ; Deramecourt, Vincent ; Johnston, Janet A. ; Evans, Denis ; Lovestone, Simon ; Letenneur, Luc ; Hernández, Isabel ; Rubinsztein, David C. ; Eiriksdottir, Gudny ; Sleegers, Kristel ; Goate, Alison M. ; Fiévet, Nathalie ; Huentelman, Matthew J. ; Gill, Michael ; Brown, Kristelle ; Kamboh, M. Ilyas ; Keller, Lina ; Barberger-Gateau, Pascale ; McGuinness, Bernadette ; Larson, Eric B. ; Myers, Amanda J. ; Dufouil, Carole ; Todd, Stephen ; Wallon, David ; Love, Seth ; Rogaeva, Ekaterina ; Gallacher, John ; St George-Hyslop, Peter ; Clarimon, Jordi ; Lleo, Alberto ; Bayer, Anthony ; Tsuang, Debby W. ; Yu, Lei ; Tsolaki, Magda ; Bossù, Paola ; Spalletta, Gianfranco ; Proitsi, Petra ; Collinge, John ; Sorbi, Sandro ; Sanchez Garcia, Florentino ; Fox, Nick C. ; Hardy, John ; Deniz Naranjo, Maria Candida ; Bosco, Paolo ; Clarke, Robert ; Brayne, Carol ; Galimberti, Daniela ; Scarpini, Elio ; Bonuccelli, Ubaldo ; Mancuso, Michelangelo ; Siciliano, Gabriele ; Moebus, Susanne ; Mecocci, Patrizia ; Del Zompo, Maria ; Maier, Wolfgang ; Hampel, Harald ; Pilotto, Alberto ; Frank-García, Ana ; Panza, Francesco ; Solfrizzi, Vincenzo ; Caffarra, Paolo ; Nacmias, Benedetta ; Perry, William ; Mayhaus, Manuel ; Lannfelt, Lars ; Hakonarson, Hakon ; Pichler, Sabrina ; Carrasquillo, Minerva M. ; Ingelsson, Martin ; Beekly, Duane ; Alvarez, Victoria ; Zou, Fanggeng ; Valladares, Otto ; Younkin, Steven G. ; Coto, Eliecer ; Hamilton-Nelson, Kara L. ; Gu, Wei ; Razquin, Cristina ; Pastor, Pau ; Mateo, Ignacio ; Owen, Michael J. ; Faber, Kelley M. ; Jonsson, Palmi V. ; Combarros, Onofre ; O'Donovan, Michael C. ; Cantwell, Laura B. ; Soininen, Hilkka ; Blacker, Deborah ; Mead, Simon ; Mosley, Thomas H. ; Bennett, David A. ; Harris, Tamara B. ; Fratiglioni, Laura ; Holmes, Clive ; Bruijn, Renee F. A. G. de ; Passmore, Peter ; Montine, Thomas J. ; Bettens, Karolien ; Rotter, Jerome I. ; Brice, Alexis ; Morgan, Kevin ; Foroud, Tatiana M. ; Kukull, Walter A. ; Hannequin, Didier ; Powell, John F. ; Nalls, Michael A. ; Ritchie, Karen ; Lunetta, Kathryn L. ; Kauwe, John S. K. ; Boerwinkle, Eric ; Riemenschneider, Matthias ; Boada, Mercè ; Hiltunen, Mikko ; Martin, Eden R. ; Schmidt, Reinhold ; Rujescu, Dan ; Dartigues, Jean-François ; Mayeux, Richard ; Tzourio, Christophe ; Hofman, Albert ; Nöthen, Markus Maria ; Graff, Caroline ; Psaty, Bruce M. ; Haines, Jonathan L. ; Lathrop, Mark ; Pericak-Vance, Margaret Ann ; Launer, Lenore J. ; Broeckhoven, Christine Van ; Farrer, Lindsay A. ; Duijn, Cornelia M. van ; Ramirez, Alfredo ; Seshadri, Sudha ; Schellenberg, Gerard D. ; Amouyel, Philippe ; Williams, Julie
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Anney, Richard ; Klei, Lambertus ; Pinto, Dalila ; Regan, Regina ; Conroy, Judith ; Magalhães, Tiago R. ; Correia, Catarina ; Abrahams, Brett S. ; Sykes, Nuala ; Pagnamenta, Alistair T. ; Almeida, Joana ; Bacchelli, Elena ; Bailey, Anthony J. ; Baird, Gillian ; Battaglia, Agatino ; Berney, Tom ; Bolshakova, Nadia ; Bölte, Sven ; Bolton, Patrick F. ; Bourgeron, Thomas ; Brennan, Sean ; Brian, Jessica ; Carson, Andrew R. ; Casallo, Guillermo ; Casey, Jillian ; Chu, Su H. ; Cochrane, Lynne ; Corsello, Christina ; Crawford, Emily L. ; Crossett, Andrew ; Dawson, Geraldine ; Jonge, Maretha de ; Delorme, Richard ; Drmic, Irene ; Duketis, Eftichia ; Duque, Frederico ; Estes, Annette ; Farrar, Penny ; Fernandez, Bridget A. ; Folstein, Susan E. ; Fombonne, Eric ; Freitag, Christine M. ; Gilbert, John ; Gillberg, Christopher ; Glessner, Joseph T. ; Goldberg, Jeremy ; Green, Jonathan ; Guter, Stephen J. ; Hakonarson, Hakon ; Heron, Elizabeth A. ; Hill, Matthew ; Holt, Richard ; Howe, Jennifer L. ; Hughes, Gillian ; Hus, Vanessa ; Igliozzi, Roberta ; Kim, Cecilia ; Klauck, Sabine M. ; Kolevzon, Alexander ; Korvatska, Olena ; Kustanovich, Vlad ; Lajonchere, Clara M. ; Lamb, Janine A. ; Laskawiec, Magdalena ; Leboyer, Marion ; Le Couteur, Ann ; Leventhal, Bennett L. ; Lionel, Anath C. ; Liu, Xiao-Qing ; Lord, Catherine ; Lotspeich, Linda ; Lund, Sabata C. ; Maestrini, Elena ; Mahoney, William ; Mantoulan, Carine ; Marshall, Christian R. ; McConachie, Helen ; McDougle, Christopher J. ; McGrath, Jane ; McMahon, William M. ; Melhem, Nadine M. ; Merikangas, Alison ; Migita, Ohsuke ; Minshew, Nancy J. ; Mirza, Ghazala K. ; Munson, Jeff ; Nelson, Stanley F. ; Noakes, Carolyn ; Noor, Abdul ; Nygren, Gudrun ; Oliveira, Guiomar ; Papanikolaou, Katerina ; Parr, Jeremy R. ; Parrini, Barbara ; Paton, Tara ; Pickles, Andrew ; Piven, Joseph ; Posey, David J. ; Poustka, Annemarie ; Poustka, Fritz ; Prasad, Aparna ; Ragoussis, Jiannis ; Renshaw, Katy ; Rickaby, Jessica ; Roberts, Wendy ; Roeder, Kathryn ; Roge, Bernadette ; Rutter, Michael L. ; Bierut, Laura Jean ; Rice, John P. ; Salt, Jeff ; Sansom, Katherine ; Sato, Daisuke ; Segurado, Ricardo ; Senman, Lili ; Shah, Naisha ; Sheffield, Val C. ; Soorya, Latha ; Sousa, Inês ; Stoppioni, Vera ; Strawbridge, Christina ; Tancredi, Raffaella ; Tansey, Katherine ; Thiruvahindrapduram, Bhooma ; Thompson, Ann P. ; Thomson, Susanne ; Tryfon, Ana ; Tsiantis, John ; Engeland, Herman van ; Vincent, John B. ; Volkmar, Fred ; Wallace, Simon ; Wang, Kai ; Wang, Zhouzhi ; Wassink, Thomas H. ; Wing, Kirsty ; Wittemeyer, Kerstin ; Wood, Shawn ; Yaspan, Brian L. ; Zurawiecki, Danielle ; Zwaigenbaum, Lonnie ; Betancur, Catalina ; Buxbaum, Joseph D. ; Cantor, Rita M. ; Cook, Edwin H. ; Coon, Hilary ; Cuccaro, Michael L. ; Gallagher, Louise ; Geschwind, Daniel H. ; Gill, Michael ; Haines, Jonathan L. ; Miller, Judith ; Monaco, Anthony P. ; Nurnberger, John I. ; Paterson, Andrew D. ; Pericak-Vance, Margaret Ann ; Schellenberg, Gerard D. ; Scherer, Stephen W. ; Sutcliffe, James S. ; Szatmari, Peter ; Vicente, Astrid M. ; Vieland, Veronica J. ; Wijsman, Ellen M. ; Devlin, Bernie ; Ennis, Sean ; Hallmayer, Joachim
Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Randall, Joshua C. ; Winkler, Thomas W. ; Kutalik, Zoltán ; I. Berndt, Sonja ; Jackson, Anne U. ; Monda, Keri L. ; Kilpeläinen, Tuomas O. ; Esko, Tõnu ; Mägi, Reedik ; Li, Shengxu ; Workalemahu, Tsegaselassie ; Feitosa, Mary F. ; Croteau-Chonka, Damien C. ; Day, Felix R. ; Fall, Tove ; Ferreira, Teresa ; Gustafsson, Stefan ; Locke, Adam E. ; Mathieson, Iain ; Scherag, André ; Vedantam, Sailaja ; Wood, Andrew R. ; Liang, Liming ; Steinthorsdottir, Valgerdur ; Thorleifsson, Gudmar ; Dermitzakis, Emmanouil T. ; Dimas, Antigone S. ; Karpe, Fredrik ; Min, Josine L. ; Nicholson, George ; Clegg, Deborah J. ; Person, Thomas ; Krohn, Jon P. ; Bauer, Sabrina ; Buechler, Christa ; Eisinger, Kristina ; Bonnefond, Amélie ; Froguel, Philippe ; Hottenga, Jouke-Jan ; Prokopenko, Inga ; Waite, Lindsay L. ; Harris, Tamara B. ; Smith, Albert Vernon ; Shuldiner, Alan R. ; McArdle, Wendy L. ; Caulfield, Mark J. ; Munroe, Patricia B. ; Grönberg, Henrik ; Chen, Yii-Der Ida ; Li, Guo ; Beckmann, Jacques S. ; Johnson, Toby ; Thorsteinsdottir, Unnur ; Teder-Laving, Maris ; Khaw, Kay-Tee ; Wareham, Nicholas J. ; Zhao, Jing Hua ; Amin, Najaf ; Oostra, Ben A. ; Kraja, Aldi T. ; Province, Michael A. ; Cupples, L. Adrienne ; Heard-Costa, Nancy L. ; Kaprio, Jaakko ; Ripatti, Samuli ; Surakka, Ida ; Collins, Francis S. ; Saramies, Jouko ; Tuomilehto, Jaakko ; Jula, Antti ; Salomaa, Veikko ; Erdmann, Jeanette ; Hengstenberg, Christian ; Loley, Christina ; Schunkert, Heribert ; Lamina, Claudia ; Wichmann, Heinz Erich ; Albrecht, Eva ; Gieger, Christian ; Hicks, Andrew A. ; Johansson, Åsa ; Pramstaller, Peter P. ; Kathiresan, Sekar ; Speliotes, Elizabeth K. ; Penninx, Brenda W. J. H. ; Hartikainen, Anna-Liisa ; Jarvelin, Marjo-Riitta ; Gyllensten, Ulf ; Boomsma, Dorret I. ; Campbell, Harry ; Wilson, James F. ; Chanock, Stephen J. ; Farrall, Martin ; Goel, Anuj ; Medina-Gomez, Carolina ; Rivadeneira, Fernando ; Estrada, Karol ; Uitterlinden, André G. ; Hofman, Albert ; Zillikens, M. Carola ; Heijer, Martin den ; Kiemeney, Lambertus Adrianus ; Maschio, Andrea ; Hall, Per ; Tyrer, Jonathan ; Teumer, Alexander ; Völzke, Henry ; Kovacs, Peter ; Tönjes, Anke ; Mangino, Massimo ; Spector, Tim D. ; Hayward, Caroline ; Rudan, Igor ; Hall, Alistair S. ; Samani, Nilesh J. ; Attwood, Antony Paul ; Sambrook, Jennifer G. ; Hung, Joseph ; Palmer, Lyle J. ; Lokki, Marja-Liisa ; Sinisalo, Juha ; Boucher, Gabrielle ; Huikuri, Heikki ; Lorentzon, Mattias ; Ohlsson, Claes ; Eklund, Niina ; Eriksson, Johan G. ; Barlassina, Cristina ; Rivolta, Carlo ; Nolte, Ilja M. ; Snieder, Harold ; Klauw, Melanie M. van der ; Vliet-Ostaptchouk, Jana V. van ; Gejman, Pablo V. ; Shi, Jianxin ; Jacobs, Kevin B. ; Wang, Zhaoming ; Bakker, Stephan J. L. ; Mateo Leach, Irene ; Navis, Gerjan ; Harst, Pim van der ; Martin, Nicholas Gordon ; Medland, Sarah E. ; Montgomery, Grant W. ; Yang, Jian ; Chasman, Daniel I. ; Ridker, Paul M. ; Rose, Lynda M. ; Lehtimäki, Terho ; Raitakari, Olli ; Absher, Devin ; Iribarren, Carlos ; Basart, Hanneke ; Hovingh, Kees G. ; Hyppönen, Elina ; Power, Chris ; Power, Chris ; Anderson, Denise ; Beilby, John P. ; Hui, Jennie ; Jolley, Jennifer ; Sager, Hendrik ; Bornstein, Stefan R. ; Schwarz, Peter E. H. ; Kristiansson, Kati ; Perola, Markus ; Lindström, Jaana ; Swift, Amy J. ; Uusitupa, Matti ; Atalay, Mustafa ; Lakka, Timo A. ; Rauramaa, Rainer ; Bolton, Jennifer L. ; Fowkes, Gerry ; Fraser, Ross M. ; Price, Jackie F. ; Fischer, Krista ; KrjutÅ¡kov, Kaarel ; Metspalu, Andres ; Mihailov, Evelin ; Langenberg, Claudia ; Luan, Jian'an ; Ong, Ken K. ; Chines, Peter S. ; Keinanen-Kiukaanniemi, Sirkka M. ; Saaristo, Timo E. ; Edkins, Sarah ; Franks, Paul W. ; Hallmans, Göran ; Shungin, Dmitry ; Morris, Andrew David ; Palmer, Colin N. A. ; Erbel, Raimund ; Moebus, Susanne ; Nöthen, Markus Maria ; Pechlivanis, Sonali ; Hveem, Kristian ; Narisu, Narisu ; Hamsten, Anders ; Humphries, Steve E. ; Strawbridge, Rona J. ; Tremoli, Elena ; Grallert, Harald ; Thorand, Barbara ; Illig, Thomas ; Koenig, Wolfgang ; Müller-Nurasyid, Martina ; Peters, Annette ; Böhm, Bernhard O. ; Kleber, Marcus E. ; März, Winfried ; Winkelmann, Bernhard R. ; Kuusisto, Johanna ; Laakso, Markku ; Arveiler, Dominique ; Cesana, Giancarlo ; Kuulasmaa, Kari ; Virtamo, Jarmo ; Yarnell, John W. G. ; Kuh, Diana ; Wong, Andrew ; Lind, Lars ; Faire, Ulf de ; Gigante, Bruna ; Magnusson, Patrik K. E. ; Pedersen, Nancy L. ; Dedoussis, George ; Dimitriou, Maria ; Kolovou, Genovefa ; Kanoni, Stavroula ; Stirrups, Kathleen ; Bonnycastle, Lori L. ; Njølstad, Inger ; Wilsgaard, Tom ; Ganna, Andrea ; Rehnberg, Emil ; Hingorani, Aroon ; Kivimaki, Mika ; Kumari, Meena ; Assimes, Themistocles L. ; Barroso, Inês ; Boehnke, Michael ; Borecki, Ingrid B. ; Deloukas, Panos ; Fox, Caroline S. ; Frayling, Timothy ; Groop, Leif C. ; Haritunians, Talin ; Hunter, David ; Ingelsson, Erik ; Kaplan, Robert ; Mohlke, Karen L. ; North, Kari E. ; Lindgren, Cecilia M. ; Qi, Lu ; Loos, Ruth J. F. ; Heid, Iris M. ; Hirschhorn, Joel N. ; McCarthy, Mark I. ; Abecasis, Gonçalo R. ; Stefansson, Kari ; Strachan, David P. ; Schlessinger, David ; O'Connell, Jeffrey R. ; Duijn, Cornelia M. van
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Casey, Jillian P. ; Magalhães, Tiago R. ; Conroy, Judith M. ; Regan, Regina ; Shah, Naisha ; Anney, Richard ; Shields, Denis C. ; Abrahams, Brett S. ; Almeida, Joana ; Bacchelli, Elena ; Bailey, Anthony J. ; Baird, Gillian ; Battaglia, Agatino ; Berney, Tom ; Bolshakova, Nadia ; Bolton, Patrick F. ; Bourgeron, Thomas ; Brennan, Sean ; Cali, Phil ; Correia, Catarina ; Corsello, Christina ; Coutanche, Marc ; Dawson, Geraldine ; Jonge, Maretha de ; Delorme, Richard ; Duketis, Eftichia ; Duque, Frederico ; Estes, Annette ; Farrar, Penny ; Fernandez, Bridget A. ; Folstein, Susan E. ; Foley, Suzanne ; Fombonne, Eric ; Freitag, Christine M. ; Gilbert, John ; Gillberg, Christopher ; Glessner, Joseph T. ; Green, Jonathan ; Guter, Stephen J. ; Hakonarson, Hakon ; Holt, Richard ; Hughes, Gillian ; Hus, Vanessa ; Igliozzi, Roberta ; Kim, Cecilia ; Klauck, Sabine M. ; Kolevzon, Alexander ; Lamb, Janine A. ; Leboyer, Marion ; Le Couteur, Ann ; Leventhal, Bennett L. ; Lord, Catherine ; Lund, Sabata C. ; Maestrini, Elena ; Mantoulan, Carine ; Marshall, Christian R. ; McConachie, Helen ; McDougle, Christopher J. ; McGrath, Jane ; McMahon, William M. ; Merikangas, Alison ; Miller, Judith ; Minopoli, Fiorella ; Mirza, Ghazala K. ; Munson, Jeff ; Nelson, Stanley F. ; Nygren, Gudrun ; Oliveira, Guiomar ; Pagnamenta, Alistair T. ; Papanikolaou, Katerina ; Parr, Jeremy R. ; Parrini, Barbara ; Pickles, Andrew ; Pinto, Dalila ; Piven, Joseph ; Posey, David J. ; Poustka, Annemarie ; Poustka, Fritz ; Ragoussis, Jiannis ; Roge, Bernadette ; Rutter, Michael L. ; Sequeira, Ana F. ; Soorya, Latha ; Sousa, Inês ; Sykes, Nuala ; Stoppioni, Vera ; Tancredi, Raffaella ; Tauber, Maïté ; Thompson, Ann P. ; Thomson, Susanne ; Tsiantis, John ; Engeland, Herman van ; Vincent, John B. ; Volkmar, Fred ; Vorstman, Jacob A. S. ; Wallace, Simon ; Wang, Kai ; Wassink, Thomas H. ; White, Kathy ; Wing, Kirsty ; Wittemeyer, Kerstin ; Yaspan, Brian L. ; Zwaigenbaum, Lonnie ; Betancur, Catalina ; Buxbaum, Joseph D. ; Cantor, Rita M. ; Cook, Edwin H. ; Coon, Hilary ; Cuccaro, Michael L. ; Geschwind, Daniel H. ; Haines, Jonathan L. ; Hallmayer, Joachim ; Monaco, Anthony P. ; Nurnberger, John I. ; Pericak-Vance, Margaret Ann ; Schellenberg, Gerard D. ; Scherer, Stephen W. ; Sutcliffe, James S. ; Szatmari, Peter ; Vieland, Veronica J. ; Wijsman, Ellen M. ; Green, Andrew ; Gill, Michael ; Gallagher, Louise ; Vicente, Astrid M. ; Ennis, Sean
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
Anney, Richard ; Klei, Lambertus ; Pinto, Dalila ; Almeida, Joana ; Bacchelli, Elena ; Baird, Gillian ; Bolshakova, Nadia ; Bölte, Sven ; Bolton, Patrick F. ; Bourgeron, Thomas ; Brennan, Sean ; Brian, Jessica ; Casey, Jillian ; Conroy, Judith ; Correia, Catarina ; Corsello, Christina ; Crawford, Emily L. ; Jonge, Maretha de ; Delorme, Richard ; Duketis, Eftichia ; Duque, Frederico ; Estes, Annette ; Farrar, Penny ; Fernandez, Bridget A. ; Folstein, Susan E. ; Fombonne, Eric ; Gilbert, John ; Gillberg, Christopher ; Glessner, Joseph T. ; Green, Andrew ; Green, Jonathan ; Guter, Stephen J. ; Heron, Elizabeth A. ; Holt, Richard ; Howe, Jennifer L. ; Hughes, Gillian ; Hus, Vanessa ; Igliozzi, Roberta ; Jacob, Suma ; Kenny, Graham P. ; Kim, Cecilia ; Kolevzon, Alexander ; Kustanovich, Vlad ; Lajonchere, Clara M. ; Lamb, Janine A. ; Law-Smith, Miriam ; Leboyer, Marion ; Le Couteur, Ann ; Leventhal, Bennett L. ; Liu, Xiao-Qing ; Lombard, Frances ; Lord, Catherine ; Lotspeich, Linda ; Lotspeich, Linda ; Lund, Sabata C. ; Magalhães, Tiago R. ; Mantoulan, Carine ; McDougle, Christopher J. ; Melhem, Nadine M. ; Merikangas, Alison ; Minshew, Nancy J. ; Mirza, Ghazala K. ; Munson, Jeff ; Noakes, Carolyn ; Nygren, Gudrun ; Papanikolaou, Katerina ; Pagnamenta, Alistair T. ; Parrini, Barbara ; Paton, Tara ; Paton, Tara ; Pickles, Andrew ; Posey, David J. ; Poustka, Fritz ; Ragoussis, Jiannis ; Regan, Regina ; Roberts, Wendy ; Roeder, Kathryn ; Roge, Bernadette ; Rutter, Michael L. ; Schlitt, Sabine ; Shah, Naisha ; Sheffield, Val C. ; Soorya, Latha ; Sousa, Inês ; Stoppioni, Vera ; Sykes, Nuala ; Tancredi, Raffaella ; Thompson, Ann P. ; Thomson, Susanne ; Tryfon, Ana ; Tsiantis, John ; Engeland, Herman van ; Vincent, John B. ; Volkmar, Fred ; Vorstman, JAS ; Wallace, Simon ; Wing, Kirsty ; Wittemeyer, Kerstin ; Wood, Shawn ; Zurawiecki, Danielle ; Zwaigenbaum, Lonnie ; Bailey, Anthony J. ; Battaglia, Agatino ; Cantor, Rita M. ; Coon, Hilary ; Cuccaro, Michael L. ; Dawson, Geraldine ; Ennis, Sean ; Freitag, Christine M. ; Geschwind, Daniel H. ; Haines, Jonathan L. ; Klauck, Sabine M. ; McMahon, William M. ; Maestrini, Elena ; Miller, Judith ; Monaco, Anthony P. ; Nelson, Stanley F. ; Nurnberger, John I. ; Oliveira, Guiomar ; Parr, Jeremy R. ; Pericak-Vance, Margaret Ann ; Piven, Joseph ; Schellenberg, Gerard D. ; Scherer, Stephen W. ; Vicente, Astrid M. ; Wassink, Thomas H. ; Wijsman, Ellen M. ; Betancur, Catalina ; Buxbaum, Joseph D. ; Cook, Edwin H. ; Gallagher, Louise ; Gill, Michael ; Hallmayer, Joachim ; Paterson, Andrew D. ; Sutcliffe, James S. ; Szatmari, Peter ; Vieland, Veronica J. ; Hakonarson, Hakon ; Devlin, Bernie
While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
El-Helou, Sabine M. ; Biegner, Anika-Kerstin ; Bode, Sebastian ; Ehl, Stephan ; Heeg, Maximilian ; Maccari, Maria E. ; Ritterbusch, Henrike ; Speckmann, Carsten ; Rusch, Stephan ; Scheible, Raphael ; Warnatz, Klaus ; Atschekzei, Faranaz ; Beider, Renata ; Ernst, Diana ; Gerschmann, Stev ; Jablonka, Alexandra ; Mielke, Gudrun ; Schmidt, Reinhold E. ; Schürmann, Gesine ; Sogkas, Georgios ; Baumann, Ulrich ; Klemann, Christian ; Viemann, Dorothee ; Bernuth, Horst von ; Krüger, Renate ; Hanitsch, Leif Gunnar ; Scheibenbogen, Carmen ; Wittke, Kirsten ; Albert, Michael H. ; Eichinger, Anna ; Hauck, Fabian ; Klein, Christoph ; Rack-Hoch, Anita ; Sollinger, Franz ; Avila, Anne ; Borte, Michael ; Borte, Stephan ; Fasshauer, Maria ; Hauenherm, Anja ; Kellner, Nils ; Müller, Anna H. ; Ülzen, Anett ; Bader, Peter ; Bakhtiar, Shahrzad ; Lee, Jae-Yun ; Heß, Ursula ; Schubert, Ralf ; Wölke, Sandra ; Zielen, Stefan ; Ghosh, Sujal ; Laws, Hans-Jürgen ; Neubert, Jennifer ; Oommen, Prasad Thomas ; Hönig, Manfred ; Schulz, Ansgar ; Steinmann, Sandra ; Schwarz, Klaus ; Dückers, Gregor ; Lamers, Beate ; Langemeyer, Vanessa ; Niehues, Tim ; Shai, Sonu ; Graf, Dagmar ; Müglich, Carmen ; Schmalzing, Marc ; Schwaneck, Eva C. ; Tony, Hans-Peter ; Dirks, Johannes ; Haase, Gabriele ; Liese, Johannes G. ; Morbach, Henner ; Föll, Dirk ; Hellige, Antje ; Wittkowski, Helmut ; Masjosthusmann, Katja ; Mohr, Michael ; Geberzahn, Linda ; Hedrich, Christian Michael ; Müller, Christiane ; Rösen-Wolff, Angela ; Roesler, Joachim ; Zimmermann, Antje ; Behrends, Uta ; Rieber, Nikolaus ; Schauer, Uwe ; Handgretinger, Rupert ; Holzer, Ursula ; Henes, Jörg Christoph ; Kanz, Lothar ; Boesecke, Christoph ; Rockstroh, Jürgen ; Schwarze-Zander, Carolynne ; Wasmuth, Jan-Christian ; Dilloo, Dagmar ; Hülsmann, Brigitte ; Schönberger, Stefan ; Schreiber, Stefan ; Zeuner, Rainald ; Ankermann, Tobias ; Bismarck, Philipp von ; Huppertz, Hans-Iko ; Kaiser-Labusch, Petra ; Greil, Johann ; Jakoby, Donate ; Kulozik, Andreas ; Metzler, Markus ; Naumann-Bartsch, Nora ; Sobik, Bettina ; Graf, Norbert ; Heine, Sabine ; Kobbe, Robin ; Lehmberg, Kai ; Müller, Ingo ; Herrmann, Friedrich ; Horneff, Gerd ; Klein, Ariane ; Peitz, Joachim ; Schmidt, Nadine ; Bielack, Stefan S. ; Groß-Wieltsch, Ute ; Classen, Carl Friedrich ; Klasen, Jessica ; Deutz, Peter ; Kamitz, Dirk ; Lassay, Lisa ; Tenbrock, Klaus ; Wagner, Norbert ; Bernbeck, Benedikt ; Brummel, Bastian ; Lara-Villacanas, Eusebia ; Münstermann, Esther ; Schneider, Dominik T. ; Tietsch, Nadine ; Westkemper, Marco ; Weiß, Michael ; Kramm, Christof M. ; Kühnle, Ingrid ; Kullman, Silke ; Girschick, Hermann ; Specker, Christof ; Vinnemeier-Laubenthal, Elisabeth ; Haenicke, Henriette ; Schulz, Claudia ; Schweigerer, Lothar ; Müller, Thomas G. ; Stiefel, Martina ; Belohradsky, Bernd H. ; Soetedjo, Veronika ; Kindle, Gerhard ; Grimbacher, Bodo
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
Pati, Sarthak ; Baid, Ujjwal ; Edwards, Brandon ; Sheller, Micah ; Wang, Shih-Han ; Reina, G. Anthony ; Foley, Patrick ; Gruzdev, Alexey ; Karkada, Deepthi ; Davatzikos, Christos ; Sako, Chiharu ; Ghodasara, Satyam ; Bilello, Michel ; Mohan, Suyash ; Vollmuth, Philipp ; Brugnara, Gianluca ; Jayachandran Preetha, Chandrakanth ; Sahm, Felix ; Maier-Hein, Klaus ; Zenk, Maximilian ; Bendszus, Martin ; Wick, Wolfgang ; Calabrese, Evan ; Rudie, Jeffrey ; Villanueva-Meyer, Javier ; Cha, Soonmee ; Ingalhalikar, Madhura ; Jadhav, Manali ; Pandey, Umang ; Saini, Jitender ; Garrett, John ; Larson, Matthew ; Jeraj, Robert ; Currie, Stuart ; Frood, Russell ; Fatania, Kavi ; Huang, Raymond Y. ; Chang, Ken ; Balaña, Carmen ; Capellades, Jaume ; Puig, Josep ; Trenkler, Johannes ; Pichler, Josef ; Necker, Georg ; Haunschmidt, Andreas ; Meckel, Stephan ; Shukla, Gaurav ; Liem, Spencer ; Alexander, Gregory S. ; Lombardo, Joseph ; Palmer, Joshua D. ; Flanders, Adam E. ; Dicker, Adam P. ; Sair, Haris I. ; Jones, Craig K. ; Venkataraman, Archana ; Jiang, Meirui ; So, Tiffany Y. ; Chen, Cheng ; Heng, Pheng Ann ; Dou, Qi ; Kozubek, Michal ; Lux, Filip ; Michálek, Jan ; Matula, Petr ; Keřkovský, Miloš ; Kopřivová, Tereza ; Dostál, Marek ; Vybíhal, Václav ; Vogelbaum, Michael A. ; Mitchell, J. Ross ; Farinhas, Joaquim ; Maldjian, Joseph A. ; Bangalore Yogananda, Chandan Ganesh ; Pinho, Marco C. ; Reddy, Divya ; Holcomb, James ; Wagner, Benjamin C. ; Ellingson, Benjamin M. ; Cloughesy, Timothy F. ; Raymond, Catalina ; Oughourlian, Talia ; Hagiwara, Akifumi ; Wang, Chencai ; To, Minh-Son ; Bhardwaj, Sargam ; Chong, Chee ; Agzarian, Marc ; Falcão, Alexandre Xavier ; Martins, Samuel B. ; Teixeira, Bernardo Corrêa de Almeida ; Sprenger, Flávia ; Menotti, David ; Lucio, Diego R. ; LaMontagne, Pamela ; Marcus, Daniel ; Wiestler, Benedikt ; Kofler, Florian ; Ezhov, Ivan ; Metz, Marie ; Jain, Rajan ; Lee, Matthew ; Lui, Yvonne W. ; McKinley, Richard ; Slotboom, Johannes ; Radojewski, Piotr ; Meier, Raphael ; Wiest, Roland Gerhard Rudi ; Murcia, Derrick ; Fu, Eric ; Haas, Rourke ; Thompson, John ; Ormond, David Ryan ; Badve, Chaitra ; Sloan, Andrew E. ; Vadmal, Vachan ; Waite, Kristin ; Colen, Rivka R. ; Pei, Linmin ; Ak, Murat ; Srinivasan, Ashok ; Bapuraj, Jayapalli Rajiv ; Rao, Arvind ; Wang, Nicholas ; Yoshiaki, Ota ; Moritani, Toshio ; Turk, Sevcan ; Lee, Joonsang ; Prabhudesai, Snehal ; Morón, Fanny ; Mandel, Jacob ; Kamnitsas, Konstantinos ; Glocker, Ben ; Dixon, Luke V. M. ; Williams, Matthew ; Zampakis, Peter ; Panagiotopoulos, Vasileios ; Tsiganos, Panagiotis ; Alexiou, Sotiris ; Haliassos, Ilias ; Zacharaki, Evangelia I. ; Moustakas, Konstantinos ; Kalogeropoulou, Christina ; Kardamakis, Dimitrios M. ; Choi, Yoon Seong ; Lee, Seung-Koo ; Chang, Jong Hee ; Ahn, Sung Soo ; Luo, Bing ; Poisson, Laila ; Wen, Ning ; Tiwari, Pallavi ; Verma, Ruchika ; Bareja, Rohan ; Yadav, Ipsa ; Chen, Jonathan ; Kumar, Neeraj ; Smits, Marion ; Voort, Sebastian R. van der ; Alafandi, Ahmed ; Incekara, Fatih ; Wijnenga, Maarten M. J. ; Kapsas, Georgios ; Gahrmann, Renske ; Schouten, Joost W. ; Dubbink, Hendrikus J. ; Vincent, Arnaud J. P. E. ; Van den Bent, Martin J. ; French, Pim J. ; Klein, Stefan ; Yuan, Yading ; Sharma, Sonam ; Tseng, Tzu-Chi ; Adabi, Saba ; Niclou, Simone P. ; Keunen, Olivier ; Hau, Ann-Christin ; Vallières, Martin ; Fortin, David ; Lepage, Martin ; Landman, Bennett ; Ramadass, Karthik ; Xu, Kaiwen ; Chotai, Silky ; Chambless, Lola B. ; Mistry, Akshitkumar ; Thompson, Reid C. ; Gusev, Yuriy ; Bhuvaneshwar, Krithika ; Sayah, Anousheh ; Bencheqroun, Camelia ; Belouali, Anas ; Madhavan, Subha ; Booth, Thomas C. ; Chelliah, Alysha ; Modat, Marc ; Shuaib, Haris ; Dragos, Carmen ; Abayazeed, Aly ; Kolodziej, Kenneth ; Hill, Michael ; Abbassy, Ahmed ; Gamal, Shady ; Mekhaimar, Mahmoud ; Qayati, Mohamed ; Reyes, Mauricio ; Park, Ji Eun ; Yun, Jihye ; Kim, Ho Sung ; Mahajan, Abhishek ; Muzi, Mark ; Benson, Sean ; Beets-Tan, Regina G. H. ; Teuwen, Jonas ; Herrera-Trujillo, Alejandro ; Trujillo, Maria ; Escobar, William ; Abello, Ana Lorena ; Bernal, Jose ; Gómez, Jhon ; Choi, Joseph ; Baek, Stephen ; Kim, Yusung ; Ismael, Heba ; Allen, Bryan ; Buatti, John M. ; Kotrotsou, Aikaterini ; Li, Hongwei ; Weiss, Tobias ; Weller, Michael ; Bink, Andrea ; Pouymayou, Bertrand ; Shaykh, Hassan F. ; Saltz, Joel ; Prasanna, Prateek ; Shrestha, Sampurna ; Mani, Kartik M. ; Payne, David ; Kurc, Tahsin ; Pelaez, Enrique ; Franco-Maldonado, Heydy ; Loayza, Francis ; Quevedo Sacoto, Andrés Sebastián ; Guevara, Pamela ; Torche, Esteban ; Mendoza, Cristobal ; Vera, Franco ; Ríos, Elvis ; López, Eduardo ; Velastin, Sergio Alejandro ; Ogbole, Godwin ; Soneye, Mayowa ; Oyekunle, Dotun ; Odafe-Oyibotha, Olubunmi ; Osobu, Babatunde ; Shu’aibu, Mustapha ; Dorcas, Adeleye ; Dako, Farouk ; Simpson, Amber L. ; Hamghalam, Mohammad ; Peoples, Jacob J. ; Hu, Ricky ; Tran, Anh ; Cutler, Danielle ; Moraes, Fabio Y. ; Boss, Michael A. ; Gimpel, James ; Kattil Veettil, Deepak ; Schmidt, Kendall ; Bialecki, Brian ; Marella, Sailaja ; Price, Cynthia ; Cimino, Lisa ; Apgar, Charles ; Shah, Prashant ; Menze, Bjoern Holger ; Barnholtz-Sloan, Jill S. ; Martin, Jason ; Bakas, Spyridon
Pati, Sarthak ; Baid, Ujjwal ; Edwards, Brandon ; Sheller, Micah ; Wang, Shih-Han ; Reina, G. Anthony ; Foley, Patrick ; Gruzdev, Alexey ; Karkada, Deepthi ; Davatzikos, Christos ; Sako, Chiharu ; Ghodasara, Satyam ; Bilello, Michel ; Mohan, Suyash ; Vollmuth, Philipp ; Brugnara, Gianluca ; Jayachandran Preetha, Chandrakanth ; Sahm, Felix ; Maier-Hein, Klaus ; Zenk, Maximilian ; Bendszus, Martin ; Wick, Wolfgang ; Calabrese, Evan ; Rudie, Jeffrey ; Villanueva-Meyer, Javier ; Cha, Soonmee ; Ingalhalikar, Madhura ; Jadhav, Manali ; Pandey, Umang ; Saini, Jitender ; Garrett, John ; Larson, Matthew ; Jeraj, Robert ; Currie, Stuart ; Frood, Russell ; Fatania, Kavi ; Huang, Raymond Y. ; Chang, Ken ; Balaña, Carmen ; Capellades, Jaume ; Puig, Josep ; Trenkler, Johannes ; Pichler, Josef ; Necker, Georg ; Haunschmidt, Andreas ; Meckel, Stephan ; Shukla, Gaurav ; Liem, Spencer ; Alexander, Gregory S. ; Lombardo, Joseph ; Palmer, Joshua D. ; Flanders, Adam E. ; Dicker, Adam P. ; Sair, Haris I. ; Jones, Craig K. ; Venkataraman, Archana ; Jiang, Meirui ; So, Tiffany Y. ; Chen, Cheng ; Heng, Pheng Ann ; Dou, Qi ; Kozubek, Michal ; Lux, Filip ; Michálek, Jan ; Matula, Petr ; Keřkovský, Miloš ; Kopřivová, Tereza ; Dostál, Marek ; Vybíhal, Václav ; Vogelbaum, Michael A. ; Mitchell, J. Ross ; Farinhas, Joaquim ; Maldjian, Joseph A. ; Bangalore Yogananda, Chandan Ganesh ; Pinho, Marco C. ; Reddy, Divya ; Holcomb, James ; Wagner, Benjamin C. ; Ellingson, Benjamin M. ; Cloughesy, Timothy F. ; Raymond, Catalina ; Oughourlian, Talia ; Hagiwara, Akifumi ; Wang, Chencai ; To, Minh-Son ; Bhardwaj, Sargam ; Chong, Chee ; Agzarian, Marc ; Falcão, Alexandre Xavier ; Martins, Samuel B. ; Teixeira, Bernardo Corrêa de Almeida ; Sprenger, Flávia ; Menotti, David ; Lucio, Diego R. ; LaMontagne, Pamela ; Marcus, Daniel ; Wiestler, Benedikt ; Kofler, Florian ; Ezhov, Ivan ; Metz, Marie ; Jain, Rajan ; Lee, Matthew ; Lui, Yvonne W. ; McKinley, Richard ; Slotboom, Johannes ; Radojewski, Piotr ; Meier, Raphael ; Wiest, Roland Gerhard Rudi ; Murcia, Derrick ; Fu, Eric ; Haas, Rourke ; Thompson, John ; Ormond, David Ryan ; Badve, Chaitra ; Sloan, Andrew E. ; Vadmal, Vachan ; Waite, Kristin ; Colen, Rivka R. ; Pei, Linmin ; Ak, Murat ; Srinivasan, Ashok ; Bapuraj, Jayapalli Rajiv ; Rao, Arvind ; Wang, Nicholas ; Yoshiaki, Ota ; Moritani, Toshio ; Turk, Sevcan ; Lee, Joonsang ; Prabhudesai, Snehal ; Morón, Fanny ; Mandel, Jacob ; Kamnitsas, Konstantinos ; Glocker, Ben ; Dixon, Luke V. M. ; Williams, Matthew ; Zampakis, Peter ; Panagiotopoulos, Vasileios ; Tsiganos, Panagiotis ; Alexiou, Sotiris ; Haliassos, Ilias ; Zacharaki, Evangelia I. ; Moustakas, Konstantinos ; Kalogeropoulou, Christina ; Kardamakis, Dimitrios M. ; Choi, Yoon Seong ; Lee, Seung-Koo ; Chang, Jong Hee ; Ahn, Sung Soo ; Luo, Bing ; Poisson, Laila ; Wen, Ning ; Tiwari, Pallavi ; Verma, Ruchika ; Bareja, Rohan ; Yadav, Ipsa ; Chen, Jonathan ; Kumar, Neeraj ; Smits, Marion ; Voort, Sebastian R. van der ; Alafandi, Ahmed ; Incekara, Fatih ; Wijnenga, Maarten M. J. ; Kapsas, Georgios ; Gahrmann, Renske ; Schouten, Joost W. ; Dubbink, Hendrikus J. ; Vincent, Arnaud J. P. E. ; Van den Bent, Martin J. ; French, Pim J. ; Klein, Stefan ; Yuan, Yading ; Sharma, Sonam ; Tseng, Tzu-Chi ; Adabi, Saba ; Niclou, Simone P. ; Keunen, Olivier ; Hau, Ann-Christin ; Vallières, Martin ; Fortin, David ; Lepage, Martin ; Landman, Bennett ; Ramadass, Karthik ; Xu, Kaiwen ; Chotai, Silky ; Chambless, Lola B. ; Mistry, Akshitkumar ; Thompson, Reid C. ; Gusev, Yuriy ; Bhuvaneshwar, Krithika ; Sayah, Anousheh ; Bencheqroun, Camelia ; Belouali, Anas ; Madhavan, Subha ; Booth, Thomas C. ; Chelliah, Alysha ; Modat, Marc ; Shuaib, Haris ; Dragos, Carmen ; Abayazeed, Aly ; Kolodziej, Kenneth ; Hill, Michael ; Abbassy, Ahmed ; Gamal, Shady ; Mekhaimar, Mahmoud ; Qayati, Mohamed ; Reyes, Mauricio ; Park, Ji Eun ; Yun, Jihye ; Kim, Ho Sung ; Mahajan, Abhishek ; Muzi, Mark ; Benson, Sean ; Beets-Tan, Regina G. H. ; Teuwen, Jonas ; Herrera-Trujillo, Alejandro ; Trujillo, Maria ; Escobar, William ; Abello, Ana Lorena ; Bernal, Jose ; Gómez, Jhon ; Choi, Joseph ; Baek, Stephen ; Kim, Yusung ; Ismael, Heba ; Allen, Bryan ; Buatti, John M. ; Kotrotsou, Aikaterini ; Li, Hongwei ; Weiss, Tobias ; Weller, Michael ; Bink, Andrea ; Pouymayou, Bertrand ; Shaykh, Hassan F. ; Saltz, Joel ; Prasanna, Prateek ; Shrestha, Sampurna ; Mani, Kartik M. ; Payne, David ; Kurc, Tahsin ; Pelaez, Enrique ; Franco-Maldonado, Heydy ; Loayza, Francis ; Quevedo Sacoto, Andrés Sebastián ; Guevara, Pamela ; Torche, Esteban ; Mendoza, Cristobal ; Vera, Franco ; Ríos, Elvis ; López, Eduardo ; Velastin, Sergio Alejandro ; Ogbole, Godwin ; Soneye, Mayowa ; Oyekunle, Dotun ; Odafe-Oyibotha, Olubunmi ; Osobu, Babatunde ; Shu’aibu, Mustapha ; Dorcas, Adeleye ; Dako, Farouk ; Simpson, Amber L. ; Hamghalam, Mohammad ; Peoples, Jacob J. ; Hu, Ricky ; Tran, Anh ; Cutler, Danielle ; Moraes, Fabio Y. ; Boss, Michael A. ; Gimpel, James ; Kattil Veettil, Deepak ; Schmidt, Kendall ; Bialecki, Brian ; Marella, Sailaja ; Price, Cynthia ; Cimino, Lisa ; Apgar, Charles ; Shah, Prashant ; Menze, Bjoern Holger ; Barnholtz-Sloan, Jill S. ; Martin, Jason ; Bakas, Spyridon
Bauer, Michael ; Glenn, Tasha ; Achtyes, Eric D. ; Agaoglu, Esen ; Altınbaş, Kürşat ; Andreassen, Ole A. ; Angelopoulos, Elias ; Ardau, Raffaella ; Arrua Vares, Edgar ; Aydin, Memduha ; Ayhan, Yavuz ; Baethge, Christopher Jan ; Bauer, Rita ; Baune, Bernhard T. ; Balaban, Ceylan ; Becerra-Palars, Claudia ; Behere, Aniruddh P. ; Behere, Prakash B. ; Belete, Habte ; Belete, Tilahun ; Belizario, Gabriel Okawa ; Bellivier, Frank ; Belmaker, Robert H. ; Benedetti, Francesco ; Berk, Michael ; Bersudsky, Yuly ; Bicakci, Şule ; Birabwa-Oketcho, Harriet ; Bjella, Thomas D. ; Brady, Conan ; Cabrera, Jorge ; Cappucciati, Marco ; Castro, Angela Marianne Paredes ; Chen, Wei-Ling ; Cheung, Eric Y. Wo ; Chiesa, Silvia ; Crowe, Marie ; Cuomo, Alessandro ; Dallaspezia, Sara ; Del Zompo, Maria ; Desai, Pratikkumar ; Dodd, Seetal ; Donix, Markus ; Etain, Bruno ; Fagiolini, Andrea ; Fellendorf, Frederike Tabea ; Ferensztajn-Rochowiak, Ewa ; Fiedorowicz, Jess G. ; Fountoulakis, Kostas N. ; Frye, Mark A. ; Geoffroy, Pierre A. ; Gonzalez-Pinto, Ana ; Gottlieb, John F. ; Grof, Paul ; Haarman, Bartholomeus C. M. ; Harima, Hirohiko ; Hasse-Sousa, Mathias ; Henry, Chantal ; Høffding, Lone ; Houenou, Josselin ; Imbesi, Massimiliano ; Isometsä, Erkki T. ; Ivkovic, Maja ; Janno, Sven ; Johnsen, Simon ; Kapczinski, Flávio ; Karakatsoulis, Gregory N. ; Kardell, Mathias ; Kessing, Lars Vedel ; Kim, Seong Jae ; König, Barbara ; Kot, Timur L. ; Koval, Michael ; Kunz, Mauricio ; Lafer, Beny ; Landén, Mikael ; Larsen, Erik R. ; Lenger, Melanie ; Lewitzka, Ute ; Licht, Rasmus W. ; Lopez-Jaramillo, Carlos ; MacKenzie, Alan ; Madsen, Helle Østergaard ; Madsen, Simone Alberte Kongstad A. ; Mahadevan, Jayant ; Mahardika, Agustine ; Manchia, Mirko ; Marsh, Wendy ; Martinez-Cengotitabengoa, Monica ; Martiny, Klaus ; Mashima, Yuki ; McLoughlin, Declan M. ; Meesters, Ybe ; Melle, Ingrid ; Meza-Urzúa, Fátima ; Ming, Mok Yee ; Monteith, Scott ; Moorthy, Muthukumaran ; Morken, Gunnar ; Mosca, Enrica ; Mozzhegorov, Anton A. ; Munoz, Rodrigo ; Mythri, Starlin V. ; Nacef, Fethi ; Nadella, Ravi K. ; Nakanotani, Takako ; Nielsen, René Ernst ; O'Donovan, Claire ; Omrani, Adel ; Osher, Yamima ; Ouali, Uta ; Pantovic-Stefanovic, Maja ; Pariwatcharakul, Pornjira ; Petite, Joanne ; Pfennig, Andrea ; Pica Ruiz, Yolanda ; Pilhatsch, Maximilian ; Pinna, Marco ; Pompili, Maurizio ; Porter, Richard ; Quiroz, Danilo ; Rabelo-da-Ponte, Francisco Diego ; Ramesar, Raj ; Rasgon, Natalie ; Ratta-apha, Woraphat ; Ratzenhofer, Michaela ; Redahan, Maria ; Reddy, M. S. ; Reif, Andreas ; Reininghaus, Eva Z. ; Richards, Jenny Gringer ; Ritter, Philipp ; Rybakowski, Janusz K. ; Sathyaputri, Leela ; Scippa, Ângela M. ; Simhandl, Christian ; Severus, Emanuel ; Smith, Daniel ; Smith, José ; Stackhouse Jr., Paul W. ; Stein, Dan J. ; Stilwell, Kellen ; Strejilevich, Sergio ; Su, Kuan-Pin ; Subramaniam, Mythily ; Sulaiman, Ahmad Hatim ; Suominen, Kirsi ; Tanra, Andi J. ; Tatebayashi, Yoshitaka ; Teh, Wen Lin ; Tondo, Leonardo ; Torrent, Carla ; Tuinstra, Daniel ; Uchida, Takahito ; Vaaler, Arne E. ; Veeh, Julia ; Vieta, Eduard ; Viswanath, Biju ; Yoldi-Negrete, Maria ; Yalcinkaya, Oguz Kaan ; Young, Allan H. ; Zgueb, Yosra ; Whybrow, Peter C.
Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.
Sardanelli, Francesco ; Aase, Hildegunn S. ; Álvarez, Marina ; Azavedo, Edward ; Baarslag, Henk J. ; Balleyguier, Corinne ; Baltzer, Pascal Andreas Thomas ; Beslagic, Vanesa ; Bick, Ulrich ; Bogdanovic-Stojanovic, Dragana ; Briediene, Ruta ; Brkljacic, Boris ; Camps Herrero, Julia ; Colin, Catherine ; Cornford, Eleanor ; Danes, Jan ; Geer, Gerard de ; Esen, Gul ; Evans, Andrew ; Fuchsjäger, Michael H. ; Gilbert, Fiona J. ; Graf, Oswald ; Hargaden, Gormlaith ; Helbich, Thomas H. ; Heywang-Köbrunner, Sylvia H. ; Ivanov, Valentin ; Jónsson, Ásbjörn ; Kuhl, Christiane Katharina ; Lisencu, Eugenia C. ; Luczynska, Elzbieta ; Mann, Ritse M. ; Marques, Jose C. ; Martincich, Laura ; Mortier, Margarete ; Müller-Schimpfle, Markus ; Ormandi, Katalin ; Panizza, Pietro ; Pediconi, Federica ; Pijnappel, Ruud M. ; Pinker, Katja ; Rissanen, Tarja ; Rotaru, Natalia ; Saguatti, Gianni ; Sella, Tamar ; Slobodníková, Jana ; Talk, Maret ; Taourel, Patrice ; Trimboli, Rubina Manuela ; Vejborg, Ilse ; Vourtsis, Athina ; Forrai, Gabor
EUSOBI and 30 national breast radiology bodies support mammography for population-based screening, demonstrated to reduce breast cancer (BC) mortality and treatment impact. According to the International Agency for Research on Cancer, the reduction in mortality is 40 % for women aged 50–69 years taking up the invitation while the probability of false-positive needle biopsy is <1 % per round and overdiagnosis is only 1–10 % for a 20-year screening. Mortality reduction was also observed for the age groups 40–49 years and 70–74 years, although with “limited evidence”. Thus, we firstly recommend biennial screening mammography for average-risk women aged 50–69 years; extension up to 73 or 75 years, biennially, is a second priority, from 40–45 to 49 years, annually, a third priority. Screening with thermography or other optical tools as alternatives to mammography is discouraged. Preference should be given to population screening programmes on a territorial basis, with double reading. Adoption of digital mammography (not film-screen or phosphor-plate computer radiography) is a priority, which also improves sensitivity in dense breasts. Radiologists qualified as screening readers should be involved in programmes. Digital breast tomosynthesis is also set to become “routine mammography” in the screening setting in the next future. Dedicated pathways for high-risk women offering breast MRI according to national or international guidelines and recommendations are encouraged.