Author: "Wellcome Trust Case Control Consortium, 2" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Wellcome Trust Case Control Consortium, 2"' showing total 83 results

Start Over Author "Wellcome Trust Case Control Consortium, 2"

83 results on '"Wellcome Trust Case Control Consortium, 2"'

1. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Author: Iglesias, Adriana I, Mishra, Aniket, Vitart, Veronique, Bykhovskaya, Yelena, Höhn, René, Springelkamp, Henriët, Cuellar-Partida, Gabriel, Gharahkhani, Puya, Bailey, Jessica N Cooke, Willoughby, Colin E, Li, Xiaohui, Yazar, Seyhan, Nag, Abhishek, Khawaja, Anthony P, Polašek, Ozren, Siscovick, David, Mitchell, Paul, Tham, Yih Chung, Haines, Jonathan L, Kearns, Lisa S, Hayward, Caroline, Shi, Yuan, van Leeuwen, Elisabeth M, Taylor, Kent D, Blue Mountains Eye Study - GWAS group, Bonnemaijer, Pieter, Rotter, Jerome I, Martin, Nicholas G, Zeller, Tanja, Mills, Richard A, Souzeau, Emmanuelle, Staffieri, Sandra E, Jonas, Jost B, Schmidtmann, Irene, Boutin, Thibaud, Kang, Jae H, Lucas, Sionne EM, Wong, Tien Yin, Beutel, Manfred E, Wilson, James F, Wellcome Trust Case Control Consortium 2 (WTCCC2), NEIGHBORHOOD consortium, Uitterlinden, André G, Vithana, Eranga N, Foster, Paul J, Hysi, Pirro G, Hewitt, Alex W, Khor, Chiea Chuen, Pasquale, Louis R, Montgomery, Grant W, Klaver, Caroline CW, Aung, Tin, Pfeiffer, Norbert, Mackey, David A, Hammond, Christopher J, Cheng, Ching-Yu, Craig, Jamie E, Rabinowitz, Yaron S, Wiggs, Janey L, Burdon, Kathryn P, van Duijn, Cornelia M, and MacGregor, Stuart
Subjects: Blue Mountains Eye Study - GWAS group, Wellcome Trust Case Control Consortium 2, NEIGHBORHOOD consortium, Eye Disease and Disorders of Vision
Abstract: Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.
Published: 2019

2. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Author: Iglesias, Adriana I, Mishra, Aniket, Vitart, Veronique, Bykhovskaya, Yelena, Höhn, René, Springelkamp, Henriët, Cuellar-Partida, Gabriel, Gharahkhani, Puya, Bailey, Jessica N Cooke, Willoughby, Colin E, Li, Xiaohui, Yazar, Seyhan, Nag, Abhishek, Khawaja, Anthony P, Polašek, Ozren, Siscovick, David, Mitchell, Paul, Tham, Yih Chung, Haines, Jonathan L, Kearns, Lisa S, Hayward, Caroline, Shi, Yuan, van Leeuwen, Elisabeth M, Taylor, Kent D, Blue Mountains Eye Study—GWAS group, Bonnemaijer, Pieter, Rotter, Jerome I, Martin, Nicholas G, Zeller, Tanja, Mills, Richard A, Souzeau, Emmanuelle, Staffieri, Sandra E, Jonas, Jost B, Schmidtmann, Irene, Boutin, Thibaud, Kang, Jae H, Lucas, Sionne EM, Wong, Tien Yin, Beutel, Manfred E, Wilson, James F, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Uitterlinden, André G, Vithana, Eranga N, Foster, Paul J, Hysi, Pirro G, Hewitt, Alex W, Khor, Chiea Chuen, Pasquale, Louis R, Montgomery, Grant W, Klaver, Caroline CW, Aung, Tin, Pfeiffer, Norbert, Mackey, David A, Hammond, Christopher J, Cheng, Ching-Yu, Craig, Jamie E, Rabinowitz, Yaron S, Wiggs, Janey L, Burdon, Kathryn P, van Duijn, Cornelia M, and MacGregor, Stuart
Subjects: Blue Mountains Eye Study—GWAS group, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2, Cornea, Humans, Marfan Syndrome, Corneal Diseases, Corneal Dystrophies, Hereditary, Keratoconus, Eye Diseases, Hereditary, Glaucoma, Open-Angle, Myopia, Ehlers-Danlos Syndrome, Proteoglycans, Gene Expression, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome, Human, Asian Continental Ancestry Group, European Continental Ancestry Group, Transforming Growth Factor beta2, Genome-Wide Association Study, Loeys-Dietz Syndrome, Mendelian Randomization Analysis, Decorin, Lumican, Fibrillin-1, ADAMTS Proteins, Corneal Dystrophies, Hereditary, Eye Diseases, Glaucoma, Open-Angle, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Genome, Human
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Published: 2018

3. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process.

Author: Springelkamp, Henriët, Höhn, René, Mishra, Aniket, Hysi, Pirro G, Khor, Chiea-Chuen, Loomis, Stephanie J, Bailey, Jessica N Cooke, Gibson, Jane, Thorleifsson, Gudmar, Janssen, Sarah F, Luo, Xiaoyan, Ramdas, Wishal D, Vithana, Eranga, Nongpiur, Monisha E, Montgomery, Grant W, Xu, Liang, Mountain, Jenny E, Gharahkhani, Puya, Lu, Yi, Amin, Najaf, Karssen, Lennart C, Sim, Kar-Seng, van Leeuwen, Elisabeth M, Iglesias, Adriana I, Verhoeven, Virginie JM, Hauser, Michael A, Loon, Seng-Chee, Despriet, Dominiek DG, Nag, Abhishek, Venturini, Cristina, Sanfilippo, Paul G, Schillert, Arne, Kang, Jae H, Landers, John, Jonasson, Fridbert, Cree, Angela J, van Koolwijk, Leonieke ME, Rivadeneira, Fernando, Souzeau, Emmanuelle, Jonsson, Vesteinn, Menon, Geeta, Blue Mountains Eye Study—GWAS group, Weinreb, Robert N, de Jong, Paulus TVM, Oostra, Ben A, Uitterlinden, André G, Hofman, Albert, Ennis, Sarah, Thorsteinsdottir, Unnur, Burdon, Kathryn P, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Spector, Timothy D, Mirshahi, Alireza, Saw, Seang-Mei, Vingerling, Johannes R, Teo, Yik-Ying, Haines, Jonathan L, Wolfs, Roger CW, Lemij, Hans G, Tai, E-Shyong, Jansonius, Nomdo M, Jonas, Jost B, Cheng, Ching-Yu, Aung, Tin, Viswanathan, Ananth C, Klaver, Caroline CW, Craig, Jamie E, Macgregor, Stuart, Mackey, David A, Lotery, Andrew J, Stefansson, Kari, Bergen, Arthur AB, Young, Terri L, Wiggs, Janey L, Pfeiffer, Norbert, Wong, Tien-Yin, Pasquale, Louis R, Hewitt, Alex W, van Duijn, Cornelia M, and Hammond, Christopher J
Subjects: Blue Mountains Eye Study—GWAS group, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2, Optic Nerve, Optic Disk, Humans, Glaucoma, Case-Control Studies, Gene Expression Profiling, Gene Frequency, Genotype, Phenotype, Polymorphism, Single Nucleotide, Asian Continental Ancestry Group, European Continental Ancestry Group, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Human Genome, Genetics, Neurodegenerative, Eye Disease and Disorders of Vision, Neurosciences, 2.1 Biological and endogenous factors, Eye
Abstract: Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Published: 2014

4. Genetic variation in VAC14 is associated with bacteremia secondary to diverse pathogens in African children

Author: Wellcome Trust Case-Control Consortium 2, The Kenyan Bacteraemia Study Group, Gilchrist, James J., Mentzer, Alexander J., Rautanen, Anna, Pirinen, Matti, Mwarumba, Salim, Njuguna, Patricia, Mturi, Neema, Williams, Thomas N., Scott, J. Anthony G., and Hill, Adrian V. S.
Published: 2018

5. Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets.

Author: Degenhardt, F, Priebe, L, Meier, S, Lennertz, L, Streit, F, Witt, SH, Hofmann, A, Becker, T, Mössner, R, Maier, W, Nenadic, I, Sauer, H, Mattheisen, M, Buizer-Voskamp, J, Ophoff, RA, GROUP Consortium, Rujescu, D, Giegling, I, Ingason, A, Wagner, M, Delobel, B, Andrieux, J, Meyer-Lindenberg, A, Heinz, A, Walter, H, Moebus, S, Corvin, A, Wellcome Trust Case Control Consortium 2, International Schizophrenia Consortium, Rietschel, M, Nöthen, MM, and Cichon, S
Subjects: GROUP Consortium, Wellcome Trust Case Control Consortium 2, International Schizophrenia Consortium, Humans, Genetic Predisposition to Disease, Schizophrenia, Gene Duplication, Adult, Aged, Middle Aged, Europe, Female, Male, Protein-Tyrosine Kinases, DGCR2, exome-sequencing, intellectual disability, RB1-inducible coiled-coil 1, schizoaffective disorder, Clinical Sciences, Public Health and Health Services, Psychology
Abstract: Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ~80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10(-5); odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ.
Published: 2013

6. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Author: International Multiple Sclerosis Genetics Consortium (IMSGC), Beecham, Ashley H, Patsopoulos, Nikolaos A, Xifara, Dionysia K, Davis, Mary F, Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas S, Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, D'Alfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F, Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R, Hintzen, Rogier, Barcellos, Lisa F, Wellcome Trust Case Control Consortium 2 (WTCCC2), International IBD Genetics Consortium (IIBDGC), Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Søndergaard, Helle Bach, Baker, Amie, Band, Gavin, Baranzini, Sergio E, Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Céline, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas MC, Blackburn, Hannah, Bomfim, Izaura L, Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J, Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G, Coman, Irène, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce AC, Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R, Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T, Donnelly, Peter, Dubois, Bénédicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y, Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, and Harrower, Timothy
Subjects: International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, International IBD Genetics Consortium, Humans, Multiple Sclerosis, Genetic Predisposition to Disease, Chromosome Mapping, Gene Frequency, Genotype, Polymorphism, Single Nucleotide, Genetic Variation, Genome-Wide Association Study, Genetic Loci, White People, Neurosciences, Prevention, Autoimmune Disease, Genetics, Brain Disorders, Human Genome, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
Published: 2013

7. Association of genetic markers with CSF oligoclonal bands in multiple sclerosis patients.

Author: Leone, Maurizio A, Barizzone, Nadia, Esposito, Federica, Lucenti, Ausiliatrice, Harbo, Hanne F, Goris, An, Kockum, Ingrid, Oturai, Annette Bang, Celius, Elisabeth Gulowsen, Mero, Inger L, Dubois, Bénédicte, Olsson, Tomas, Søndergaard, Helle Bach, Cusi, Daniele, Lupoli, Sara, Andreassen, Bettina Kulle, International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Myhr, Kjell-Morten, Guerini, Franca R, PROGEMUS Group, PROGRESSO Group, Comi, Giancarlo, Martinelli-Boneschi, Filippo, and D'Alfonso, Sandra
Subjects: International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, PROGEMUS Group, PROGRESSO Group, Humans, Multiple Sclerosis, Oligoclonal Bands, Genetic Markers, Polymorphism, Single Nucleotide, Adult, Middle Aged, Female, Male, Meta-Analysis as Topic, Genome-Wide Association Study, Young Adult, HLA-DRB1 Chains, Human Genome, Autoimmune Disease, Clinical Research, Genetics, 2.1 Biological and endogenous factors, General Science & Technology
Abstract: Objectiveto explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.MethodsWe genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.ResultsHLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10(-7)) outside the HLA region (65 Mb).Discussiongenetic factors predispose to the development of OCB.
Published: 2013

8. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.

Author: Tsoi, Lam C, Spain, Sarah L, Knight, Jo, Ellinghaus, Eva, Stuart, Philip E, Capon, Francesca, Ding, Jun, Li, Yanming, Tejasvi, Trilokraj, Gudjonsson, Johann E, Kang, Hyun M, Allen, Michael H, McManus, Ross, Novelli, Giuseppe, Samuelsson, Lena, Schalkwijk, Joost, Ståhle, Mona, Burden, A David, Smith, Catherine H, Cork, Michael J, Estivill, Xavier, Bowcock, Anne M, Krueger, Gerald G, Weger, Wolfgang, Worthington, Jane, Tazi-Ahnini, Rachid, Nestle, Frank O, Hayday, Adrian, Hoffmann, Per, Winkelmann, Juliane, Wijmenga, Cisca, Langford, Cordelia, Edkins, Sarah, Andrews, Robert, Blackburn, Hannah, Strange, Amy, Band, Gavin, Pearson, Richard D, Vukcevic, Damjan, Spencer, Chris CA, Deloukas, Panos, Mrowietz, Ulrich, Schreiber, Stefan, Weidinger, Stephan, Koks, Sulev, Kingo, Külli, Esko, Tonu, Metspalu, Andres, Lim, Henry W, Voorhees, John J, Weichenthal, Michael, Wichmann, H Erich, Chandran, Vinod, Rosen, Cheryl F, Rahman, Proton, Gladman, Dafna D, Griffiths, Christopher EM, Reis, Andre, Kere, Juha, Collaborative Association Study of Psoriasis (CASP), Genetic Analysis of Psoriasis Consortium, Psoriasis Association Genetics Extension, Wellcome Trust Case Control Consortium 2, Nair, Rajan P, Franke, Andre, Barker, Jonathan NWN, Abecasis, Goncalo R, Elder, James T, and Trembath, Richard C
Subjects: Collaborative Association Study of Psoriasis, Genetic Analysis of Psoriasis Consortium, Psoriasis Association Genetics Extension, Wellcome Trust Case Control Consortium 2, T-Lymphocytes, Skin, Humans, Psoriasis, Genetic Predisposition to Disease, Guanylate Cyclase, GTPase-Activating Proteins, Membrane Proteins, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Core Binding Factor Alpha 3 Subunit, STAT3 Transcription Factor, DEAD-box RNA Helicases, CARD Signaling Adaptor Proteins, Immunity, Innate, Genome-Wide Association Study, Genetic Loci, DEAD Box Protein 58, Polymorphism, Single Nucleotide, Immunity, Innate, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
Published: 2012

9. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Author: International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Sawcer, Stephen, Hellenthal, Garrett, Pirinen, Matti, Spencer, Chris CA, Patsopoulos, Nikolaos A, Moutsianas, Loukas, Dilthey, Alexander, Su, Zhan, Freeman, Colin, Hunt, Sarah E, Edkins, Sarah, Gray, Emma, Booth, David R, Potter, Simon C, Goris, An, Band, Gavin, Oturai, Annette Bang, Strange, Amy, Saarela, Janna, Bellenguez, Céline, Fontaine, Bertrand, Gillman, Matthew, Hemmer, Bernhard, Gwilliam, Rhian, Zipp, Frauke, Jayakumar, Alagurevathi, Martin, Roland, Leslie, Stephen, Hawkins, Stanley, Giannoulatou, Eleni, D'alfonso, Sandra, Blackburn, Hannah, Martinelli Boneschi, Filippo, Liddle, Jennifer, Harbo, Hanne F, Perez, Marc L, Spurkland, Anne, Waller, Matthew J, Mycko, Marcin P, Ricketts, Michelle, Comabella, Manuel, Hammond, Naomi, Kockum, Ingrid, McCann, Owen T, Ban, Maria, Whittaker, Pamela, Kemppinen, Anu, Weston, Paul, Hawkins, Clive, Widaa, Sara, Zajicek, John, Dronov, Serge, Robertson, Neil, Bumpstead, Suzannah J, Barcellos, Lisa F, Ravindrarajah, Rathi, Abraham, Roby, Alfredsson, Lars, Ardlie, Kristin, Aubin, Cristin, Baker, Amie, Baker, Katharine, Baranzini, Sergio E, Bergamaschi, Laura, Bergamaschi, Roberto, Bernstein, Allan, Berthele, Achim, Boggild, Mike, Bradfield, Jonathan P, Brassat, David, Broadley, Simon A, Buck, Dorothea, Butzkueven, Helmut, Capra, Ruggero, Carroll, William M, Cavalla, Paola, Celius, Elisabeth G, Cepok, Sabine, Chiavacci, Rosetta, Clerget-Darpoux, Françoise, Clysters, Katleen, Comi, Giancarlo, Cossburn, Mark, Cournu-Rebeix, Isabelle, Cox, Mathew B, Cozen, Wendy, Cree, Bruce AC, Cross, Anne H, Cusi, Daniele, Daly, Mark J, Davis, Emma, de Bakker, Paul IW, Debouverie, Marc, D'hooghe, Marie Beatrice, Dixon, Katherine, Dobosi, Rita, Dubois, Bénédicte, and Ellinghaus, David
Subjects: International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, T-Lymphocytes, Helper-Inducer, Humans, Multiple Sclerosis, Genetic Predisposition to Disease, HLA-A Antigens, HLA-DR Antigens, Sample Size, Cell Differentiation, Immunity, Cellular, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, Alleles, Genome, Human, Europe, Genome-Wide Association Study, HLA-DRB1 Chains, Genetics, Neurosciences, Neurodegenerative, Clinical Research, Brain Disorders, Autoimmune Disease, Human Genome, 2.1 Biological and endogenous factors, Neurological, Inflammatory and immune system, General Science & Technology
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Published: 2011

10. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Adriana I. Iglesias, Aniket Mishra, Veronique Vitart, Yelena Bykhovskaya, René Höhn, Henriët Springelkamp, Gabriel Cuellar-Partida, Puya Gharahkhani, Jessica N. Cooke Bailey, Colin E. Willoughby, Xiaohui Li, Seyhan Yazar, Abhishek Nag, Anthony P. Khawaja, Ozren Polašek, David Siscovick, Paul Mitchell, Yih Chung Tham, Jonathan L. Haines, Lisa S. Kearns, Caroline Hayward, Yuan Shi, Elisabeth M. van Leeuwen, Kent D. Taylor, Blue Mountains Eye Study—GWAS group, Pieter Bonnemaijer, Jerome I. Rotter, Nicholas G. Martin, Tanja Zeller, Richard A. Mills, Emmanuelle Souzeau, Sandra E. Staffieri, Jost B. Jonas, Irene Schmidtmann, Thibaud Boutin, Jae H. Kang, Sionne E. M. Lucas, Tien Yin Wong, Manfred E. Beutel, James F. Wilson, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), André G. Uitterlinden, Eranga N. Vithana, Paul J. Foster, Pirro G. Hysi, Alex W. Hewitt, Chiea Chuen Khor, Louis R. Pasquale, Grant W. Montgomery, Caroline C. W. Klaver, Tin Aung, Norbert Pfeiffer, David A. Mackey, Christopher J. Hammond, Ching-Yu Cheng, Jamie E. Craig, Yaron S. Rabinowitz, Janey L. Wiggs, Kathryn P. Burdon, Cornelia M. van Duijn, and Stuart MacGregor
Subjects: Science
Abstract: Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.
Published: 2018
Full Text: View/download PDF

11. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Adriana I. Iglesias, Aniket Mishra, Veronique Vitart, Yelena Bykhovskaya, René Höhn, Henriët Springelkamp, Gabriel Cuellar-Partida, Puya Gharahkhani, Jessica N. Cooke Bailey, Colin E. Willoughby, Xiaohui Li, Seyhan Yazar, Abhishek Nag, Anthony P. Khawaja, Ozren Polašek, David Siscovick, Paul Mitchell, Yih Chung Tham, Jonathan L. Haines, Lisa S. Kearns, Caroline Hayward, Yuan Shi, Elisabeth M. van Leeuwen, Kent D. Taylor, Blue Mountains Eye Study - GWAS group, Pieter Bonnemaijer, Jerome I. Rotter, Nicholas G. Martin, Tanja Zeller, Richard A. Mills, Emmanuelle Souzeau, Sandra E. Staffieri, Jost B. Jonas, Irene Schmidtmann, Thibaud Boutin, Jae H. Kang, Sionne E. M. Lucas, Tien Yin Wong, Manfred E. Beutel, James F. Wilson, Wellcome Trust Case Control Consortium 2 (WTCCC2), NEIGHBORHOOD consortium, André G. Uitterlinden, Eranga N. Vithana, Paul J. Foster, Pirro G. Hysi, Alex W. Hewitt, Chiea Chuen Khor, Louis R. Pasquale, Grant W. Montgomery, Caroline C. W. Klaver, Tin Aung, Norbert Pfeiffer, David A. Mackey, Christopher J. Hammond, Ching-Yu Cheng, Jamie E. Craig, Yaron S. Rabinowitz, Janey L. Wiggs, Kathryn P. Burdon, Cornelia M. van Duijn, and Stuart MacGregor
Subjects: Science
Abstract: Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.
Published: 2019
Full Text: View/download PDF

12. GWAS meta-analysis of 16 790 patients with Barrett’s oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level

Author: Schröder, Julia, Chegwidden, Laura, Maj, Carlo, Gehlen, Jan, Speller, Jan, Böhmer, Anne C., Borisov, Oleg, Hess, Timo, Kreuser, Nicole, Venerito, Marino, Alakus, Hakan, May, Andrea, Gerges, Christian, Schmidt, Thomas, Thieme, Rene, Heider, Dominik, Hillmer, Axel M., Reingruber, Julian, Lyros, Orestis, Dietrich, Arne, Hoffmeister, Albrecht, Mehdorn, Matthias, Lordick, Florian, Stocker, Gertraud, Hohaus, Michael, Reim, Daniel, Kandler, Jennis, Müller, Michaela, Ebigbo, Alanna, Fuchs, Claudia, Bruns, Christiane J., Hölscher, Arnulf H., Lang, Hauke, Grimminger, Peter P., Dakkak, Dani, Vashist, Yogesh, May, Sandra, Görg, Siegfried, Franke, Andre, Ellinghaus, David, Galavotti, Sara, Veits, Lothar, Weismüller, Josef, Dommermuth, Jens, Benner, Udo, Rösch, Thomas, Messmann, Helmut, Schumacher, Brigitte, Neuhaus, Horst, Schmidt, Carsten, Wissinowski, Thaddäus T., Nöthen, Markus M., Dong, Jing, Ong, Jue-Sheng, Buas, Matthew F., Thrift, Aaron P., Vaughan, Thomas L., Tomlinson, Ian, Whiteman, David C., Fitzgerald, Rebecca Claire, Jankowski, Janusz, Vieth, Michael, Mayr, Andreas, Gharahkhani, Puya, MacGregor, Stuart, Gockel, Ines, Palles, Claire, Schumacher, Johannes, Prenen, Hans, Wellcome Trust Case Control Consortium 2 (WTCCC2), Esophageal Adenocarcinoma Genetics Consortium (EAGLE), Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), Wellcome Trust Case Control Consortium 2 (WTCCC2), Esophageal Adenocarcinoma Genetics Consortium (EAGLE), and Barrett's and Esophageal Adenocarcinoma Consortium (BEACON)
Subjects: Gastroenterology, Human medicine, Biology
Abstract: ObjectiveOesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett’s oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling.DesignWe combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis.ResultsThe GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models.ConclusionOur findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.
Published: 2023

13. Common DNA Markers Can Account for More Than Half of the Genetic Influence on Cognitive Abilities

Author: Wellcome Trust Case Control Consortium 2, Plomin, Robert, Haworth, Claire M. A., Meaburn, Emma L., Price, Thomas S., and Davis, Oliver S. P.
Published: 2013
Full Text: View/download PDF

14. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Author: Diagnostiek & Vroege Psychose Medisch, Brain, Onderzoeksgroep 11, Onderzoek Bob Oranje, Hersenen-Medisch 1, Wellcome Trust Case Control Consortium 2, Diagnostiek & Vroege Psychose Medisch, Brain, Onderzoeksgroep 11, Onderzoek Bob Oranje, Hersenen-Medisch 1, and Wellcome Trust Case Control Consortium 2
Published: 2021

15. Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database.

Author: Christina M Lill, Johannes T Roehr, Matthew B McQueen, Fotini K Kavvoura, Sachin Bagade, Brit-Maren M Schjeide, Leif M Schjeide, Esther Meissner, Ute Zauft, Nicole C Allen, Tian Liu, Marcel Schilling, Kari J Anderson, Gary Beecham, Daniela Berg, Joanna M Biernacka, Alexis Brice, Anita L DeStefano, Chuong B Do, Nicholas Eriksson, Stewart A Factor, Matthew J Farrer, Tatiana Foroud, Thomas Gasser, Taye Hamza, John A Hardy, Peter Heutink, Erin M Hill-Burns, Christine Klein, Jeanne C Latourelle, Demetrius M Maraganore, Eden R Martin, Maria Martinez, Richard H Myers, Michael A Nalls, Nathan Pankratz, Haydeh Payami, Wataru Satake, William K Scott, Manu Sharma, Andrew B Singleton, Kari Stefansson, Tatsushi Toda, Joyce Y Tung, Jeffery Vance, Nick W Wood, Cyrus P Zabetian, andMe Genetic Epidemiology of Parkinson's Disease Consortium, International Parkinson's Disease Genomics Consortium, Parkinson's Disease GWAS Consortium, Wellcome Trust Case Control Consortium 2), Peter Young, Rudolph E Tanzi, Muin J Khoury, Frauke Zipp, Hans Lehrach, John P A Ioannidis, and Lars Bertram
Subjects: Genetics, QH426-470
Abstract: More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 × 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3 × 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.
Published: 2012
Full Text: View/download PDF

16. Genome-wide association and functional follow-up reveals new loci for kidney function.

Author: Cristian Pattaro, Anna Köttgen, Alexander Teumer, Maija Garnaas, Carsten A Böger, Christian Fuchsberger, Matthias Olden, Ming-Huei Chen, Adrienne Tin, Daniel Taliun, Man Li, Xiaoyi Gao, Mathias Gorski, Qiong Yang, Claudia Hundertmark, Meredith C Foster, Conall M O'Seaghdha, Nicole Glazer, Aaron Isaacs, Ching-Ti Liu, Albert V Smith, Jeffrey R O'Connell, Maksim Struchalin, Toshiko Tanaka, Guo Li, Andrew D Johnson, Hinco J Gierman, Mary Feitosa, Shih-Jen Hwang, Elizabeth J Atkinson, Kurt Lohman, Marilyn C Cornelis, Åsa Johansson, Anke Tönjes, Abbas Dehghan, Vincent Chouraki, Elizabeth G Holliday, Rossella Sorice, Zoltan Kutalik, Terho Lehtimäki, Tõnu Esko, Harshal Deshmukh, Sheila Ulivi, Audrey Y Chu, Federico Murgia, Stella Trompet, Medea Imboden, Barbara Kollerits, Giorgio Pistis, CARDIoGRAM Consortium, ICBP Consortium, CARe Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Tamara B Harris, Lenore J Launer, Thor Aspelund, Gudny Eiriksdottir, Braxton D Mitchell, Eric Boerwinkle, Helena Schmidt, Margherita Cavalieri, Madhumathi Rao, Frank B Hu, Ayse Demirkan, Ben A Oostra, Mariza de Andrade, Stephen T Turner, Jingzhong Ding, Jeanette S Andrews, Barry I Freedman, Wolfgang Koenig, Thomas Illig, Angela Döring, H-Erich Wichmann, Ivana Kolcic, Tatijana Zemunik, Mladen Boban, Cosetta Minelli, Heather E Wheeler, Wilmar Igl, Ghazal Zaboli, Sarah H Wild, Alan F Wright, Harry Campbell, David Ellinghaus, Ute Nöthlings, Gunnar Jacobs, Reiner Biffar, Karlhans Endlich, Florian Ernst, Georg Homuth, Heyo K Kroemer, Matthias Nauck, Sylvia Stracke, Uwe Völker, Henry Völzke, Peter Kovacs, Michael Stumvoll, Reedik Mägi, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Yurii S Aulchenko, Ozren Polasek, Nick Hastie, Veronique Vitart, Catherine Helmer, Jie Jin Wang, Daniela Ruggiero, Sven Bergmann, Mika Kähönen, Jorma Viikari, Tiit Nikopensius, Michael Province, Shamika Ketkar, Helen Colhoun, Alex Doney, Antonietta Robino, Franco Giulianini, Bernhard K Krämer, Laura Portas, Ian Ford, Brendan M Buckley, Martin Adam, Gian-Andri Thun, Bernhard Paulweber, Margot Haun, Cinzia Sala, Marie Metzger, Paul Mitchell, Marina Ciullo, Stuart K Kim, Peter Vollenweider, Olli Raitakari, Andres Metspalu, Colin Palmer, Paolo Gasparini, Mario Pirastu, J Wouter Jukema, Nicole M Probst-Hensch, Florian Kronenberg, Daniela Toniolo, Vilmundur Gudnason, Alan R Shuldiner, Josef Coresh, Reinhold Schmidt, Luigi Ferrucci, David S Siscovick, Cornelia M van Duijn, Ingrid Borecki, Sharon L R Kardia, Yongmei Liu, Gary C Curhan, Igor Rudan, Ulf Gyllensten, James F Wilson, Andre Franke, Peter P Pramstaller, Rainer Rettig, Inga Prokopenko, Jacqueline C M Witteman, Caroline Hayward, Paul Ridker, Afshin Parsa, Murielle Bochud, Iris M Heid, Wolfram Goessling, Daniel I Chasman, W H Linda Kao, and Caroline S Fox
Subjects: Genetics, QH426-470
Abstract: Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
Published: 2012
Full Text: View/download PDF

17. A two-stage meta-analysis identifies several new loci for Parkinson's disease.

Author: International Parkinson's Disease Genomics Consortium (IPDGC) and Wellcome Trust Case Control Consortium 2 (WTCCC2)
Subjects: Genetics, QH426-470
Abstract: A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p
Published: 2011
Full Text: View/download PDF

18. Complement genes contribute sex-biased vulnerability in diverse disorders

Author: Schizophrenia Working Group of the Psychiatric Genomics Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case–Control Consortium 2, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Psychosis Endophenotypes International Consortium, and Wellcome Trust Case–Control Consortium 2
Abstract: Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3–6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a sour
Published: 2020
Full Text: View/download PDF

19. Complement genes contribute sex-biased vulnerability in diverse disorders

Author: Onderzoek, Brain, Onderzoeksgroep 11, Beeldverwerking ISI, Hersenen-Medisch 1, Hersenen-Bedrijfsvoering, Infectieziekten onderzoek1 (Bont), Infection & Immunity, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, Psychosis Endophenotype International Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Onderzoek, Brain, Onderzoeksgroep 11, Beeldverwerking ISI, Hersenen-Medisch 1, Hersenen-Bedrijfsvoering, Infectieziekten onderzoek1 (Bont), Infection & Immunity, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, Psychosis Endophenotype International Consortium, and Schizophrenia Working Group of the Psychiatric Genomics Consortium
Published: 2020

20. A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes

Author: Meng, Weihua, Shah, Kaanan P, Pollack, Samuela, Toppila, Iiro, Hebert, Harry L, McCarthy, Mark I, Groop, Leif, Ahlqvist, Emma, Lyssenko, Valeriya, Agardh, Elisabet, Daniell, Mark, Kaidonis, Georgia, Craig, Jamie E, Mitchell, Paul, Liew, Gerald, Kifley, Annette, Wang, Jie Jin, Christiansen, Mark W, Jensen, Richard A, Penman, Alan, Hancock, Heather A, Chen, Ching J, Correa, Adolfo, Kuo, Jane Z, Li, Xiaohui, Chen, Yii-der I, Rotter, Jerome I, Klein, Ronald, Klein, Barbara, Wong, Tien Y, Morris, Andrew D, Doney, Alexander SF, Colhoun, Helen M, Price, Alkes L, Burdon, Kathryn P, Groop, Per-Henrik, Sandholm, Niina, Grassi, Michael A, Sobrin, Lucia, Palmer, Colin NA, and Wellcome Trust Case Control Consortium 2 (WTCCC2), Surrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) study group
Subjects: Adult, Male, Genotyping Techniques, Clinical Sciences, Eye, Ophthalmology & Optometry, White People, NOX4, Opthalmology and Optometry, Diabetes Mellitus, diabetic complications, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Eye Disease and Disorders of Vision, Metabolic and endocrine, Diabetic Retinopathy, Laser Coagulation, genome-wide association study, diabetes, Diabetes, Neurosciences, Single Nucleotide, Middle Aged, Surrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) study group, diabetic retinopathy, Wellcome Trust Case Control Consortium 2 (WTCCC2), Scotland, NADPH Oxidase 4, Female, Type 2, Genome-Wide Association Study
Abstract: PurposeDiabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.MethodsA genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Schemeor who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts.ResultsFive hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05×10-9 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values=7.41×10-8 and 1.23×10-8 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p=0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p=0.429).ConclusionThis genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.
Published: 2018

21. Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Author: Wellcome Trust Case Control Consortium 2, Schizophrenia Working Group of the Psychiatric Genomics Consorti, Wellcome Trust Case Control Consortium 2, and Schizophrenia Working Group of the Psychiatric Genomics Consorti
Abstract: Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.
Published: 2019

22. Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia.

Author: Harold, Denise, Harold, Denise, Connolly, Siobhan, Riley, Brien P, Kendler, Kenneth S, McCarthy, Shane E, McCombie, William R, Richards, Alex, Owen, Michael J, O'Donovan, Michael C, Walters, James, Wellcome Trust Case Control Consortium 2, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Donohoe, Gary, Gill, Michael, Corvin, Aiden, Morris, Derek W, Harold, Denise, Harold, Denise, Connolly, Siobhan, Riley, Brien P, Kendler, Kenneth S, McCarthy, Shane E, McCombie, William R, Richards, Alex, Owen, Michael J, O'Donovan, Michael C, Walters, James, Wellcome Trust Case Control Consortium 2, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Donohoe, Gary, Gill, Michael, Corvin, Aiden, and Morris, Derek W
Abstract: Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.
Published: 2019

23. Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders

Author: Calafato, MS, Thygesen, JH, Ranlund, S, Zartaloudi, E, Cahn, W, Crespo-Facorro, B, Díez-Revuelta, Á, Di Forti, M, Consortium, Genetic Risk And Outcome Of Psychosis (Group), Hall, M-H, Iyegbe, C, Jablensky, A, Kahn, R, Kalaydjieva, L, Kravariti, E, Lin, K, McDonald, C, McIntosh, AM, McQuillin, A, (PEIC), Psychosis Endophenotypes International Consortium, Picchioni, M, Rujescu, D, Shaikh, M, Toulopoulou, T, Os, JV, Vassos, E, Walshe, M, Powell, J, Lewis, CM, Murray, RM, Bramon, E, (WTCCC2), Wellcome Trust Case Control Consortium 2, Toulopoulou, Timothea, Genetic Risk and Outcome of Psychosis (GROUP) consortium, Psychosis Endophenotypes International Consortium (PEIC), Universidad de Cantabria, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), and Psychiatrie & Neuropsychologie
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, LOCI, polygenic, Disease, FAMILY-HISTORY, DISEASE, 0302 clinical medicine, Risk Factors, psychotic disorders, EMERGING MOLECULAR ARCHITECTURE, Family history, POPULATION, education.field_of_study, Psychotic disorders, PSYCHIATRIC-DISORDERS, Middle Aged, 3. Good health, Europe, Psychiatry and Mental health, polygenic risk scores, Schizophrenia, Female, CLINICAL-IMPLICATIONS, Risk assessment, Adult, Psychosis, medicine.medical_specialty, Bipolar disorder, Population, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, mental disorders, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, GXE RESEARCH, GENOME-WIDE ASSOCIATION, education, Psychiatry, business.industry, Australia, prediction, medicine.disease, schizophrenia, Polygenic risk scores, 030104 developmental biology, Logistic Models, Case-Control Studies, Polygenic, business, ROC CURVE, Prediction, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: BACKGROUND: There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.AimsTo investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls. METHOD: Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls. RESULTS: Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest. CONCLUSIONS: Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interestR.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian. Funding: This work was funded by the Medical Research Council (G0901310), the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z), the European Union’s Seventh Framework Programme for research, technological development and demonstration (grant 602450). This study was also supported by the NIHR Biomedical Research Centre at University College London (mental health theme) and by the NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry – Kings College London. Further support: NHIR Academic Clinical fellowship awarded to M.S.C.. E.B. acknowledges research funding from: BMA Margaret Temple grants 2016 and 2006, MRC – Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation’s NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry Kings College London. The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to C.I.). The BMA Margaret Temple grant 2016 to J. H.T. European Research Council Marie Curie award to A.D.-R. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental healthcare organisations. Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en de kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan Zorggroep, Prins Clauscentrum Sittard, RIAGG Roermond, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Groningen: University Medical Center Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psychomedical center (The Hague). Utrecht: University Medical Center Utrecht and the mental health institutions Altrecht, GGZ Centraal, Riagg Amersfoort and Delta. The sample from Spain was collected at the Hospital Universitario Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Carlos III Health Institute PI020499, PI050427, PI060507, Plan Nacional de Drugs Research Grant 2005- Orden sco/3246/2004, SENY Fundació Research Grant CI 2005-0308007 and Fundación Marqués de Valdecilla API07/011. The present data were obtained at the Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: MINECO Exp.: SAF2013-46292-R.
Published: 2018
Full Text: View/download PDF

24. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Author: Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Barrett's And Esophageal Adenocarcinoma Consortium (BEACON), Esophageal Adenocarcinoma GenEtics Consortium (EAGLE), Wellcome Trust Case Control Consortium 2 (WTCCC2), Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, De Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert HM, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, Schumacher, Johannes, Fitzgerald, Rebecca [0000-0002-3434-3568], Caldas, Carlos [0000-0003-3547-1489], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Risk, Barrett Esophagus, Esophageal Neoplasms, Humans, Adenocarcinoma, Polymorphism, Single Nucleotide, digestive system diseases, Genome-Wide Association Study
Abstract: BACKGROUND: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p
Published: 2016

25. Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children

Author: Kenyan Bacteraemia Study Group, Wellcome Trust Case Control Consortium 2 (WTCCC2), Rautanen, Anna, Pirinen, Matti, Mills, Tara C, Rockett, Kirk A, Strange, Amy, Ndungu, Anne W, Naranbhai, Vivek, Gilchrist, James J, Bellenguez, Céline, Freeman, Colin, Band, Gavin, Bumpstead, Suzannah J, Edkins, Sarah, Giannoulatou, Eleni, Gray, Emma, Dronov, Serge, Hunt, Sarah E, Langford, Cordelia, Pearson, Richard D, Su, Zhan, Vukcevic, Damjan, Macharia, Alex W, Uyoga, Sophie, Ndila, Carolyne, Mturi, Neema, Njuguna, Patricia, Mohammed, Shebe, Berkley, James A, Mwangi, Isaiah, Mwarumba, Salim, Kitsao, Barnes S, Lowe, Brett S, Morpeth, Susan C, Khandwalla, Iqbal, Kilifi Bacteraemia Surveillance Group, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Deloukas, Panos, Peltonen, Leena, Williams, Thomas N, Scott, J Anthony G, Chapman, Stephen J, Donnelly, Peter, Hill, Adrian VS, Spencer, Chris CA, Markus, Hugh [0000-0002-9794-5996], Sawcer, Stephen [0000-0001-7685-0974], and Apollo - University of Cambridge Repository
Subjects: Polymorphism, Genetic, Adolescent, Infant, Newborn, Infant, Bacteremia, Pneumonia, Pneumococcal, Kenya, Streptococcus pneumoniae, Risk Factors, Case-Control Studies, Child, Preschool, parasitic diseases, Humans, RNA, Long Noncoding, Child, Genome-Wide Association Study
Abstract: Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10(-9); OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.
Published: 2016

26. Low-frequency and common genetic variation in ischemic stroke : the METASTROKE collaboration

Author: Malik, R., Traylor, M., Pulit, S.L., Bevan, S., Hopewell, J.C., Holliday, E.G., Zhao, W., Abrantes, P., Amouyel, P., Attia, J.R., Battey, T.W., Berger, K., Boncoraglio, G.B., Chauhan, G., Cheng, Y.C., Chen, W.M., Clarke, R., Cotlarciuc, I., Debette, S., Falcone, G.J., Ferro, J.M., Gamble, D.M., Ilinca, A., Kittner, S.J., Kourkoulis, C.E., Lemmens, R., Levi, C.R., Lichtner, P., Lindgren, A., Liu, J., Meschia, J.F., Mitchell, B.D., Oliveira, S.A., Pera, J., Reiner, A.P., Rothwell, P.M., Sharma, P., Slowik, A., Sudlow, C.L., Tatlisumak, T., Thijs, V., Vicente, A.M., Woo, D., Seshadri, S., Saleheen, D., Rosand, J., Markus, H.S., Worrall, B.B., Dichgans, M., ISGC Analysis Group, METASTROKE collaboration, Wellcome Trust Case Control Consortium 2 (WTCCC2), and NINDS Stroke Genetics Network (SiGN)
Subjects: 0301 basic medicine, medicine.medical_specialty, Genome-wide association study, Polymorphism, Single Nucleotide, Gastroenterology, Article, Brain Ischemia, Doenças Cardio e Cérebro-vasculares, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, Internal medicine, ABO blood group system, Genetic variation, Humans, Medicine, Cooperative Behavior, 1000 Genomes Project, Allele frequency, Stroke, Ischemic Stroke, Genetic association, Genetics, business.industry, Genetic Variation, Correction, medicine.disease, 030104 developmental biology, Case-Control Studies, Ischemic stroke, Cardiology, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Erratum in: Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration. [Neurology. 2016] Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p , 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency ,5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p , 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.
Published: 2016

27. Serum iron levels and the risk of Parkinson Disease: a Mendelian randomization study

Author: Pichler I, Del Greco M. F, Gögele M, Lill CM, Bertram L, Do CB, Eriksson N, Foroud T, Myers RH, PD GWAS Consortium, Nalls M, Keller MF, International Parkinson's Disease Genomics Consortium, Wellcome Trust Case Control Consortium 2, Benyamin B, Whitfield JB, Genetics of Iron Status Consortium, Pramstaller PP, Hicks AA, Thompson JR, Minelli C., Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simón Sánchez J, Schulte C, Lesage S, Arepalli S, Barker R, Ben Shlomo Y, Berendse HW, Berg D, Bhatia K, de Bie RM, Biffi A, Bloem B, Bochdanovits Z, Bonin M, Bras JM, Brockmann K, Brooks J, Burn DJ, Charlesworth G, Chen H, Chinnery PF, Chong S, Clarke CE, Cookson MR, Cooper JM, Corvol JC, Counsell C, Damier P, Dartigues JF, Deloukas P, Deuschl G, Dexter DT, van Dijk KD, Dillman A, Durif F, Dürr A, Edkins S, Evans JR, Foltynie T, Gao J, Gardner M, Gibbs JR, Goate A, Gray E, Guerreiro R, Harris C, van Hilten JJ, Hofman A, Hollenbeck A, Holton J, Hu M, Huang X, Huber H, Hudson G, Hunt SE, Illig T, Lambert JC, Langford C, Lees A, Lichtner P, Limousin P, Lopez G, Lorenz D, McNeill A, Moorby C, Moore M, Morris HR, Morrison KE, Mudanohwo E, O'Sullivan SS, Pearson J, Perlmutter JS, Pollak P, Post B, Potter S, Ravina B, Revesz T, Riess O, Rivadeneira F, Rizzu P, Ryten M, Sawcer S, Schapira A, Scheffer H, Shaw K, Shoulson I, Sidransky E, Smith C, Spencer CC, Stockton JD, Strange A, Talbot K, Tanner CM, Tashakkori Ghanbaria A, Trabzuni D, Traynor BJ, Uitterlinden AG, Velseboer D, Vidailhet M, Walker R, van de Warrenburg B, Wickremaratchi M, Williams N, Williams Gray CH, Winder Rhodes S, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW, Donnelly P, Barroso I, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Duncanson A, Jankowski J, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Band G, Bellenguez C, Freeman C, Hellenthal G, Giannoulatou E, Pirinen M, Pearson R, Su Z, Vukcevic D, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Hammond N, Jayakumar A, McCann OT, Liddle J, Potter SC, Ravindrarajah R, Ricketts M, Waller M, Weston P, Widaa S, Whittaker P, McCarthy MI, Ouwehand WH, Radhakrishnan A, Sambrook J, Toniolo D, Camaschella C, Metspalu A, Esko T, Gieger C, Ried J, Meitinger T, Oexle K, Winkelmann J, Swinkels D, Vermeulen S, van Duijn C, Broer L, Beilby J, Hui J, Anderson D, Visscher P, Martin N., TRAGLIA, MICHELA, Pichler, Irene, Del Greco M, Fabiola, Gögele, Martin, Lill, Christina M, Benyamin, Beben, Minelli, Cosetta, PD GWAS Consortium, International Parkinson’s Disease Genomics Consortium, Wellcome Trust Case Control Consortium, Genetics of Iron Status Consortium, Pollak, Pierre, Functional Genomics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Human genetics, NCA - Brain mechanisms in health and disease, ANS - Amsterdam Neuroscience, Neurology, Graduate School, Pichler, I, Del Greco M., F, Gögele, M, Lill, Cm, Bertram, L, Do, Cb, Eriksson, N, Foroud, T, Myers, Rh, PD GWAS, Consortium, Nalls, M, Keller, Mf, International Parkinson's Disease Genomics, Consortium, Wellcome Trust Case Control Consortium, 2, Benyamin, B, Whitfield, Jb, Genetics of Iron Status, Consortium, Pramstaller, Pp, Hicks, Aa, Thompson, Jr, Minelli, C., Plagnol, V, Hernandez, Dg, Sharma, M, Sheerin, Um, Saad, M, Simón Sánchez, J, Schulte, C, Lesage, S, Arepalli, S, Barker, R, Ben Shlomo, Y, Berendse, Hw, Berg, D, Bhatia, K, de Bie, Rm, Biffi, A, Bloem, B, Bochdanovits, Z, Bonin, M, Bras, Jm, Brockmann, K, Brooks, J, Burn, Dj, Charlesworth, G, Chen, H, Chinnery, Pf, Chong, S, Clarke, Ce, Cookson, Mr, Cooper, Jm, Corvol, Jc, Counsell, C, Damier, P, Dartigues, Jf, Deloukas, P, Deuschl, G, Dexter, Dt, van Dijk, Kd, Dillman, A, Durif, F, Dürr, A, Edkins, S, Evans, Jr, Foltynie, T, Gao, J, Gardner, M, Gibbs, Jr, Goate, A, Gray, E, Guerreiro, R, Harris, C, van Hilten, Jj, Hofman, A, Hollenbeck, A, Holton, J, Hu, M, Huang, X, Huber, H, Hudson, G, Hunt, Se, Illig, T, Lambert, Jc, Langford, C, Lees, A, Lichtner, P, Limousin, P, Lopez, G, Lorenz, D, Mcneill, A, Moorby, C, Moore, M, Morris, Hr, Morrison, Ke, Mudanohwo, E, O'Sullivan, S, Pearson, J, Perlmutter, J, Pollak, P, Post, B, Potter, S, Ravina, B, Revesz, T, Riess, O, Rivadeneira, F, Rizzu, P, Ryten, M, Sawcer, S, Schapira, A, Scheffer, H, Shaw, K, Shoulson, I, Sidransky, E, Smith, C, Spencer, Cc, Stockton, Jd, Strange, A, Talbot, K, Tanner, Cm, Tashakkori Ghanbaria, A, Trabzuni, D, Traynor, Bj, Uitterlinden, Ag, Velseboer, D, Vidailhet, M, Walker, R, van de Warrenburg, B, Wickremaratchi, M, Williams, N, Williams Gray, Ch, Winder Rhodes, S, Martinez, M, Hardy, J, Heutink, P, Brice, A, Gasser, T, Singleton, Ab, Wood, Nw, Donnelly, P, Barroso, I, Blackwell, Jm, Bramon, E, Brown, Ma, Casas, Jp, Corvin, A, Duncanson, A, Jankowski, J, Markus, H, Mathew, Cg, Palmer, Cn, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Su, Z, Vukcevic, D, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Mccarthy, Mi, Ouwehand, Wh, Radhakrishnan, A, Sambrook, J, Toniolo, D, Traglia, Michela, Camaschella, C, Metspalu, A, Esko, T, Gieger, C, Ried, J, Meitinger, T, Oexle, K, Winkelmann, J, Swinkels, D, Vermeulen, S, van Duijn, C, Broer, L, Beilby, J, Hui, J, Anderson, D, Visscher, P, and Martin, N.
Subjects: Relative risk reduction, Iron, Mendelian randomization analysis, Physiology, Genome-wide association study, Biology, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, SDG 17 - Partnerships for the Goals, Risk Factors, Mendelian randomization, medicine, Humans, Genetic Predisposition to Disease, Iron/blood, Genetic Association Studies, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, Parkinson Disease/blood/genetics, Confounding, Parkinson Disease, Mendelian Randomization Analysis, General Medicine, Iron metabolism, 3. Good health, ddc:616.8, Parkinson disease, Meta-analysis, Hereditary hemochromatosis, Serum iron, Medicine, 030217 neurology & neurosurgery, Research Article
Abstract: In this study, Mendelian randomization was used to study genes known to modify iron levels, and the effect of iron on Parkinson's disease (PD) risk was estimated. Based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date, the findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson's disease for every 10 µg/dL increase in iron. The results of this analysis have potentially important implications for future research into the prevention of Parkinson's disease. Please see later in the article for the Editors' Summary, Background Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. Methods and Findings We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%–6%; p = 0.001) per 10 µg/dl increase in serum iron. Conclusions Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made. Please see later in the article for the Editors' Summary, Editors' Summary Background Parkinson disease is a degenerative disorder of the central nervous system caused by the death of dopamine-generating cells in the substania nigra, a region of the midbrain. The earliest symptoms are usually movement-related and include tremor, slow movements, and difficulty walking, and later cognitive and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease. Parkinson disease affects around ten million people world-wide and incidence increases with age, with men more affected than women. To date, the causes of Parkinson disease remain unknown although a combination of genetic and environmental factors is thought to play a role. Identifying possible modifiable risks is an important step in the possible prevention of Parkinson disease. Why Was This Study Done? Previous studies have shown a possible association between lower blood levels of iron in people with Parkinson disease compared with controls, although the quality of these studies makes this finding difficult to interpret. So in this study, the researchers used a mendelian randomization approach to investigate whether there was any evidence of an effect of blood iron levels on the risk of Parkinson disease and if so to further explore the direction and scale of any link. Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in situations where it is inappropriate to perform a randomized controlled trial. What Did the Researchers Do and Find? The researchers estimated the effect of blood iron levels on the risk of Parkinson disease using three polymorphisms in two genes, HFE and TMPRSS6. For each polymorphism, they performed a meta-analysis combining the results of studies investigating the genetic effect on iron levels, which included almost 22,000 people from Europe and Australia, and a meta-analysis of studies investigating the genetic effect on the risk of Parkinson disease, which included a total of 20,809 people with Parkinson disease and 88,892 controls from Europe and North America. They then performed three separate mendelian randomization analyses to estimate the effect of iron on Parkinson disease for the three polymorphisms. By combining the three estimates, they obtained a statistically significant odds ratio of 0.97 for Parkinson disease per 10 µg/dl increase in iron, corresponding to a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in blood iron. Since genotype influences on blood iron levels represent differences that generally persist throughout adult life, the combined mendelian randomization estimate reflects an effect of iron over the course of a lifetime. What Do These Findings Mean? These findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in iron. This finding is important as it suggests that increased blood iron levels may have a protective effect against Parkinson disease, although the underlying mechanism remains unclear. Furthermore, although mendelian randomization is an increasingly used approach to address the issue of classical confounding, there may be remaining confounding factors specific of mendelian randomization that may influence the interpretation of this study. Nevertheless, the results of this analysis have potentially important implications for future research into the prevention of Parkinson disease. Further studies on the underlying mechanisms are needed before any specific treatment recommendations can be proposed. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001462. The National Institutes of Neurological Disorder and Stroke, MedlinePlus, and NHS Choices have several pages with comprehensive information on Parkinson disease Wikipedia gives an explanation of mendelian randomization (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Published: 2013
Full Text: View/download PDF

28. Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Author: Ripke, S, O'Dushlaine, C, Chambert, K, Moran, Jl, Kähler, Ak, Akterin, S, Bergen, Se, Collins, Al, Crowley, Jj, Fromer, M, Kim, Y, Lee, Sh, Magnusson, Pk, Sanchez, N, Stahl, Ea, Williams, S, Wray, Nr, Xia, K, Bettella, F, Borglum, Ad, Bulik Sullivan, Bk, Cormican, P, Craddock, N, Leeuw, De, C, Durmishi, N, Gill, M, Golimbet, V, Hamshere, Ml, Holmans, P, Hougaard, Dm, Kendler, Ks, Lin, K, Morris, Dw, Mors, O, Mortensen, Pb, Neale, Bm, O'Neill, Fa, Owen, Mj, Milovancevic, Mp, Posthuma, D, Powell, J, Richards, Al, Riley, Bp, Ruderfer, D, Rujescu, D, Sigurdsson, E, Silagadze, T, Smit, Ab, Stefansson, H, Steinberg, S, Suvisaari, J, Tosato, Sarah, Verhage, M, Walters, Jt, Multicenter Genetic Studies of Schizophrenia Consortium, Levinson, Df, Gejman, Pv, Laurent, C, Mowry, Bj, O'Donovan, Mc, Pulver, Ae, Schwab, Sg, Wildenauer, Db, Dudbridge, F, Shi, J, Albus, M, Alexander, M, Campion, D, Cohen, D, Dikeos, D, Duan, J, Eichhammer, P, Godard, S, Hansen, M, Lerer, Fb, Liang, Ky, Maier, W, Mallet, J, Nertney, Da, Nestadt, G, Norton, N, Papadimitriou, Gn, Ribble, R, Sanders, Ar, Silverman, Jm, Walsh, D, Williams, Nm, Wormley, B, Psychosis Endophenotypes International Consortium, Arranz, Mj, Bakker, S, Bender, S, Bramon, E, Collier, D, Crespo Facorro, B, Hall, J, Iyegbe, C, Jablensky, A, Kahn, Rs, Kalaydjieva, L, Lawrie, S, Lewis, Cm, Linszen, Dh, Mata, I, Mcintosh, A, Murray, Rm, Ophoff, Ra, Van, Os, J, Walshe, M, Weisbrod, M, Wiersma, D, Wellcome Trust Case Control Consortium 2, Donnelly, P, Barroso, I, Blackwell, Jm, Brown, Ma, Casas, Jp, Corvin, Ap, Deloukas, P, Duncanson, A, Jankowski, J, Markus, Hs, Mathew, Cg, Palmer, Cn, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cc, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, Rd, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, Se, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Tashakkori Ghanbaria, A, Waller, Mj, Weston, P, Widaa, S, Whittaker, P, Mccarthy, Mi, Stefansson, K, Scolnick, E, Purcell, S, Mccarroll, Sa, Sklar, P, Hultman, Cm, Sullivan, P. F., Functional Genomics, Molecular and Cellular Neurobiology, AIMMS, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Adult Psychiatry, Ripke, Stephan, O'Dushlaine, Colm, Chambert, Kimberly, Moran, Jennifer L, Lee, Sang Hong, Sullivan, Patrick F, Multicenter Genetic Studies of Schizophrenia Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY USA Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA deCODE Genet, Reykjavik, Iceland Aarhus Univ Hosp, Risskov, Denmark Aarhus Univ, Ctr Integrat Sequencing iSEQ, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Copenhagen, Denmark Univ Dublin Trinity Coll, Dept Psychiat, Dublin 2, Ireland Cardiff Univ, Sch Med, Ctr Psychiat Genet & Genom, MRC, Cardiff CF10 3AX, S Glam, Wales Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, Netherlands Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands Radboud Univ Nijmegen, Inst Comp & Informat Sci, NL-6525 ED Nijmegen, Netherlands Univ Clin Psychiat, Dept Child & Adolescent Psychiat, Skopje, Macedonia Univ Dublin Trinity Coll, Neuropsychiat Genet Res Grp, Dublin 2, Ireland Russian Acad Med Sci, Mental Hlth Res Ctr, Moscow 109801, Russia Statens Serum Inst, DK-2300 Copenhagen, Denmark Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA Kings Coll London, Inst Psychiat, London, England Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark Aarhus Univ, Natl Ctr Register Based Res, Aarhus, DenmarkQueens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland Univ Belgrade, Fac Med, Belgrade, Serbia Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands Kings Coll London, Dept Neurosci, London, England Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA USA Univ Halle, Dept Psychiat, Halle, Germany Univ Munich, Dept Psychiat, D-80539 Munich, Germany Univ Iceland, Dept Psychiat, Reykjavik, Iceland Landspitali University Hospital Reykjavik, Iceland Tbilisi State Univ, Dept Psychiat, GE-380086 Tbilisi, Rep of Georgia Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Amsterdam, Netherlands Vrije Univ Amsterdam, Dept Mol & Cellular Neurosci, Amsterdam, Netherlands Natl Inst Hlth & Welf, Mental Hlth & Subst Abuse Serv, Helsinki, Finland Univ Verona, Sect Psychiat, I-37100 Verona, Italy UCL, Inst Cognit Neurosci, London, England UCL, Mental Hlth Sci Unit, London, England Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA Harvard Univ, Sch Med, Dept Genet, Boston, MA USA, Child and Adolescent Psychiatry / Psychology, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Human genetics, NCA - Brain mechanisms in health and disease, and NCA - Neurobiology of mental health
Subjects: Male, Candidate gene, SNP, Single-nucleotide polymorphism, Genome-wide association study, Disease, Biology, heritability, neuronal calcium signaling, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genetics, medicine, Humans, GWAS, Genetic Predisposition to Disease, Bipolar disorder, 030304 developmental biology, Genetic association, Sweden, Genetics & Heredity, 0303 health sciences, medicine.disease, 3. Good health, genome sequencing, schizophrenia, Schizophrenia, Meta-analysis, Case-Control Studies, genetic variation, Female, genome-wide scan, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder. NIMH R01 MH077139 R01 MH095034 Stanley Center for Psychiatric Research Sylvan Herman Foundation Friedman Brain Institute at the Mount Sinai School of Medicine Karolinska Institutet, Karolinska University Hospital Swedish Research Council Swedish County Council Soderstrom Konigska Foundation Netherlands Scientific Organization NWO 645-000-003 info:eu-repo/grantAgreement/EC/FP7/223423 Danish Strategic Research Council H. Lundbeck A/S Faculty of Health Sciences at Aarhus University Lundbeck Foundation Stanley Research Foundation Wellcome Trust 085475/B/08/Z 085475/Z/08/Z
Published: 2013
Full Text: View/download PDF

29. Association of genetic markers with CSF oligoclonal bands in multiple sclerosis patients. PLoS One

Author: Leone MA, Barizzone N, Esposito F, Lucenti A, Harbo HF, Goris A, Kockum I, Oturai AB, Celius EG, Mero IL, Dubois B, Olsson T, Søndergaard HB, Cusi D, Lupoli S, Andreassen BK, International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Myhr KM, Guerini FR, PROGEMUS Group, PROGRESSO Group, Martinelli Boneschi F, D'Alfonso S., COMI , GIANCARLO, Leone, Ma, Barizzone, N, Esposito, F, Lucenti, A, Harbo, Hf, Goris, A, Kockum, I, Oturai, Ab, Celius, Eg, Mero, Il, Dubois, B, Olsson, T, Søndergaard, Hb, Cusi, D, Lupoli, S, Andreassen, Bk, International Multiple Sclerosis Genetics, Consortium, Wellcome Trust Case Control Consortium, 2, Myhr, Km, Guerini, Fr, Progemus, Group, Progresso, Group, Comi, Giancarlo, Martinelli Boneschi, F, and D'Alfonso, S.
Published: 2013

30. Comparison of methods to account for relatedness in genome-wide association studies with family-based data

Author: Jakris Eu-Ahsunthornwattana, E Nancy Miller, Michaela Fakiola, Wellcome Trust Case Control Consortium 2, Selma M B Jeronimo, Jenefer M Blackwell, and Heather J Cordell
Subjects: lcsh:Genetics, lcsh:QH426-470
Abstract: Approaches based on linear mixed models (LMMs) have recently gained popularity for modelling population substructure and relatedness in genome-wide association studies. In the last few years, a bewildering variety of different LMM methods/software packages have been developed, but it is not always clear how (or indeed whether) any newly-proposed method differs from previously-proposed implementations. Here we compare the performance of several LMM approaches (and software implementations, including EMMAX, GenABEL, FaST-LMM, Mendel, GEMMA and MMM) via their application to a genome-wide association study of visceral leishmaniasis in 348 Brazilian families comprising 3626 individuals (1972 genotyped). The implementations differ in precise details of methodology implemented and through various user-chosen options such as the method and number of SNPs used to estimate the kinship (relatedness) matrix. We investigate sensitivity to these choices and the success (or otherwise) of the approaches in controlling the overall genome-wide error-rate for both real and simulated phenotypes. We compare the LMM results to those obtained using traditional family-based association tests (based on transmission of alleles within pedigrees) and to alternative approaches implemented in the software packages MQLS, ROADTRIPS and MASTOR. We find strong concordance between the results from different LMM approaches, and all are successful in controlling the genome-wide error rate (except for some approaches when applied naively to longitudinal data with many repeated measures). We also find high correlation between LMMs and alternative approaches (apart from transmission-based approaches when applied to SNPs with small or non-existent effects). We conclude that LMM approaches perform well in comparison to competing approaches. Given their strong concordance, in most applications, the choice of precise LMM implementation cannot be based on power/type I error considerations but must instead be based on considerations such as speed and ease-of-use.
Published: 2014

31. Genome-wide association study of intraocular pressure identifies the GLCCI1/ICA1 region as a glaucoma susceptibility locus

Author: (BMES), Blue Mountains Eye Study, (WTCCC2), Wellcome Trust Case Control Consortium 2, Strange, A, Bellenguez, C, Freeman, C, Pirinen, M, Su, Z, Band, G, Pearson, R, Vukcevic, D, Rautanen, A, Spencer, C, and Donnelly, P
Subjects: genetic structures, sense organs, eye diseases
Abstract: To discover quantitative trait loci for intraocular pressure, a major risk factor for glaucoma and the only modifiable one, we performed a genome-wide association study on a discovery cohort of 2175 individuals from Sydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, P(combined) = 1.10 × 10(-8)). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30-0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.
Published: 2013

32. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error

Author: Cheng, Ching-Yu, Schache, Maria, Ikram, M Kamran, Young, Terri L, Guggenheim, Jeremy A, Vitart, Veronique, MacGregor, Stuart, Verhoeven, Virginie JM, Barathi, Veluchamy A, Liao, Jiemin, Hysi, Pirro G, Bailey-Wilson, Joan E, St Pourcain, Beate, Kemp, John P, McMahon, George, Timpson, Nicholas J, Evans, David M, Montgomery, Grant W, Mishra, Aniket, Wang, Ya Xing, Wang, Jie Jin, Rochtchina, Elena, Polasek, Ozren, Wright, Alan F, Amin, Najaf, van Leeuwen, Elisabeth M, Wilson, James F, Pennell, Craig E, van Duijn, Cornelia M, de Jong, Paulus TVM, Vingerling, Johannes R, Zhou, Xin, Chen, Peng, Li, Ruoying, Tay, Wan-Ting, Zheng, Yingfeng, Chew, Merwyn, Consortium for Refractive Error and Myopia, Burdon, Kathryn P, Craig, Jamie E, Iyengar, Sudha K, Igo, Robert P, Lass, Jonathan H, Fuchs' Genetics Multi-Center Study Group, Chew, Emily Y, Haller, Toomas, Mihailov, Evelin, Metspalu, Andres, Wedenoja, Juho, Simpson, Claire L, Wojciechowski, Robert, Höhn, René, Mirshahi, Alireza, Zeller, Tanja, Pfeiffer, Norbert, Lackner, Karl J, Wellcome Trust Case Control Consortium 2, Bettecken, Thomas, Meitinger, Thomas, Oexle, Konrad, Pirastu, Mario, Portas, Laura, Nag, Abhishek, Williams, Katie M, Yonova-Doing, Ekaterina, Klein, Ronald, Klein, Barbara E, Hosseini, S Mohsen, Paterson, Andrew D, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions, and Complications Research Group, Makela, Kari-Matti, Lehtimaki, Terho, Kahonen, Mika, Raitakari, Olli, Yoshimura, Nagahisa, Matsuda, Fumihiko, Chen, Li Jia, Pang, Chi Pui, Yip, Shea Ping, Yap, Maurice KH, Meguro, Akira, Mizuki, Nobuhisa, Inoko, Hidetoshi, Foster, Paul J, Zhao, Jing Hua, Vithana, Eranga, Tai, E-Shyong, Fan, Qiao, Xu, Liang, Campbell, Harry, Fleck, Brian, Rudan, Igor, Aung, Tin, Hofman, Albert, Uitterlinden, André G, Bencic, Goran, Khor, Chiea-Chuen, Forward, Hannah, Pärssinen, Olavi, and Mitchell, Paul
Subjects: Adult, Male, Adolescent, Gene Expression, Eye, Medical and Health Sciences, White People, Asian People, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Axial Length, Polymorphism, Aetiology, Eye Proteins, Eye Disease and Disorders of Vision, Aged, Genetics & Heredity, Consortium for Refractive Error and Myopia, Wellcome Trust Case Control Consortium 2, Human Genome, Single Nucleotide, Middle Aged, Biological Sciences, and Complications Research Group, Refractive Errors, Fuchs' Genetics Multi-Center Study Group, Genetic Loci, Female, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions, Signal Transduction, Genome-Wide Association Study
Abstract: Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.
Published: 2013

33. Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets

Author: Degenhardt, F., Priebe, L., Nenadic, I., Sauer, H., Mattheisen, M., Buizer-Voskamp, J., Ophoff, R. A., Consortium, GROUP, Rujescu, D., Giegling, I., Ingason, A., Wagner, M., Meier, S., Delobel, B., Andrieux, J., Meyer-Lindenberg, A., Heinz, A., Walter, H., Moebus, S., Corvin, A., Wellcome Trust Case Control Consortium 2, International Schizophrenia Consortium, Rietschel, M., Nöthen, M. M., Lennertz, L., Cichon, S., Kahn, René S, Linszen, Don H, van Os, Jim, Wiersma, Durk, Bruggeman, Richard, Cahn, Wiepke, de Haan, Lieuwe, Krabbendam, Lydia, Myin-Germeys, Inez, Streit, F., Witt, S. H., Hofmann, A., Becker, T., Mössner, R., Maier, W., Germeys, Inez, Adult Psychiatry, and ANS - Amsterdam Neuroscience
Subjects: Adult, Male, Candidate gene, Medizin, Autophagy-Related Proteins, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Polymorphism (computer science), Gene Duplication, Gene duplication, genetics [Protein-Tyrosine Kinases], Medicine, Humans, Genetic Predisposition to Disease, genetics [Schizophrenia], DGCR2, Copy-number variation, ddc:610, genetics [Genetic Predisposition to Disease], Gene, Biological Psychiatry, Exome sequencing, 030304 developmental biology, Aged, Genetics, 0303 health sciences, business.industry, genetics [Gene Duplication], RB1-inducible coiled-coil 1, Odds ratio, Middle Aged, Protein-Tyrosine Kinases, exome-sequencing, schizoaffective disorder, 3. Good health, Europe, Psychiatry and Mental health, intellectual disability, RB1CC1 protein, human, Behavioral medicine, Schizophrenia, Original Article, Female, business, 030217 neurology & neurosurgery
Abstract: Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ~80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10(-5); odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ. ispartof: Translational Psychiatry vol:3 issue:11 ispartof: location:United States status: published
Published: 2013
Full Text: View/download PDF

34. Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

Author: LeishGEN Consortium, Wellcome Trust Case Control Consortium 2, Fakiola, Michaela, Strange, Amy, Cordell, Heather J, Miller, E Nancy, Pirinen, Matti, Su, Zhan, Mishra, Anshuman, Mehrotra, Sanjana, Monteiro, Gloria R, Band, Gavin, Bellenguez, Céline, Dronov, Serge, Edkins, Sarah, Freeman, Colin, Giannoulatou, Eleni, Gray, Emma, Hunt, Sarah E, Lacerda, Henio G, Langford, Cordelia, Pearson, Richard, Pontes, Núbia N, Rai, Madhukar, Singh, Shri P, Smith, Linda, Sousa, Olivia, Vukcevic, Damjan, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Wilson, Mary E, Deloukas, Panos, Peltonen, Leena, Christiansen, Frank, Witt, Campbell, Jeronimo, Selma MB, Sundar, Shyam, Spencer, Chris CA, Blackwell, Jenefer M, and Donnelly, Peter
Abstract: To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P(combined) = 2.76 × 10(-17) and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.
Published: 2013

35. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Author: The Esophageal Adenocarcinoma Genetics Consortium and The Wellcome Trust Case Control Consortium 2
Subjects: digestive system diseases
Abstract: Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined = 4.09 × 10−9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13–1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined = 2.74 × 10−10; OR = 1.14, 95% CI = 1.10–1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
Published: 2012

36. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Author: International Stroke Genetics Consortium (ISGC), Wellcome Trust Case Control Consortium 2 (WTCCC2), Bellenguez, Céline, Bevan, Steve, Gschwendtner, Andreas, Spencer, Chris CA, Burgess, Annette I, Pirinen, Matti, Jackson, Caroline A, Traylor, Matthew, Strange, Amy, Su, Zhan, Band, Gavin, Syme, Paul D, Malik, Rainer, Pera, Joanna, Norrving, Bo, Lemmens, Robin, Freeman, Colin, Schanz, Renata, James, Tom, Poole, Deborah, Murphy, Lee, Segal, Helen, Cortellini, Lynelle, Cheng, Yu-Ching, Woo, Daniel, Nalls, Michael A, Müller-Myhsok, Bertram, Meisinger, Christa, Seedorf, Udo, Ross-Adams, Helen, Boonen, Steven, Wloch-Kopec, Dorota, Valant, Valerie, Slark, Julia, Furie, Karen, Delavaran, Hossein, Langford, Cordelia, Deloukas, Panos, Edkins, Sarah, Hunt, Sarah, Gray, Emma, Dronov, Serge, Peltonen, Leena, Gretarsdottir, Solveig, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Stefansson, Kari, Boncoraglio, Giorgio B, Parati, Eugenio A, Attia, John, Holliday, Elizabeth, Levi, Chris, Franzosi, Maria-Grazia, Goel, Anuj, Helgadottir, Anna, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Duncanson, Audrey, Jankowski, Janusz, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Worrall, Bradford B, Kittner, Steven J, Mitchell, Braxton D, Kissela, Brett, Meschia, James F, Thijs, Vincent, Lindgren, Arne, Macleod, Mary Joan, Slowik, Agnieszka, Walters, Matthew, Rosand, Jonathan, Sharma, Pankaj, Farrall, Martin, Sudlow, Cathie LM, Rothwell, Peter M, Dichgans, Martin, Donnelly, Peter, and Markus, Hugh S
Abstract: Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
Published: 2012

37. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Author: Evans, Dm, Spencer, Cc, Pointon, Jj, Su, Z, Harvey, D, Kochan, G, Oppermann, U, Dilthey, A, Pirinen, M, Stone, Ma, Appleton, L, Moutsianas, L, Leslie, S, Wordsworth, T, Kenna, Tj, Karaderi, T, Thomas, Gp, Ward, Mm, Weisman, Mh, Farrar, C, Bradbury, La, Danoy, P, Inman, Rd, Maksymowych, W, Gladman, D, Rahman, P, Spondyloarthritis Research Consortium of Canada, Morgan, A, Marzo Ortega, H, Bowness, P, Gaffney, K, Gaston, Js, Smith, M, Bruges Armas, J, Couto, Ar, Sorrentino, Rosa, Paladini, Fabiana, Ferreira, Ma, Xu, H, Liu, Y, Jiang, L, Lopez Larrea, C, Díaz Peña, R, López Vázquez, A, Zayats, T, Band, G, Bellenguez, C, Blackburn, H, Blackwell, Jm, Bramon, E, Bumpstead, Sj, Casas, Jp, Corvin, A, Craddock, N, Deloukas, P, Dronov, S, Duncanson, A, Edkins, S, Freeman, C, Gillman, M, Gray, E, Gwilliam, R, Hammond, N, Hunt, Se, Jankowski, J, Jayakumar, A, Langford, C, Liddle, J, Markus, Hs, Mathew, Cg, Mccann, Ot, Mccarthy, Mi, Palmer, Cn, Peltonen, L, Plomin, R, Potter, Sc, Rautanen, A, Ravindrarajah, R, Ricketts, M, Samani, N, Sawcer, Sj, Strange, A, Trembath, Rc, Viswanathan, Ac, Waller, M, Weston, P, Whittaker, P, Widaa, S, Wood, Nw, Mcvean, G, Reveille, Jd, Wordsworth, Bp, Brown, Ma, Donnelly, P, Australo Anglo American Spondyloarthritis Consortium, and Wellcome Trust Case Control Consortium, 2
Subjects: Receptors, Peptide, HLA-B27, ERAP1, ANKYLOSING SPONDYLITIS, Inflammatory arthritis, Population, Genome-wide association study, Human leukocyte antigen, Biology, CD8-Positive T-Lymphocytes, Bioinformatics, Aminopeptidases, White People, Minor Histocompatibility Antigens, Meta-Analysis as Topic, Genetics, medicine, Humans, Spondylitis, Ankylosing, education, Spondylitis, HLA-B27 Antigen, education.field_of_study, Ankylosing spondylitis, HLA-B27, Polymorphism, Genetic, Interleukin-12 Subunit p40, Membrane Proteins, medicine.disease, Endoplasmic reticulum aminopeptidase 2, Peptide Fragments, CARD Signaling Adaptor Proteins, Core Binding Factor Alpha 3 Subunit, Latent TGF-beta Binding Proteins, Receptors, Tumor Necrosis Factor, Type I, Case-Control Studies, Immunology, Disease Susceptibility, Receptors, Prostaglandin E, EP4 Subtype, Genome-Wide Association Study
Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
Published: 2011

38. Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21

Author: UK Parkinson's Disease Consortium, Wellcome Trust Case Control Consortium 2, Spencer, Chris CA, Plagnol, Vincent, Strange, Amy, Gardner, Michelle, Paisan-Ruiz, Coro, Band, Gavin, Barker, Roger A, Bellenguez, Celine, Bhatia, Kailash, Blackburn, Hannah, Blackwell, Jennie M, Bramon, Elvira, Brown, Martin A, Brown, Matthew A, Burn, David, Casas, Juan-Pablo, Chinnery, Patrick F, Clarke, Carl E, Corvin, Aiden, Craddock, Nicholas, Deloukas, Panos, Edkins, Sarah, Evans, Jonathan, Freeman, Colin, Gray, Emma, Hardy, John, Hudson, Gavin, Hunt, Sarah, Jankowski, Janusz, Langford, Cordelia, Lees, Andrew J, Markus, Hugh S, Mathew, Christopher G, McCarthy, Mark I, Morrison, Karen E, Palmer, Colin NA, Pearson, Justin P, Peltonen, Leena, Pirinen, Matti, Plomin, Robert, Potter, Simon, Rautanen, Anna, Sawcer, Stephen J, Su, Zhan, Trembath, Richard C, Viswanathan, Ananth C, Williams, Nigel W, Morris, Huw R, Donnelly, Peter, and Wood, Nicholas W
Abstract: We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P< 10(-4)). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P< 10(-10)) and found evidence for an additional independent association in 4q22/SNCA. A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease.
Published: 2011

39. An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.

Author: Morris, DW, Pearson, RD, Cormican, P, Kenny, EM, O'Dushlaine, CT, Perreault, L-PL, Giannoulatou, E, Tropea, D, Maher, BS, Wormley, B, Kelleher, E, Fahey, C, Molinos, I, Bellini, S, Pirinen, M, Strange, A, Freeman, C, Thiselton, DL, Elves, RL, Regan, R, Ennis, S, Dinan, TG, McDonald, C, Murphy, KC, O'Callaghan, E, Waddington, JL, Walsh, D, O'Donovan, M, Grozeva, D, Craddock, N, Stone, J, Scolnick, E, Purcell, S, Sklar, P, Coe, B, Eichler, EE, Ophoff, R, Buizer, J, Szatkiewicz, J, Hultman, C, Sullivan, P, Gurling, H, Mcquillin, A, St Clair, D, Rees, E, Kirov, G, Walters, J, Blackwood, D, Johnstone, M, Donohoe, G, International Schizophrenia Consortium, SGENE+ Consortium, O'Neill, FA, Wellcome Trust Case Control Consortium 2, Kendler, KS, Gill, M, Riley, BP, Spencer, CCA, Corvin, A, Morris, DW, Pearson, RD, Cormican, P, Kenny, EM, O'Dushlaine, CT, Perreault, L-PL, Giannoulatou, E, Tropea, D, Maher, BS, Wormley, B, Kelleher, E, Fahey, C, Molinos, I, Bellini, S, Pirinen, M, Strange, A, Freeman, C, Thiselton, DL, Elves, RL, Regan, R, Ennis, S, Dinan, TG, McDonald, C, Murphy, KC, O'Callaghan, E, Waddington, JL, Walsh, D, O'Donovan, M, Grozeva, D, Craddock, N, Stone, J, Scolnick, E, Purcell, S, Sklar, P, Coe, B, Eichler, EE, Ophoff, R, Buizer, J, Szatkiewicz, J, Hultman, C, Sullivan, P, Gurling, H, Mcquillin, A, St Clair, D, Rees, E, Kirov, G, Walters, J, Blackwood, D, Johnstone, M, Donohoe, G, International Schizophrenia Consortium, SGENE+ Consortium, O'Neill, FA, Wellcome Trust Case Control Consortium 2, Kendler, KS, Gill, M, Riley, BP, Spencer, CCA, and Corvin, A
Abstract: Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, ∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.
Published: 2014

40. Variability in working memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway.

Author: Nicodemus, Kristin K, Nicodemus, Kristin K, Hargreaves, April, Morris, Derek, Anney, Richard, Schizophrenia Psychiatric Genome-wide Association Study (GWAS) Consortium, Wellcome Trust Case Control Consortium 2, Gill, Michael, Corvin, Aiden, Donohoe, Gary, Nicodemus, Kristin K, Nicodemus, Kristin K, Hargreaves, April, Morris, Derek, Anney, Richard, Schizophrenia Psychiatric Genome-wide Association Study (GWAS) Consortium, Wellcome Trust Case Control Consortium 2, Gill, Michael, Corvin, Aiden, and Donohoe, Gary
Abstract: ImportanceWe investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained.ObjectivesTo (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score.Design, setting, and participantsPatients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis).Main outcomes and measuresParticipants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition.ResultsHigher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (rang
Published: 2014

41. Genome-wide association and functional follow-up reveals new loci for kidney function.

Author: CARDIoGRAM Consortium, ICBP Consortium, CARe Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Pattaro, C., Köttgen, A., Teumer, A., Garnaas, M., Böger, C.A., Fuchsberger, C., Olden, M., Chen, M.H., Tin, A., Taliun, D., Li, M., Gao, X., Gorski, M., Yang, Q., Hundertmark, C., Foster, M.C., O'Seaghdha, C.M., Glazer, N., Isaacs, A., Liu, C.T., Smith, A.V., O'Connell, J.R., Struchalin, M., Tanaka, T., Li, G., Johnson, A.D., Gierman, H.J., Feitosa, M., Hwang, S.J., Atkinson, E.J., Lohman, K., Cornelis, M.C., Johansson, Å., Tönjes, A., Dehghan, A., Chouraki, V., Holliday, E.G., Sorice, R., Kutalik, Z., Lehtimäki, T., Esko, T., Deshmukh, H., Ulivi, S., Chu, A.Y., Murgia, F., Trompet, S., Imboden, M., Kollerits, B., Pistis, G., Harris, T.B., Launer, L.J., Aspelund, T., Eiriksdottir, G., Mitchell, B.D., Boerwinkle, E., Schmidt, H., Cavalieri, M., Rao, M., Hu, F.B., Demirkan, A., Oostra, B.A., de Andrade, M., Turner, S.T., Ding, J., Andrews, J.S., Freedman, B.I., Koenig, W., Illig, T., Döring, A., Wichmann, H.E., Kolcic, I., Zemunik, T., Boban, M., Minelli, C., Wheeler, H.E., Igl, W., Zaboli, G., Wild, S.H., Wright, A.F., Campbell, H., Ellinghaus, D., Nöthlings, U., Jacobs, G., Biffar, R., Endlich, K., Ernst, F., Homuth, G., Kroemer, H.K., Nauck, M., Stracke, S., Völker, U., Völzke, H., Kovacs, P., Stumvoll, M., Mägi, R., Hofman, A., Uitterlinden, A.G., Rivadeneira, F., Aulchenko, Y.S., Polasek, O., Hastie, N., Vitart, V., Helmer, C., Wang, J.J., Ruggiero, D., Bergmann, S., Kähönen, M., Viikari, J., Nikopensius, T., Province, M., Ketkar, S., Colhoun, H., Doney, A., Robino, A., Giulianini, F., Krämer, B.K., Portas, L., Ford, I., Buckley, B.M., Adam, M., Thun, G.A., Paulweber, B., Haun, M., Sala, C., Metzger, M., Mitchell, P., Ciullo, M., Kim, S.K., Vollenweider, P., Raitakari, O., Metspalu, A., Palmer, C., Gasparini, P., Pirastu, M., Jukema, J.W., Probst-Hensch, N.M., Kronenberg, F., Toniolo, D., Gudnason, V., Shuldiner, A.R., Coresh, J., Schmidt, R., Ferrucci, L., Siscovick, D.S., van Duijn, C.M., Borecki, I., Kardia, S.L., Liu, Y., Curhan, G.C., Rudan, I., Gyllensten, U., Wilson, J.F., Franke, A., Pramstaller, P.P., Rettig, R., Prokopenko, I., Witteman, J.C., Hayward, C., Ridker, P., Parsa, A., Bochud, M., Heid, I.M., Goessling, W., Chasman, D.I., Kao, W.H., Fox, C.S., CARDIoGRAM Consortium, ICBP Consortium, CARe Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Pattaro, C., Köttgen, A., Teumer, A., Garnaas, M., Böger, C.A., Fuchsberger, C., Olden, M., Chen, M.H., Tin, A., Taliun, D., Li, M., Gao, X., Gorski, M., Yang, Q., Hundertmark, C., Foster, M.C., O'Seaghdha, C.M., Glazer, N., Isaacs, A., Liu, C.T., Smith, A.V., O'Connell, J.R., Struchalin, M., Tanaka, T., Li, G., Johnson, A.D., Gierman, H.J., Feitosa, M., Hwang, S.J., Atkinson, E.J., Lohman, K., Cornelis, M.C., Johansson, Å., Tönjes, A., Dehghan, A., Chouraki, V., Holliday, E.G., Sorice, R., Kutalik, Z., Lehtimäki, T., Esko, T., Deshmukh, H., Ulivi, S., Chu, A.Y., Murgia, F., Trompet, S., Imboden, M., Kollerits, B., Pistis, G., Harris, T.B., Launer, L.J., Aspelund, T., Eiriksdottir, G., Mitchell, B.D., Boerwinkle, E., Schmidt, H., Cavalieri, M., Rao, M., Hu, F.B., Demirkan, A., Oostra, B.A., de Andrade, M., Turner, S.T., Ding, J., Andrews, J.S., Freedman, B.I., Koenig, W., Illig, T., Döring, A., Wichmann, H.E., Kolcic, I., Zemunik, T., Boban, M., Minelli, C., Wheeler, H.E., Igl, W., Zaboli, G., Wild, S.H., Wright, A.F., Campbell, H., Ellinghaus, D., Nöthlings, U., Jacobs, G., Biffar, R., Endlich, K., Ernst, F., Homuth, G., Kroemer, H.K., Nauck, M., Stracke, S., Völker, U., Völzke, H., Kovacs, P., Stumvoll, M., Mägi, R., Hofman, A., Uitterlinden, A.G., Rivadeneira, F., Aulchenko, Y.S., Polasek, O., Hastie, N., Vitart, V., Helmer, C., Wang, J.J., Ruggiero, D., Bergmann, S., Kähönen, M., Viikari, J., Nikopensius, T., Province, M., Ketkar, S., Colhoun, H., Doney, A., Robino, A., Giulianini, F., Krämer, B.K., Portas, L., Ford, I., Buckley, B.M., Adam, M., Thun, G.A., Paulweber, B., Haun, M., Sala, C., Metzger, M., Mitchell, P., Ciullo, M., Kim, S.K., Vollenweider, P., Raitakari, O., Metspalu, A., Palmer, C., Gasparini, P., Pirastu, M., Jukema, J.W., Probst-Hensch, N.M., Kronenberg, F., Toniolo, D., Gudnason, V., Shuldiner, A.R., Coresh, J., Schmidt, R., Ferrucci, L., Siscovick, D.S., van Duijn, C.M., Borecki, I., Kardia, S.L., Liu, Y., Curhan, G.C., Rudan, I., Gyllensten, U., Wilson, J.F., Franke, A., Pramstaller, P.P., Rettig, R., Prokopenko, I., Witteman, J.C., Hayward, C., Ridker, P., Parsa, A., Bochud, M., Heid, I.M., Goessling, W., Chasman, D.I., Kao, W.H., and Fox, C.S.
Abstract: Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
Published: 2012

42. Genetic Factors Influencing Coagulation Factor XIII B-Subunit Contribute to Risk of Ischemic Stroke.

Author: Hanscombe, Ken B., Traylor, Matthew, Hysi, Pirro G., Bevan, Stephen, Dichgans, Martin, Rothwell, Peter M., Worrall, Bradford B., Seshadri, Sudha, Sudlow, Cathie, Williams, Frances M. K., Markus, Hugh S., Lewis, Cathryn M., METASTROKE Consortium, and Wellcome Trust Case Control Consortium 2
Published: 2015
Full Text: View/download PDF

43. A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain.

Author: Meng, W, Deshmukh, H A, van Zuydam, N R, Liu, Y, Donnelly, L A, Zhou, K, Morris, A D, Colhoun, H M, Palmer, C N A, Smith, B H, Wellcome Trust Case Control Consortium 2 (WTCCC2), and Surrogate Markers for Micro- and Macro-Vascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) Study Group
Abstract: Background: Neuropathic pain, caused by a lesion or a disease affecting the somatosensory system, is one of the most common complications in diabetic patients. The purpose of this study is to identify genetic factors contributing to this type of pain in a general diabetic population.Method: We accessed the Genetics of Diabetes Audit and Research Tayside (GoDARTS) datasets that contain prescription information and monofilament test results for 9439 diabetic patients, among which 6927 diabetic individuals were genotyped by Affymetrix SNP6.0 or Illumina OmniExpress chips. Cases of neuropathic pain were defined as diabetic patients with a prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain and in whom monofilament test result was positive for sensory neuropathy in at least one foot. Controls were individuals who did not have a record of receiving any opioid analgesics. Imputation of non-genotyped SNPs was performed by IMPUTE2, with reference files from 1000 Genomes Phase I datasets.Results: After data cleaning and relevant exclusions, imputed genotypes of 572 diabetic neuropathic pain cases and 2491 diabetic controls were used in the Fisher's exact test. We identified a cluster in the Chr8p21.3, next to GFRA2 with a lowest p-value of 1.77 × 10(-7) at rs17428041. The narrow-sense heritability of this phenotype was 11.00%.Conclusion: This genome-wide association study on diabetic neuropathic pain suggests new evidence for the involvement of variants near GFRA2 with the disorder, which needs to be verified in an independent cohort and at the molecular level. [ABSTRACT FROM AUTHOR]
Published: 2015
Full Text: View/download PDF

44. Genetic Copy Number Variants, Cognition and Psychosis: A Meta-analysis and a Family Study

Author: Thygesen, Johan Hilge, Presman, Amelia, Harju-Seppänen, Jasmine, Irizar, Haritz, Calafato, Stella, Zartaloudi, Eirini, Jones, Rebecca, Ranlund, Siri, Kuchenbaecker, Karoline, Lin, Kuang, Cahn, Wiepke, Crespo-Facorro, Benedicto, de Zwarte, Sonja MC, Austin-Zimmerman, Isabelle, Bhat, Anjali, Díez, Álvaro, Di Forti, Marta, Genetic Risk and Outcome of Psychosis (GROUP), Iyegbe, Conrad, Jablensky, Assen, Hall, Mei-Hua, Kahn, Rene, Kalaydjieva, Luba, Kravariti, Eugenia, McDonald, Colm, McIntosh, Andrew M, McQuillin, Andrew, Muir, Rebecca, Psychosis Endophenotypes International Consortium (PEIC), Picchioni, Marco, Prata, Diana P, Rujescu, Dan, Schulze, Katja, Shaikh, Madiha, Toulopoulou, Timothea, van Haren, Neeltje, van Os, Jim, Vassos, Evangelos, Walshe, Muriel, Wellcome Trust Case Control Consortium 2 (WTCCC2), Bell, Vaughan, Powell, John, Lewis, Cathryn, Murray, Robin M, and Bramon, Elvira
Subjects: CNVs, schizophrenia, cognition, mental disorders, 3. Good health
Abstract: The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVsincrease the risk of developing schizophrenia. Several cognitive measures are purportedschizophrenia endophenotypes andmayrepresent an intermediate point between genetics and theillness.This paper investigates the influence of CNVs on cognition. We conducted a systematicreview and meta-analysis of the literature exploring the effect of CNV burden on generalintelligence. We included 10 primary studies with a total of 18,847 participants and found noevidence ofassociation. In a new psychosis family study, we investigated the effects of CNVs onspecific cognitive abilities. We examined the burden of large andrare CNVs (>200Kb

45. Genetic Copy Number Variants, Cognition and Psychosis: A Meta-analysis and a Family Study

Author: Thygesen, Johan Hilge, Presman, Amelia, Harju-Seppänen, Jasmine, Irizar, Haritz, Calafato, Stella, Zartaloudi, Eirini, Jones, Rebecca, Ranlund, Siri, Kuchenbaecker, Karoline, Lin, Kuang, Cahn, Wiepke, Crespo-Facorro, Benedicto, de Zwarte, Sonja MC, Austin-Zimmerman, Isabelle, Bhat, Anjali, Díez, Álvaro, Di Forti, Marta, Genetic Risk And Outcome Of Psychosis (GROUP), Iyegbe, Conrad, Jablensky, Assen, Hall, Mei-Hua, Kahn, Rene, Kalaydjieva, Luba, Kravariti, Eugenia, McDonald, Colm, McIntosh, Andrew M, McQuillin, Andrew, Muir, Rebecca, Psychosis Endophenotypes International Consortium (PEIC), Picchioni, Marco, Prata, Diana P, Rujescu, Dan, Schulze, Katja, Shaikh, Madiha, Toulopoulou, Timothea, van Haren, Neeltje, van Os, Jim, Vassos, Evangelos, Walshe, Muriel, Wellcome Trust Case Control Consortium 2 (WTCCC2), Bell, Vaughan, Powell, John, Lewis, Cathryn, Murray, Robin M, and Bramon, Elvira
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, CNVs, schizophrenia, cognition, endocrine system diseases, mental disorders, 3. Good health
Abstract: The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included 10 primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200Kb

46. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias, Adriana I, Mishra, Aniket, Vitart, Veronique, Bykhovskaya, Yelena, Höhn, René, Springelkamp, Henriët, Cuellar-Partida, Gabriel, Gharahkhani, Puya, Bailey, Jessica N Cooke, Willoughby, Colin E, Li, Xiaohui, Yazar, Seyhan, Nag, Abhishek, Khawaja, Anthony P, Polašek, Ozren, Siscovick, David, Mitchell, Paul, Tham, Yih Chung, Haines, Jonathan L, Kearns, Lisa S, Hayward, Caroline, Shi, Yuan, Van Leeuwen, Elisabeth M, Taylor, Kent D, Blue Mountains Eye Study—GWAS Group, Bonnemaijer, Pieter, Rotter, Jerome I, Martin, Nicholas G, Zeller, Tanja, Mills, Richard A, Souzeau, Emmanuelle, Staffieri, Sandra E, Jonas, Jost B, Schmidtmann, Irene, Boutin, Thibaud, Kang, Jae H, Lucas, Sionne EM, Wong, Tien Yin, Beutel, Manfred E, Wilson, James F, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Uitterlinden, André G, Vithana, Eranga N, Foster, Paul J, Hysi, Pirro G, Hewitt, Alex W, Khor, Chiea Chuen, Pasquale, Louis R, Montgomery, Grant W, Klaver, Caroline CW, Aung, Tin, Pfeiffer, Norbert, Mackey, David A, Hammond, Christopher J, Cheng, Ching-Yu, Craig, Jamie E, Rabinowitz, Yaron S, Wiggs, Janey L, Burdon, Kathryn P, Van Duijn, Cornelia M, and MacGregor, Stuart
Subjects: Lumican, genetic structures, Fibrillin-1, Quantitative Trait Loci, Gene Expression, Keratoconus, Polymorphism, Single Nucleotide, White People, Corneal Diseases, Marfan Syndrome, Cornea, Transforming Growth Factor beta2, ADAMTS Proteins, Quantitative Trait, Heritable, Asian People, Myopia, Humans, Corneal Dystrophies, Hereditary, Loeys-Dietz Syndrome, Genome, Human, Eye Diseases, Hereditary, Mendelian Randomization Analysis, eye diseases, 3. Good health, Ehlers-Danlos Syndrome, Proteoglycans, sense organs, Decorin, Glaucoma, Open-Angle, Genome-Wide Association Study
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

47. Genetic loci for retinal arteriolar microcirculation

Author: Sim, Xueling, Jensen, Richard A, Ikram, M Kamran, Cotch, Mary Frances, Li, Xiaohui, MacGregor, Stuart, Xie, Jing, Smith, Albert Vernon, Boerwinkle, Eric, Mitchell, Paul, Klein, Ronald, Klein, Barbara EK, Glazer, Nicole L, Lumley, Thomas, McKnight, Barbara, Psaty, Bruce M, De Jong, Paulus TVM, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G, Van Duijn, Cornelia M, Aspelund, Thor, Eiriksdottir, Gudny, Harris, Tamara B, Jonasson, Fridbert, Launer, Lenore J, Wellcome Trust Case Control Consortium 2, Attia, John, Baird, Paul N, Harrap, Stephen, Holliday, Elizabeth G, Inouye, Michael, Rochtchina, Elena, Scott, Rodney J, Viswanathan, Ananth, Global BPGen Consortium, Li, Guo, Smith, Nicholas L, Wiggins, Kerri L, Kuo, Jane Z, Taylor, Kent D, Hewitt, Alex W, Martin, Nicholas G, Montgomery, Grant W, Sun, Cong, Young, Terri L, Mackey, David A, Van Zuydam, Natalie R, Doney, Alex SF, Palmer, Colin NA, Morris, Andrew D, Rotter, Jerome I, Tai, E Shyong, Gudnason, Vilmundur, Vingerling, Johannes R, Siscovick, David S, Wang, Jie Jin, and Wong, Tien Y
Subjects: Aged, 80 and over, Male, Genotype, Models, Genetic, MEF2 Transcription Factors, Microcirculation, Retinal Vessels, Middle Aged, White People, 3. Good health, Arterioles, Genetic Loci, Chromosomes, Human, Pair 5, Humans, Female, Aged, Genome-Wide Association Study
Abstract: Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value

48. Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness

Author: Bigdeli, T. B, Ripke, S, Bacanu, Sa, Lee, S. H, Wray, Nr, Gejman, P. V, Rietschel, M, Cichon, S, St Clair, D, Corvin, A, Kirov, G, Mcquillin, A, Gurling, H, Rujescu, D, Andreassen, O. A, Werge, T, Blackwood, D. H. R, Pato, C. N, Pato, M. T, Malhotra, A. K, O'Donovan, M. C, Kendler, K. S, Fanous, A. H, Neale, Bm, Walters, Jt, Farh, Kh, Holmans, Pa, Lee, P, Bulik Sullivan, B, Collier, Da, Huang, H, Pers, Th, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Begemann, M, Belliveau, Ra, Bene, J, Bergen, Se, Bevilacqua, E, Bigdeli, Tb, Black, Dw, Børglum, Ad, Bruggeman, R, Buccola, Ng, Buckner, Rl, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, Rm, Carr, Vj, Carrera, N, Catts, Sv, Chambert, Kd, Chan, Rc, Chen, Ry, Chen, Ey, Cheng, W, Cheung, Ef, Chong, Sa, Cloninger, C, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, Jj, Curtis, D, Davidson, M, Davis, Kl, Degenhardt, F, Del, Favero, J, Delisi, Le, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott Price, V, Essioux, L, Fanous, Ah, Farrell, Ms, Frank, J, Franke, L, Freedman, R, Freimer, Nb, Friedl, M, Friedman, Ji, Fromer, M, Genovese, G, Georgieva, L, Gershon, Es, Giegling, I, Giusti Rodríguez, P, Godard, S, Goldstein, Ji, Golimbet, V, Gopal, S, Gratten, J, Grove, J, Haan, De, L, Hammer, C, Hamshere, Ml, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, Am, Henskens, Fa, Herms, S, Hirschhorn, Jn, Hoffmann, P, Hofman, A, Hollegaard, Mv, Hougaard, Dm, Ikeda, M, Joa, I, Julìa, A, Kahn, Rs, Kalaydjieva, L, Karachanak Yankova, S, Karjalainen, J, Kavanagh, D, Keller, Mc, Kelly, Bj, Kennedy, Jl, Khrunin, A, Kim, Y, Klovins, J, Knowles, Ja, Konte, B, Kucinskas, V, Kucinskiene, Za, Kuzelova Ptackova, H, Kähler, Ak, Laurent, C, Keong, Jl, Lee, S, Legge, Se, Lerer, B, Li, M, Li, T, Liang, Ky, Lieberman, J, Limborska, S, Loughland, Cm, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, Pk, Maher, Bs, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, Mccarley, Rw, Mcdonald, C, Mcintosh, Am, Meier, S, Meijer, Cj, Melegh, B, Melle, I, Mesholam Gately, Ri, Metspalu, A, Michie, Pt, Milani, L, Milanova, V, Mokrab, Y, Morris, Dw, Mors, O, Mortensen, Pb, Murphy, Kc, Murray, Rm, Myin Germeys, I, Müller Myhsok, B, Nelis, M, Nenadic, I, Nertney, Da, Nestadt, G, Nicodemus, Kk, Nikitina Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, F, Sy, Oh, Olincy, A, Olsen, L, Jv, Os, Pantelis, C, Papadimitriou, Gn, Papiol, S, Parkhomenko, E, Pato, Mt, Paunio, T, Pejovic Milovancevic, M, Perkins, Do, Pietiläinen, O, Pimm, J, Pocklington, Aj, Powell, J, Price, A, Pulver, Ae, Purcell, Sm, Quested, D, Rasmussen, Hb, Reichenberg, A, Reimers, Ma, Richards, Al, Roffman, Jl, Roussos, P, Ruderfer, Dm, Salomaa, V, Sanders, Ar, Schall, U, Schubert, Cr, Schulze, Tg, Schwab, Sg, Scolnick, Em, Scott, Rj, Seidman, Lj, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, Jm, Sim, K, Slominsky, P, Smoller, Jw, Hc, So, Spencer, Cc, Stahl, Ea, Stefansson, H, Steinberg, S, Stogmann, E, Straub, Re, Strengman, E, Strohmaier, J, Stroup, T, Subramaniam, M, Suvisaari, J, Svrakic, Dm, Szatkiewicz, Jp, Söderman, E, Thirumalai, S, Toncheva, D, Tooney, Pa, Tosato, Sarah, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, Bt, Weiser, M, Wildenauer, Db, Williams, Nm, Williams, S, Witt, Sh, Wolen, Ar, Wong, Eh, Wormley, Bk, Jq, Wu, Hs, Xi, Zai, Cc, Zheng, X, Zimprich, F, Stefansson, K, Visscher, Pm, Adolfsson, R, Andreassen, Oa, Blackwood, Dh, Bramon, E, Buxbaum, Jd, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, Pv, Gill, M, Hultman, Cm, Iwata, N, Jablensky, Av, Jönsson, Eg, Kendler, Ks, Knight, J, Lencz, T, Levinson, Df, Qs, Li, Liu, J, Malhotra, Ak, Mccarroll, Sa, Moran, Jl, Mowry, Bj, Nöthen, Mm, Ophoff, Ra, Owen, Mj, Palotie, A, Pato, Cn, Petryshen, Tl, Posthuma, D, Riley, Bp, Sham, Pc, Sklar, P, Clair, Ds, Weinberger, Dr, Wendland, Jr, Daly, Mj, Sullivan, Pf, O'Donovan, Mc, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Bigdeli, Tim B, Ripke, Stephan, Bacanu, Silviu-Alin, Lee, Sang Hong, Fanous, Ayman H, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Psychosis Endophenotype International Consortium, Wellcome Trust Case-Control Consortium 2, Other departments, Adult Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), and Del-Favero, Jurgen
Subjects: 0301 basic medicine, Multifactorial Inheritance, Bipolar Disorder, Inheritance Patterns, Genome-wide association study, Single-nucleotide polymorphism, polygenic, heritability, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, SNP, GWAS, Family, Genetic Predisposition to Disease, Family history, Allele, Genetics (clinical), Genetic association, Genetics & Heredity, Psychiatry, Genetics, Depressive Disorder, Major, family history, Models, Genetic, Case-control study, medicine.disease, 3. Good health, schizophrenia, Psychiatry and Mental health, 030104 developmental biology, Schizophrenia, Case-Control Studies, Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N=978), cases reporting no such family history (N=4,503), and unscreened controls (N=8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R-2=0.0021; P=0.00331; P-value threshold
Published: 2016
Full Text: View/download PDF

49. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author: Bénédicte Dubois, Lucia Corrado, Deborah F. Mason, Allan G. Kermode, Pentti J. Tienari, Annette Bang Oturai, Charles Hillier, Adrian J. Ivinson, Stephen L. Hauser, Ashley Beecham, Jeannette Lechner-Scott, Vincent Thijs, Jonathan L. Haines, Sarah Edkins, Alexander T. Dilthey, Daniele Cusi, Guy Nagels, David A. Hafler, Mark Slee, Petra Nilsson, James S. Wiley, Lou Brundin, Amy Strange, Elizabeth Visser, Mireia Sospedra, Athena Hadjixenofontos, Sergio E. Baranzini, Jenny Link, Robert Andrews, Viola Biberacher, Helle Bach Søndergaard, Vittorio Martinelli, Tomas Olsson, Gillian L Hall, Stephen Sawcer, Stacy J. Caillier, Per Soelberg Sørensen, Céline Bellenguez, Cornelia M. van Duijn, Frauke Zipp, Nikolaos A. Patsopoulos, Cristin McCabe, Colin Freeman, Simon Broadley, Luisa Bernardinelli, Margaret A. Pericak-Vance, Jan Hillert, Wassila Carpentier, Sandip Shaunak, Anne Spurkland, Barnaby Fiddes, Judith Field, Jan Lycke, Christina M. Lill, Federica Esposito, Ioanna Konidari, Elisabeth Gulowsen Celius, Christian Gieger, Helmut Butzkueven, Ling Shen, James F. Wilson, Magdalena Lindén, Tejas S. Shah, Amie Baker, Dionysia K. Xifara, Hong Quach, Laura Bergamaschi, Rogier Q. Hintzen, Jacob L. McCauley, Janna Saarela, J W Thorpe, Christine Lebrun-Frenay, Felix Luessi, Sandra D'Alfonso, B. E. Kendall, Helga Westerlind, Giancarlo Comi, Nathalie Schnetz-Boutaud, Paola Brambilla, Chris Cotsapas, Anders Hamsten, William Camu, Achim Berthele, Kjell-Morten Myhr, Clive Hawkins, Richard Nicholas, James Harley, Carl A. Anderson, Keijo Koivisto, Irene Coman, Neil Robertson, Hakon Hakonarson, Finn Sellebjerg, Fredrik Piehl, Alessia Di Sapio, Loukas Moutsianas, Mehdi Alizadeh, Lars Alfredsson, Catherine Schaefer, David Rog, Virpi Leppa, C. Martin, Bruce A.C. Cree, Christopher Halfpenny, Irina Elovaara, Filippo Martinelli-Boneschi, Cordelia Langford, Hanne F. Harbo, Wim Robberecht, Isabelle Cournu-Rebeix, Steve Vucic, Izaura Lima Bomfim, Irene Y. Frohlich, Michelle Lee, Bertrand Fontaine, Bernhard Hemmer, Eva Zindler, Chris C. A. Spencer, Malin Larsson, Simon Shields, Ilijas Jelcic, Juliane Winkelmann, Jorge R. Oksenberg, Alastair Wilkins, Silvia Delgado, Volker Siffrin, Helena C. Kronsbein, Bruno Brochet, Panos Deloukas, Daniela Galimberti, Nikos Evangelou, Rebecca C. Selter, Maja Jagodic, Martin Duddy, Timothy Harrower, Per Hall, Nadia Barizzone, Siân Price, Matti Pirinen, Pierre-Antoine Gourraud, Thomas M.C. Binder, Giuseppe Liberatore, Mark Lathrop, M.-M. Hoshi, Garrett Hellenthal, Melissa Sorosina, Thomas Korn, Clara Guaschino, Roland Martin, Jeremy Hobart, Marco Salvetti, Peter Donnelly, Ingrid Kockum, An Goris, Alastair Compston, Mariaemma Rodegher, Dorothea Buck, Clara P. Manrique, Christiane Graetz, Benedicte A. Lie, Trevor J. Kilpatrick, Andrew Graham, Anu Kemppinen, Maria Ban, Gil McVean, John Zajicek, Hannah Blackburn, Mary F. Davis, Emilie Sundqvist, Bruce V. Taylor, Maurizio Leone, Lisa F. Barcellos, Fabio Macciardi, Gilles Defer, Vincent Damotte, Satu Männistö, Graeme J. Stewart, Gordon Mazibrada, Inger Lise Mero, Andre Franke, Philip L. De Jager, Verena Grummel, Mauri Reunanen, David R. Booth, Anna Ticca, Angela Jochim, Leentje Cosemans, Julia Y Mescheriakova, Cristina Agliardi, Paola Cavalla, Jeffrey C. Barrett, Sarah E. Hunt, Gavin Band, School of Life Sciences, University of Technology Sydney (UTS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Profium Oy [Helsinki], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Michigan Technological University (MTU), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Karolinska Institutet [Stockholm], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Statistics [Oxford], Centro Dino Ferrari [Milano], Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Epidémiologie et Analyses en Santé Publique : risques, maladies chroniques et handicap (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Epidemiology and Biostatistics (MEB), University College of London [London] (UCL), Fondation Jean Dausset CEPH, Centre Hospitalier Universitaire de Nice (CHU Nice), Dublin Institute of Technology (DIT), University of California [Irvine] (UCI), University of California, Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Kaiser Permanente, Universität Zürich [Zürich] = University of Zurich (UZH), University Hospitals Leuven [Leuven], Department Biostatistics University of North Carolina, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institute of Bioinformatics and Systems Biology [München], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Yale University School of Medicine, Big Data Institute, Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Faculty of Engineering, Neuroprotection & Neuromodulation, Internal Medicine Specializations, Neurology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), University of Oxford, Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of California [Irvine] (UC Irvine), University of California (UC), Cardiology, Epidemiology, Oral and Maxillofacial Surgery, International Multiple Sclerosis Genetics, Consortium, Beecham, Ah, Patsopoulos, Na, Xifara, Dk, Davis, Mf, Kemppinen, A, Cotsapas, C, Shah, T, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli Boneschi, F, Taylor, B, Harbo, Hf, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, Jr, Hintzen, R, Barcellos, Lf, Wellcome Trust Case Control Consortium, 2, International IBD Genetics, Consortium, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Søndergaard, Hb, Baker, A, Band, G, Baranzini, Se, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, Tm, Blackburn, H, Bomfim, Il, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, Sj, Camu, W, Carpentier, W, Cavalla, P, Celius, Eg, Coman, I, Comi, Giancarlo, Corrado, L, Cosemans, L, Cournu Rebeix, I, Cree, Ba, Cusi, D, Damotte, V, Defer, G, Delgado, Sr, Deloukas, P, di Sapio, A, Dilthey, At, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, Iy, Galimberti, D, Gieger, C, Gourraud, Pa, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, Se, Jagodic, M, Jelčić, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun Frenay, C, Lechner Scott, J, Lee, Mh, Leone, Ma, Leppä, V, Liberatore, G, Lie, Ba, Lill, Cm, Lindén, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Männistö, S, Manrique, Cp, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, Mccabe, C, Mero, Il, Mescheriakova, J, Moutsianas, L, Myhr, Km, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, Se, Quach, H, Reunanen, M, Robberecht, W, Robertson, Np, Rodegher, M, Rog, D, Salvetti, M, Schnetz Boutaud, Nc, Sellebjerg, F, Selter, Rc, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, P, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, Em, Vucic, S, Westerlind, H, Wiley, J, Wilkins, A, Wilson, Jf, Winkelmann, J, Zajicek, J, Zindler, E, Haines, Jl, Pericak Vance, Ma, Ivinson, Aj, Stewart, G, Hafler, D, Hauser, Sl, Compston, A, Mcvean, G, De Jager, P, Sawcer, Sj, and Mccauley, J. L.
Subjects: Multiple Sclerosis, Genotype, [SDV]Life Sciences [q-bio], European Continental Ancestry Group, Genome-wide association study, CLEC16A, Biology, multiple sclerosis, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, Gene Frequency, Polymorphism (computer science), Journal Article, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genotyping, Allele frequency, 030304 developmental biology, 0303 health sciences, Research Support, Non-U.S. Gov't, Multiple sclerosis, Chromosome Mapping, Genetic Variation, medicine.disease, 3. Good health, Genetic Loci, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract: International audience; Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
Published: 2016
Full Text: View/download PDF

50. Childhood intelligence is heritable, highly polygenic and associated with FNBP1L

Author: Danielle Posthuma, Claire M. A. Haworth, Peter M. Visscher, Nicholas J. Timpson, Robert Plomin, Beate St Pourcain, Robert M. Kirkpatrick, Oliver S. P. Davis, Beben Benyamin, Dorret I. Boomsma, Rolieke A. M. Cents, Susan M. Ring, M-Ja Brion, Lyle J. Palmer, John M. Starr, Nicholas G. Martin, Henning Tiemeier, Emma L. Meaburn, S. E. Medland, David M. Evans, Grant W. Montgomery, Sarah E. Harris, Gary Davies, E.J.C. de Geus, Matt McGue, Xiangjun Xiao, G Davey Smith, Wendy L. McArdle, Craig E. Pennell, Narelle K. Hansell, Thomas S. Price, Vincent W. V. Jaddoe, John P. Kemp, P Scheet, William G. Iacono, Ian J. Deary, Jian Yang, Sanja Franić, Margaret J. Wright, James J. Hudziak, Frank C. Verhulst, Michael B. Miller, D C Liewald, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Child and Adolescent Psychiatry / Psychology, Erasmus MC other, Psychiatry, Benyamin, B, Pourcain, BSt, Davis, OS, Davies, G, Visscher, PM, Wellcome Trust Case Control Consortium 2 (WTCCC2), Human genetics, NCA - Brain mechanisms in health and disease, and NCA - Neurobiology of mental health
Subjects: Male, Netherlands Twin Register (NTR), Carrier Proteins/genetics, Multifactorial Inheritance, Adolescent, Genotyping Techniques, Intelligence, Genome-wide association study, polygenic, Polymorphism, Single Nucleotide, Article, White People, cognitive, Cohort Studies, Cellular and Molecular Neuroscience, Quantitative Trait, Heritable, Humans, Human height, European Continental Ancestry Group/genetics, Child, Molecular Biology, Genetics, Intelligence Tests, Intelligence quotient, association, Intelligence/genetics, Heritability, intelligence, Genetic architecture, FNBP1L, Cognitive test, Psychiatry and Mental health, Phenotype, IQ, Meta-analysis, Female, Psychology, Carrier Proteins, Software, Genome-Wide Association Study
Abstract: Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17 989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10 -15, 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10 -5), 3.5% (P=10 -3) and 0.5% (P=6 × 10 -5) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance. © 2014 Macmillan Publishers Limited All rights reserved.
Published: 2014
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

83 results on '"Wellcome Trust Case Control Consortium, 2"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources