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{userid:"molven", "articletype":"article","pages":"1380-1385","author":"Jason Flannick, Nicola L Beer, Alexander G Bick, Vineeta Agarwala, Janne Molnes, Namrata Gupta, No\u00ebl P Burtt, Jose C Florez, James B Meigs, Herman Taylor, Valeriya Lyssenko, Henrik Irgens, Ervin Fox, Frank Burslem, Stefan Johansson, M Julia Brosnan, Jeff K Trimmer, Christopher Newton-Cheh, Tiinamaija Tuomi, Anders Molven, James G Wilson, Christopher J O'Donnell, Sekar Kathiresan, Joel N Hirschhorn, P\u00e5l R Nj\u00f8lstad, Tim Rolph, J G Seidman, Stacey Gabriel, David R Cox, Christine E Seidman, Leif Groop, David Altshuler","year":"2013","title":"Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.","month":"Nov","journal":"Nature genetics","publisher":"","volume":"45","number":"11","note":"","tags":"Adult,Base Sequence,Basic Helix-Loop-Helix Transcription Factors,Chromosome Mapping,Diabetes Mellitus, Type 2,Female,Genetic Predisposition to Disease,Genetic Variation,Hepatocyte Nuclear Factor 1-alpha,Hepatocyte Nuclear Factor 1-beta,Hepatocyte Nuclear Factor 4,Homeodomain Proteins,Humans,Male,Middle Aged,Phenotype,Protein-Serine-Threonine Kinases,Risk,Sequence Analysis, DNA,Trans-Activators,Young Adult","booktitle":"","editor":"","abstract":"Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.","address":"","school":"","issn":"1546-1718","doi":"10.1038\/ng.2794","isi":"","pubmed":"24097065","key":"Flannick2013","howpublished":"","urllink":"","refid":124,"weight":124}
,

{userid:"shibu.john", "refid":"13","repocollections":"","attachment":"","_thumb":"","articletype":"article","sectionheading":"","title":"Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.","year":"2015","author":"Angharad M Roberts, James S Ware, Daniel S Herman, Sebastian Schafer, John Baksi, Alexander G Bick, Rachel J Buchan, Roddy Walsh, Shibu John, Samuel Wilkinson, Francesco Mazzarotto, Leanne E Felkin, Sungsam Gong, Jacqueline A L MacArthur, Fiona Cunningham, Jason Flannick, Stacey B Gabriel, David M Altshuler, Peter S Macdonald, Matthias Heinig, Anne M Keogh, Christopher S Hayward, Nicholas R Banner, Dudley J Pennell, Declan P O'Regan, Tan Ru San, Antonio de Marvao, Timothy J W Dawes, Ankur Gulati, Emma J Birks, Magdi H Yacoub, Michael Radke, Michael Gotthardt, James G Wilson, Christopher J O'Donnell, Sanjay K Prasad, Paul J R Barton, Diane Fatkin, Norbert Hubner, Jonathan G Seidman, Christine E Seidman, Stuart A Cook","journal":"Science translational medicine","volume":"7","number":"270","pages":"","month":"Jan","doi":"10.1126\/scitranslmed.3010134","pubmed":"25589632","pdflink":"","urllink":"","abstract":"The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http:\/\/cardiodb.org\/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.","note":"","tags":"","weight":13,"publisher":"","booktitle":"","editor":"","address":"","school":"","issn":"1946-6242","isi":"","key":"Roberts2015","howpublished":""}
,

{userid:"qicheng.ma", "refid":5,"repocollections":"","attachment":"","_thumb":"","articletype":"article","sectionheading":"","title":"Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.","year":"","author":"Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research, Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson Bostr\u00f6m K, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, R\u00e5stam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sj\u00f6gren M, Sterner M, Surti A, Svensson M, Svensson M, Tewhey R, Blumenstiel B, Parkin M, Defelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B, Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, Purcell S.","journal":"Science. 2007 Jun 1;316(5829):1331-6. Epub 2007 Apr 26.","volume":"","number":"","pages":"","month":"","doi":"","pubmed":"17463246","pdflink":"","urllink":"","abstract":"","note":"","tags":""}
,

{userid:"g.j.wolbink", "articletype":"article","pages":"1216-1223","author":"Soumya Raychaudhuri, Elaine F Remmers, Annette T Lee, Rachel Hackett, Candace Guiducci, No\u00ebl P Burtt, Lauren Gianniny, Benjamin D Korman, Leonid Padyukov, Fina A S Kurreeman, Monica Chang, Joseph J Catanese, Bo Ding, Sandra Wong, Annette H M van der Helm-van Mil, Benjamin M Neale, Jonathan Coblyn, Jing Cui, Paul P Tak, Gert Jan Wolbink, J Bart A Crusius, Irene E van der Horst-Bruinsma, Lindsey A Criswell, Christopher I Amos, Michael F Seldin, Daniel L Kastner, Kristin G Ardlie, Lars Alfredsson, Karen H Costenbader, David Altshuler, Tom W J Huizinga, Nancy A Shadick, Michael E Weinblatt, Niek de Vries, Jane Worthington, Mark Seielstad, Rene E M Toes, Elizabeth W Karlson, Ann B Begovich, Lars Klareskog, Peter K Gregersen, Mark J Daly, Robert M Plenge","year":"2008","title":"Common variants at CD40 and other loci confer risk of rheumatoid arthritis.","month":"Oct","journal":"Nature genetics","publisher":"","volume":"40","number":"10","note":"","tags":"Antigens, CD40,Arthritis, Rheumatoid,Case-Control Studies,Chromosome Mapping,Chromosomes, Human,Genetic Predisposition to Disease,Genome, Human,Haplotypes,Humans,Linkage (Genetics),Polymorphism, Single Nucleotide,Genetic Linkage","booktitle":"","editor":"","abstract":"To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).","address":"","school":"","issn":"1546-1718","doi":"10.1038\/ng.233","isi":"","pubmed":"18794853","key":"Raychaudhuri2008","howpublished":"","urllink":"","refid":"16","weight":"16"}
,

{userid:"kato", "articletype":"article","pages":"1249-1262","author":"Isabella Pacchiarotti, David J Bond, Ross J Baldessarini, Willem A Nolen, Heinz Grunze, Rasmus W Licht, Robert M Post, Michael Berk, Guy M Goodwin, Gary S Sachs, Leonardo Tondo, Robert L Findling, Eric A Youngstrom, Mauricio Tohen, Juan Undurraga, Ana Gonz\u00e1lez-Pinto, Joseph F Goldberg, Ay\u015feg\u00fcl Yildiz, Lori L Altshuler, Joseph R Calabrese, Philip B Mitchell, Michael E Thase, Athanasios Koukopoulos, Francesc Colom, Mark A Frye, Gin S Malhi, Konstantinos N Fountoulakis, Gustavo V\u00e1zquez, Roy H Perlis, Terence A Ketter, Frederick Cassidy, Hagop Akiskal, Jean-Michel Azorin, Marc Valent\u00ed, Diego Hidalgo Mazzei, Beny Lafer, Tadafumi Kato, Lorenzo Mazzarini, Anabel Mart\u00ednez-Aran, Gordon Parker, Daniel Souery, Ay\u015feg\u00fcl Ozerdem, Susan L McElroy, Paolo Girardi, Michael Bauer, Lakshmi N Yatham, Carlos A Zarate, Andrew A Nierenberg, Boris Birmaher, Shigenobu Kanba, Rif S El-Mallakh, Alessandro Serretti, Zoltan Rihmer, Allan H Young, Georgios D Kotzalidis, Glenda M MacQueen, Charles L Bowden, S Nassir Ghaemi, Carlos Lopez-Jaramillo, Janusz Rybakowski, Kyooseob Ha, Giulio Perugi, Siegfried Kasper, Jay D Amsterdam, Robert M Hirschfeld, Fl\u00e1vio Kapczinski, Eduard Vieta","year":"2013","title":"The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders.","month":"Nov","journal":"The American journal of psychiatry","publisher":"","volume":"170","number":"11","note":"","tags":"Advisory Committees,Affect,Antidepressive Agents,Bipolar Disorder,Consensus,Delphi Technique,Humans,Suicide,Treatment Outcome","booktitle":"","editor":"","abstract":"The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.","address":"","school":"","issn":"1535-7228","doi":"10.1176\/appi.ajp.2013.13020185","isi":"","pubmed":"24030475","key":"Pacchiarotti2013","howpublished":"","urllink":"","refid":238,"weight":238}
,

{userid:"g.j.wolbink", "articletype":"article","pages":"1313-1318","author":"Soumya Raychaudhuri, Brian P Thomson, Elaine F Remmers, Stephen Eyre, Anne Hinks, Candace Guiducci, Joseph J Catanese, Gang Xie, Eli A Stahl, Robert Chen, Lars Alfredsson, Christopher I Amos, Kristin G Ardlie,  , Anne Barton, John Bowes, Noel P Burtt, Monica Chang, Jonathan Coblyn, Karen H Costenbader, Lindsey A Criswell, J Bart A Crusius, Jing Cui, Phillip L De Jager, Bo Ding, Paul Emery, Edward Flynn, Pille Harrison, Lynne J Hocking, Tom W J Huizinga, Daniel L Kastner, Xiayi Ke, Fina A S Kurreeman, Annette T Lee, Xiangdong Liu, Yonghong Li, Paul Martin, Ann W Morgan, Leonid Padyukov, David M Reid, Mark Seielstad, Michael F Seldin, Nancy A Shadick, Sophia Steer, Paul P Tak, Wendy Thomson, Annette H M van der Helm-van Mil, Irene E van der Horst-Bruinsma, Michael E Weinblatt, Anthony G Wilson, Gert Jan Wolbink, Paul Wordsworth,  , David Altshuler, Elizabeth W Karlson, Rene E M Toes, Niek de Vries, Ann B Begovich, Katherine A Siminovitch, Jane Worthington, Lars Klareskog, Peter K Gregersen, Mark J Daly, Robert M Plenge","year":"2009","title":"Genetic variants at CD28, PRDM1 and CD2\/CD58 are associated with rheumatoid arthritis risk.","month":"Dec","journal":"Nature genetics","publisher":"","volume":"41","number":"12","note":"","tags":"Antigens, CD2,Antigens, CD28,Antigens, CD58,Arthritis, Rheumatoid,Case-Control Studies,Genetic Predisposition to Disease,Genetic Variation,Genotype,Humans,Polymorphism, Single Nucleotide,Repressor Proteins,Risk Factors","booktitle":"","editor":"","abstract":"To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P < 0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls. We used Gene Relationships Across Implicated Loci (GRAIL), a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three were convincingly validated: CD2-CD58 (rs11586238, P = 1 x 10(-6) replication, P = 1 x 10(-9) overall), CD28 (rs1980422, P = 5 x 10(-6) replication, P = 1 x 10(-9) overall) and PRDM1 (rs548234, P = 1 x 10(-5) replication, P = 2 x 10(-8) overall). An additional four were replicated (P < 0.0023): TAGAP (rs394581, P = 0.0002 replication, P = 4 x 10(-7) overall), PTPRC (rs10919563, P = 0.0003 replication, P = 7 x 10(-7) overall), TRAF6-RAG1 (rs540386, P = 0.0008 replication, P = 4 x 10(-6) overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 x 10(-5) overall). Many of these loci are also associated to other immunologic diseases.","address":"","school":"","issn":"1546-1718","doi":"10.1038\/ng.479","isi":"","pubmed":"19898481","key":"Raychaudhuri2009","howpublished":"","urllink":"","refid":"3","weight":"3"}
,

{userid:"molven", "articletype":"article","pages":"357-363","author":"Jason Flannick, Gudmar Thorleifsson, Nicola L Beer, Suzanne B R Jacobs, Niels Grarup, No\u00ebl P Burtt, Anubha Mahajan, Christian Fuchsberger, Gil Atzmon, Rafn Benediktsson, John Blangero, Don W Bowden, Ivan Brandslund, Julia Brosnan, Frank Burslem, John Chambers, Yoon Shin Cho, Cramer Christensen, Desir\u00e9e A Douglas, Ravindranath Duggirala, Zachary Dymek, Yossi Farjoun, Timothy Fennell, Pierre Fontanillas, Tom Fors\u00e9n, Stacey Gabriel, Benjamin Glaser, Daniel F Gudbjartsson, Craig Hanis, Torben Hansen, Astradur B Hreidarsson, Kristian Hveem, Erik Ingelsson, Bo Isomaa, Stefan Johansson, Torben J\u00f8rgensen, Marit Eika J\u00f8rgensen, Sekar Kathiresan, Augustine Kong, Jaspal Kooner, Jasmina Kravic, Markku Laakso, Jong-Young Lee, Lars Lind, Cecilia M Lindgren, Allan Linneberg, Gisli Masson, Thomas Meitinger, Karen L Mohlke, Anders Molven, Andrew P Morris, Shobha Potluri, Rainer Rauramaa, Rasmus Ribel-Madsen, Ann-Marie Richard, Tim Rolph, Veikko Salomaa, Ayellet V Segr\u00e8, Hanna Sk\u00e4rstrand, Valgerdur Steinthorsdottir, Heather M Stringham, Patrick Sulem, E Shyong Tai, Yik Ying Teo, Tanya Teslovich, Unnur Thorsteinsdottir, Jeff K Trimmer, Tiinamaija Tuomi, Jaakko Tuomilehto, Fariba Vaziri-Sani, Benjamin F Voight, James G Wilson, Michael Boehnke, Mark I McCarthy, P\u00e5l R Nj\u00f8lstad, Oluf Pedersen,  ,  , Leif Groop, David R Cox, Kari Stefansson, David Altshuler","year":"2014","title":"Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.","month":"Apr","journal":"Nature genetics","publisher":"","volume":"46","number":"4","note":"","tags":"Animals,Base Sequence,Blood Glucose,Cation Transport Proteins,Diabetes Mellitus, Type 2,Genetic Association Studies,Genotype,Humans,Ion Transport,Mice,Mice, Knockout,Molecular Sequence Data,Mutation, Missense,Proinsulin,Sequence Analysis, DNA","booktitle":"","editor":"","abstract":"Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 \u00d7 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 \u00d7 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.","address":"","school":"","issn":"1546-1718","doi":"10.1038\/ng.2915","isi":"","pubmed":"24584071","key":"Flannick2014","howpublished":"","urllink":"","refid":194,"weight":194}
,

{userid:"chan.voong", "articletype":"article","pages":"","author":"Mia M Gaudet, Karoline B Kuchenbaecker, Joseph Vijai, Robert J Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M Dunning, Andrew Lee, Joe Dennis, Sue Healey, Ed Dicks, Penny Soucy, Olga M Sinilnikova, Vernon S Pankratz, Xianshu Wang, Ronald C Eldridge, Daniel C Tessier, Daniel Vincent, Francois Bacot, Frans B L Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet,  , Paolo Peterlongo, Rita K Schmutzler, Katherine L Nathanson, Marion Piedmonte, Christian F Singer, Mads Thomassen,  , Thomas v O Hansen, Susan L Neuhausen, Ignacio Blanco, Mark H Greene, Judith Garber, Jeffrey N Weitzel, Irene L Andrulis, David E Goldgar, Emma D'Andrea, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Elizabeth J van Rensburg, Adalgeir Arason, Gad Rennert, Ans M W van den Ouweland, Annemarie H van der Hout, Carolien M Kets, Cora M Aalfs, Juul T Wijnen, Margreet G E M Ausems,  ,  , Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D Gareth Evans, Chris Jacobs, Julian Adlard, Marc Tischkowitz, Mary E Porteous, Francesca Damiola,  , Lisa Golmard, Laure Barjhoux, Michel Longy, Muriel Belotti, Sandra Fert Ferrer, Sylvie Mazoyer, Amanda B Spurdle, Siranoush Manoukian, Monica Barile, Maurizio Genuardi, Norbert Arnold, Alfons Meindl, Christian Sutter, Barbara Wappenschmidt, Susan M Domchek, Georg Pfeiler, Eitan Friedman, Uffe Birk Jensen, Mark Robson, Sohela Shah, Conxi Lazaro, Phuong L Mai, Javier Benitez, Melissa C Southey, Marjanka K Schmidt, Peter A Fasching, Julian Peto, Manjeet K Humphreys, Qin Wang, Kyriaki Michailidou, Elinor J Sawyer, Barbara Burwinkel, Pascal Gu\u00e9nel, Stig E Bojesen, Roger L Milne, Hermann Brenner, Magdalena Lochmann,  , Kristiina Aittom\u00e4ki, Thilo D\u00f6rk, Sara Margolin, Arto Mannermaa, Diether Lambrechts, Jenny Chang-Claude, Paolo Radice, Graham G Giles, Christopher A Haiman, Robert Winqvist, Peter Devillee, Montserrat Garc\u00eda-Closas, Nils Schoof, Maartje J Hooning, Angela Cox, Paul D P Pharoah, Anna Jakubowska, Nick Orr, Anna Gonz\u00e1lez-Neira, Guillermo Pita, M Rosario Alonso, Per Hall, Fergus J Couch, Jacques Simard, David Altshuler, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, Kenneth Offit","year":"2013","title":"Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.","month":"03","journal":"PLoS genetics","publisher":"","volume":"9","number":"3","note":"","tags":"Adult,Aged,Alleles,BRCA1 Protein,BRCA2 Protein,Breast Neoplasms,Chromosomes, Human, Pair 6,Female,Genetic Predisposition to Disease,Genome-Wide Association Study,Genotype,Heterozygote,Humans,Middle Aged,Mutation,Polymorphism, Single Nucleotide,Risk Factors","booktitle":"","editor":"","abstract":"Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1\/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A\/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR\u200a=\u200a0.85, 95% CI 0.80-0.90, P = 3.9 \u00d7 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.","address":"","school":"","issn":"1553-7404","doi":"10.1371\/journal.pgen.1003173","isi":"","pubmed":"23544012","key":"Gaudet2013","howpublished":"","urllink":"","refid":47,"weight":47}
,

{userid:"chan.voong", "articletype":"article","pages":"","author":"Mia M Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M Korn, Candace Guiducci, Ayellet V Segr\u00e8, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay,  GEMO Study Collaborators, Frans B L Hogervorst, Matti A Rookus, J Margriet Coll\u00e9e, Nicoline Hoogerbrugge, Kees E P van Roozendaal,  , Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V Blank, Trinidad Cald\u00e9s, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittom\u00e4ki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T Johannsson, Rosa B Barkardottir, Peter Devilee, Olofunmilayo I Olopade, Susan L Neuhausen, Xianshu Wang, Zachary S Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Paolo Radice, Catherine M Phelan, Steven Narod, Gad Rennert, Flavio Lejbkowicz, Anath Flugelman, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik,  , Amanda E Toland, Marco Montagna, Emma D'Andrea, Eitan Friedman, Yael Laitman, Ake Borg, Mary Beattie, Susan J Ramus, Susan M Domchek, Katherine L Nathanson, Tim Rebbeck, Amanda B Spurdle, Xiaoqing Chen, Helene Holland,  , Esther M John, John L Hopper, Saundra S Buys, Mary B Daly, Melissa C Southey, Mary Beth Terry, Nadine Tung, Thomas V Overeem Hansen, Finn C Nielsen, Mark H Greene, Mark I Greene, Phuong L Mai, Ana Osorio, Mercedes Dur\u00e1n, Raquel Andres, Javier Ben\u00edtez, Jeffrey N Weitzel, Judy Garber, Ute Hamann,  , Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Julian Barwell, Andrew K Godwin, Rita K Schmutzler, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Dorothea Gadzicki, Michael Dean, Bert Gold, Robert J Klein, Fergus J Couch, Georgia Chenevix-Trench, Douglas F Easton, Mark J Daly, Antonis C Antoniou, David M Altshuler, Kenneth Offit","year":"2010","title":"Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.","month":"Oct","journal":"PLoS genetics","publisher":"","volume":"6","number":"10","note":"","tags":"Adult,BRCA2 Protein,Breast Neoplasms,Chromosomes, Human, Pair 10,Chromosomes, Human, Pair 20,DNA-Binding Proteins,European Continental Ancestry Group,Female,Gene Frequency,Genetic Predisposition to Disease,Genome-Wide Association Study,Haplotypes,Heterozygote,Humans,Linkage Disequilibrium,Middle Aged,Mutation,Penetrance,Polymorphism, Single Nucleotide,Receptor, Fibroblast Growth Factor, Type 2,Risk Factors,Transcription Factors","booktitle":"","editor":"","abstract":"The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (\u03bb) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.","address":"","school":"","issn":"1553-7404","doi":"10.1371\/journal.pgen.1001183","isi":"","pubmed":"21060860","key":"Gaudet2010","howpublished":"","urllink":"","refid":94,"weight":94}
,

{userid:"chan.voong", "articletype":"article","pages":"685-699","author":"Kate M Im, Tomas Kirchhoff, Xianshu Wang, Todd Green, Clement Y Chow, Joseph Vijai, Joshua Korn, Mia M Gaudet, Zachary Fredericksen, V Shane Pankratz, Candace Guiducci, Andrew Crenshaw, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M Sinilnikova, Phuong L Mai, Mark H Greene, Marion Piedmonte, Wendy S Rubinstein,  , Frans B Hogervorst, Matti A Rookus, J Margriet Coll\u00e9e, Nicoline Hoogerbrugge, Christi J van Asperen, Hanne E J Meijers-Heijboer, Cees E Van Roozendaal, Trinidad Caldes, Pedro Perez-Segura, Anna Jakubowska, Jan Lubinski, Tomasz Huzarski, Pawe\u0142 Blecharz, Heli Nevanlinna, Kristiina Aittom\u00e4ki, Conxi Lazaro, Ignacio Blanco, Rosa B Barkardottir, Marco Montagna, Emma D'Andrea,  , Peter Devilee, Olufunmilayo I Olopade, Susan L Neuhausen, Bernard Peissel, Bernardo Bonanni, Paolo Peterlongo, Christian F Singer, Gad Rennert, Flavio Lejbkowicz, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik,  , Amanda Ewart Toland, Maria Adelaide Caligo,  , Mary S Beattie, Salina Chan,  , Susan M Domchek, Katherine L Nathanson, Timothy R Rebbeck, Catherine Phelan, Steven Narod, Esther M John, John L Hopper, Saundra S Buys, Mary B Daly, Melissa C Southey, Mary-Beth Terry, Nadine Tung, Thomas V O Hansen, Ana Osorio, Javier Benitez, Mercedes Dur\u00e1n, Jeffrey N Weitzel, Judy Garber, Ute Hamann,  , Susan Peock, Margaret Cook, Clare T Oliver, Debra Frost, Radka Platte, D Gareth Evans, Ros Eeles, Louise Izatt, Joan Paterson, Carole Brewer, Shirley Hodgson, Patrick J Morrison, Mary Porteous, Lisa Walker, Mark T Rogers, Lucy E Side, Andrew K Godwin, Rita K Schmutzler, Barbara Wappenschmidt, Yael Laitman, Alfons Meindl, Helmut Deissler, Raymonda Varon-Mateeva, Sabine Preisler-Adams, Karin Kast, Laurence Venat-Bouvet, Dominique Stoppa-Lyonnet, Georgia Chenevix-Trench, Douglas F Easton, Robert J Klein, Mark J Daly, Eitan Friedman, Michael Dean, Andrew G Clark, David M Altshuler, Antonis C Antoniou, Fergus J Couch, Kenneth Offit, Bert Gold","year":"2011","title":"Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.","month":"Nov","journal":"Human genetics","publisher":"","volume":"130","number":"5","note":"","tags":"Arthritis,BRCA1 Protein,BRCA2 Protein,Base Sequence,Computer Simulation,Deafness,Female,Founder Effect,Genotype,Haplotypes,Heterozygote,Humans,Jews,Polychondritis, Relapsing,Sequence Deletion","booktitle":"","editor":"","abstract":"Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1\u00a0Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4\u00a0Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.","address":"","school":"","issn":"1432-1203","doi":"10.1007\/s00439-011-1003-z","isi":"","pubmed":"21597964","key":"Im2011","howpublished":"","urllink":"","refid":84,"weight":84}
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