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39 results on '"Koks, Sulev"'

1. Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND Courage-PD [sponsor], Sugier, Pierre-Emmanuel, Lucotte, Elise A., Domenighetti, Cloé, Law, Matthew H., Iles, Mark M., Brown, Kevin, Amos, Christopher, McKay, James D., Hung, Rayjean J., Karimi, Mojgan, Bacq-Daian, Delphine, Boland-Augé, Anne, Olaso, Robert, Deleuze, Jean-François, Lesueur, Fabienne, Ostroumova, Evgenia, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, consortium, The Epithyr, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimios, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy, Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Rödström, Emil Ygland, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Landoulsi, Zied, consortium, Courage-PD, Truong, Thérèse, Elbaz, Ales, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND Courage-PD [sponsor], Sugier, Pierre-Emmanuel, Lucotte, Elise A., Domenighetti, Cloé, Law, Matthew H., Iles, Mark M., Brown, Kevin, Amos, Christopher, McKay, James D., Hung, Rayjean J., Karimi, Mojgan, Bacq-Daian, Delphine, Boland-Augé, Anne, Olaso, Robert, Deleuze, Jean-François, Lesueur, Fabienne, Ostroumova, Evgenia, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, consortium, The Epithyr, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimios, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy, Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Rödström, Emil Ygland, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Landoulsi, Zied, consortium, Courage-PD, Truong, Thérèse, and Elbaz, Ales
Abstract: Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly dri
Published: 2023

2. Investigating short structural variants within FUS, RAB27B and TARDBP for associations with sporadic amyotrophic lateral sclerosis

Author: Akkari, Anthony, Li, Dunhui, Flynn, Loren, Koks, Sulev, Pytte, Julia, Vicars, Caitlyn, Akkari, Anthony, Li, Dunhui, Flynn, Loren, Koks, Sulev, Pytte, Julia, and Vicars, Caitlyn
Abstract: Over the past decade, 90% of amyotrophic lateral sclerosis (ALS) clinical trials have failed. Furthermore, 90% of sporadic cases have unknown genetic cause. Short structural variants (sSVs) are repetitive genomic regions implicated in complex diseases, with the potential to be utilised for clinical trial enrichment. The purpose of this study was to investigate sporadic ALS (sALS) missing heritability via interrogating novel sSVs, and to determine their potential as genetic biomarkers. This project aimed to develop assays for characterisation and high-throughput genotyping of sSVs within ALS-linked genes FUS and TARDBP, and the novel gene, RAB27B, to perform case-control analyses. Three loci; FUS rs34242298, TARDBP rs34839760 and RAB27B rs3060044, were selected using an sSV evaluation algorithm. Polymorphic nature was characterised via polymerase chain reaction-based assays and Sanger sequencing. High-throughput genotyping of sALS patients and healthy controls was undertaken via capillary electrophoresis, followed by case-control analyses in RStudio to identify statistically significant (p<0.05) associations with disease risk and/or site-of-onset. Reduced sALS risk was associated with Short rs3060044 alleles with ≤17GT repeats (p<0.05), driven by 16GT allele carriage. Increased disease risk correlated with carriage of a Long allele (>17GT repeats) (p<0.05), driven by the 21GT allele (p=0.00625). Analysis of rs34839760 revealed the 20A allele was associated with bulbar-onset phenotype (p<0.05), while rs34242298 was not associated with sALS. This exploratory study reinforces the requirement for sSV investigation in complex diseases. Two novel sALS genetic loci were identified; rs3060044 and rs34839760, which enhance our understanding of the aetiology and pathomechanisms underlying sALS. This data is the first to implicate RAB27B as an sALS gene, presenting a tantalising direction for future sALS exploration. Replication studies and functional investigations are warrant
Published: 2022

3. Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], JPND Courage-PD [sponsor], Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Ashok Kumar Sreelatha, Ashwin, Schulte, Claudia, Grover, Sandeep, Mohamed, Océane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Genetics, The Comprehensive Unbiased Risk Factor Assessment For, Consortium, Environment In Parkinson S Disease Courage-P. D., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], JPND Courage-PD [sponsor], Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Ashok Kumar Sreelatha, Ashwin, Schulte, Claudia, Grover, Sandeep, Mohamed, Océane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Genetics, The Comprehensive Unbiased Risk Factor Assessment For, and Consortium, Environment In Parkinson S Disease Courage-P. D.
Abstract: Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95 confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P-difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society
Published: 2022

4. Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], JPND Courage-PD [sponsor], Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Ashok Kumar Sreelatha, Ashwin, Schulte, Claudia, Grover, Sandeep, Mohamed, Océane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Genetics, The Comprehensive Unbiased Risk Factor Assessment For, Consortium, Environment In Parkinson S Disease Courage-P. D., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], JPND Courage-PD [sponsor], Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Ashok Kumar Sreelatha, Ashwin, Schulte, Claudia, Grover, Sandeep, Mohamed, Océane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Genetics, The Comprehensive Unbiased Risk Factor Assessment For, and Consortium, Environment In Parkinson S Disease Courage-P. D.
Abstract: Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95 confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P-difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society
Published: 2022

5. Whole genome and exome sequencing reference datasets from a multi-center and cross-platform benchmark study

Author: Zhao, Yongmei, Fang, Li Tai, Shen, Tsai-wei, Choudhari, Sulbha, Talsania, Keyur, Chen, Xiongfong, Shetty, Jyoti, Kriga, Yuliya, Tran, Bao, Zhu, Bin, Chen, Zhong, Chen, Wanqiu, Wang, Charles, Jaeger, Erich, Meerzaman, Daoud, Lu, Charles, Idler, Kenneth, Ren, Luyao, Zheng, Yuanting, Shi, Leming, Petitjean, Virginie, Sultan, Marc, Hung, Tiffany, Peters, Eric, Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Foox, Jonathan, Mason, Christopher E., Xiao, Chunlin, Hong, Huixiao, Xiao, Wenming, Zhao, Yongmei, Fang, Li Tai, Shen, Tsai-wei, Choudhari, Sulbha, Talsania, Keyur, Chen, Xiongfong, Shetty, Jyoti, Kriga, Yuliya, Tran, Bao, Zhu, Bin, Chen, Zhong, Chen, Wanqiu, Wang, Charles, Jaeger, Erich, Meerzaman, Daoud, Lu, Charles, Idler, Kenneth, Ren, Luyao, Zheng, Yuanting, Shi, Leming, Petitjean, Virginie, Sultan, Marc, Hung, Tiffany, Peters, Eric, Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Foox, Jonathan, Mason, Christopher E., Xiao, Chunlin, Hong, Huixiao, and Xiao, Wenming
Abstract: With the rapid advancement of sequencing technologies, next generation sequencing (NGS) analysis has been widely applied in cancer genomics research. More recently, NGS has been adopted in clinical oncology to advance personalized medicine. Clinical applications of precision oncology require accurate tests that can distinguish tumor-specific mutations from artifacts introduced during NGS processes or data analysis. Therefore, there is an urgent need to develop best practices in cancer mutation detection using NGS and the need for standard reference data sets for systematically measuring accuracy and reproducibility across platforms and methods. Within the SEQC2 consortium context, we established paired tumor-normal reference samples and generated whole-genome (WGS) and whole-exome sequencing (WES) data using sixteen library protocols, seven sequencing platforms at six different centers. We systematically interrogated somatic mutations in the reference samples to identify factors affecting detection reproducibility and accuracy in cancer genomes. These large cross-platform/site WGS and WES datasets using well-characterized reference samples will represent a powerful resource for benchmarking NGS technologies, bioinformatics pipelines, and for the cancer genomics studies.
Published: 2021
Full Text: View/download PDF

6. Whole genome and exome sequencing reference datasets from a multi-center and cross-platform benchmark study

Author: Zhao, Yongmei, Fang, Li Tai, Shen, Tsai-wei, Choudhari, Sulbha, Talsania, Keyur, Chen, Xiongfong, Shetty, Jyoti, Kriga, Yuliya, Tran, Bao, Zhu, Bin, Chen, Zhong, Chen, Wanqiu, Wang, Charles, Jaeger, Erich, Meerzaman, Daoud, Lu, Charles, Idler, Kenneth, Ren, Luyao, Zheng, Yuanting, Shi, Leming, Petitjean, Virginie, Sultan, Marc, Hung, Tiffany, Peters, Eric, Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Foox, Jonathan, Mason, Christopher E., Xiao, Chunlin, Hong, Huixiao, Xiao, Wenming, Zhao, Yongmei, Fang, Li Tai, Shen, Tsai-wei, Choudhari, Sulbha, Talsania, Keyur, Chen, Xiongfong, Shetty, Jyoti, Kriga, Yuliya, Tran, Bao, Zhu, Bin, Chen, Zhong, Chen, Wanqiu, Wang, Charles, Jaeger, Erich, Meerzaman, Daoud, Lu, Charles, Idler, Kenneth, Ren, Luyao, Zheng, Yuanting, Shi, Leming, Petitjean, Virginie, Sultan, Marc, Hung, Tiffany, Peters, Eric, Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Foox, Jonathan, Mason, Christopher E., Xiao, Chunlin, Hong, Huixiao, and Xiao, Wenming
Abstract: With the rapid advancement of sequencing technologies, next generation sequencing (NGS) analysis has been widely applied in cancer genomics research. More recently, NGS has been adopted in clinical oncology to advance personalized medicine. Clinical applications of precision oncology require accurate tests that can distinguish tumor-specific mutations from artifacts introduced during NGS processes or data analysis. Therefore, there is an urgent need to develop best practices in cancer mutation detection using NGS and the need for standard reference data sets for systematically measuring accuracy and reproducibility across platforms and methods. Within the SEQC2 consortium context, we established paired tumor-normal reference samples and generated whole-genome (WGS) and whole-exome sequencing (WES) data using sixteen library protocols, seven sequencing platforms at six different centers. We systematically interrogated somatic mutations in the reference samples to identify factors affecting detection reproducibility and accuracy in cancer genomes. These large cross-platform/site WGS and WES datasets using well-characterized reference samples will represent a powerful resource for benchmarking NGS technologies, bioinformatics pipelines, and for the cancer genomics studies.
Published: 2021
Full Text: View/download PDF

7. Whole genome and exome sequencing reference datasets from a multi-center and cross-platform benchmark study

Author: Zhao, Yongmei, Fang, Li Tai, Shen, Tsai-wei, Choudhari, Sulbha, Talsania, Keyur, Chen, Xiongfong, Shetty, Jyoti, Kriga, Yuliya, Tran, Bao, Zhu, Bin, Chen, Zhong, Chen, Wanqiu, Wang, Charles, Jaeger, Erich, Meerzaman, Daoud, Lu, Charles, Idler, Kenneth, Ren, Luyao, Zheng, Yuanting, Shi, Leming, Petitjean, Virginie, Sultan, Marc, Hung, Tiffany, Peters, Eric, Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Foox, Jonathan, Mason, Christopher E., Xiao, Chunlin, Hong, Huixiao, Xiao, Wenming, Zhao, Yongmei, Fang, Li Tai, Shen, Tsai-wei, Choudhari, Sulbha, Talsania, Keyur, Chen, Xiongfong, Shetty, Jyoti, Kriga, Yuliya, Tran, Bao, Zhu, Bin, Chen, Zhong, Chen, Wanqiu, Wang, Charles, Jaeger, Erich, Meerzaman, Daoud, Lu, Charles, Idler, Kenneth, Ren, Luyao, Zheng, Yuanting, Shi, Leming, Petitjean, Virginie, Sultan, Marc, Hung, Tiffany, Peters, Eric, Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Foox, Jonathan, Mason, Christopher E., Xiao, Chunlin, Hong, Huixiao, and Xiao, Wenming
Abstract: With the rapid advancement of sequencing technologies, next generation sequencing (NGS) analysis has been widely applied in cancer genomics research. More recently, NGS has been adopted in clinical oncology to advance personalized medicine. Clinical applications of precision oncology require accurate tests that can distinguish tumor-specific mutations from artifacts introduced during NGS processes or data analysis. Therefore, there is an urgent need to develop best practices in cancer mutation detection using NGS and the need for standard reference data sets for systematically measuring accuracy and reproducibility across platforms and methods. Within the SEQC2 consortium context, we established paired tumor-normal reference samples and generated whole-genome (WGS) and whole-exome sequencing (WES) data using sixteen library protocols, seven sequencing platforms at six different centers. We systematically interrogated somatic mutations in the reference samples to identify factors affecting detection reproducibility and accuracy in cancer genomes. These large cross-platform/site WGS and WES datasets using well-characterized reference samples will represent a powerful resource for benchmarking NGS technologies, bioinformatics pipelines, and for the cancer genomics studies.
Published: 2021
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8. Mendelian randomization study of smoking, alcohol, and coffee drinking in relation to Parkinso's disease

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND [sponsor], Domenighetti, Cloe, Sugier, Pierre Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, Mohamed, Oceane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaieva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Hardin, Marie-Christophe, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza-Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotak, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart Pc, Bloom, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrom, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Farien, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, DImitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND [sponsor], Domenighetti, Cloe, Sugier, Pierre Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, Mohamed, Oceane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaieva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Hardin, Marie-Christophe, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza-Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotak, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart Pc, Bloom, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrom, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Farien, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, DImitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, and Elbaz, Alexis
Abstract: Background:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective:To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods:We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results:We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion:Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
Published: 2021

9. Mendelian randomization study of smoking, alcohol, and coffee drinking in relation to Parkinso's disease

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND [sponsor], Domenighetti, Cloe, Sugier, Pierre Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, Mohamed, Oceane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaieva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Hardin, Marie-Christophe, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza-Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotak, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart Pc, Bloom, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrom, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Farien, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, DImitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND [sponsor], Domenighetti, Cloe, Sugier, Pierre Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, Mohamed, Oceane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaieva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Hardin, Marie-Christophe, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza-Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotak, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart Pc, Bloom, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrom, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Farien, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, DImitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, and Elbaz, Alexis
Abstract: Background:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective:To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods:We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results:We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion:Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
Published: 2021

10. Mendelian randomization study of smoking, alcohol, and coffee drinking in relation to Parkinso's disease

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND [sponsor], Domenighetti, Cloe, Sugier, Pierre Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, Mohamed, Oceane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaieva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Hardin, Marie-Christophe, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza-Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotak, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart Pc, Bloom, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrom, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Farien, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, DImitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND [sponsor], Domenighetti, Cloe, Sugier, Pierre Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, Mohamed, Oceane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaieva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Hardin, Marie-Christophe, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza-Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotak, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart Pc, Bloom, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrom, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Farien, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, DImitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, and Elbaz, Alexis
Abstract: Background:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective:To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods:We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results:We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion:Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
Published: 2021

11. Establishing community reference samples, data and call sets for benchmarking cancer mutation detection using whole-genome sequencing

Author: Fang, Li Tai, Zhu, Bin, Zhao, Yongmei, Chen, Wanqiu, Yang, Zhaowei, Kerrigan, Liz, Langenbach, Kurt, de Mars, Maryellen, Lu, Charles, Idler, Kenneth, Jacob, Howard, Zheng, Yuanting, Ren, Luyao, Yu, Ying, Jaeger, Erich, Schroth, Gary P., Abaan, Ogan D., Talsania, Keyur, Lack, Justin, Shen, Tsai-Wei, Chen, Zhong, Stanbouly, Seta, Tran, Bao, Shetty, Jyoti, Kriga, Yuliya, Meerzaman, Daoud, Nguyen, Cu, Petitjean, Virginie, Sultan, Marc, Cam, Margaret, Mehta, Monika, Hung, Tiffany, Peters, Eric, Kalamegham, Rasika, Sahraeian, Sayed Mohammad Ebrahim, Mohiyuddin, Marghoob, Guo, Yunfei, Yao, Lijing, Song, Lei, Lam, Hugo Y. K., Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Jensen, Roderick, V, Pirooznia, Mehdi, Li, Zhipan, Xiao, Chunlin, Sherry, Stephen T., Kusko, Rebecca, Moos, Malcolm, Donaldson, Eric, Tezak, Zivana, Ning, Baitang, Tong, Weida, Li, Jing, Duerken-Hughes, Penelope, Catalanotti, Claudia, Maheshwari, Shamoni, Shuga, Joe, Liang, Winnie S., Keats, Jonathan, Adkins, Jonathan, Tassone, Erica, Zismann, Victoria, McDaniel, Timothy, Trent, Jeffrey, Foox, Jonathan, Butler, Daniel, Mason, Christopher E., Hong, Huixiao, Shi, Leming, Wang, Charles, Xiao, Wenming, Fang, Li Tai, Zhu, Bin, Zhao, Yongmei, Chen, Wanqiu, Yang, Zhaowei, Kerrigan, Liz, Langenbach, Kurt, de Mars, Maryellen, Lu, Charles, Idler, Kenneth, Jacob, Howard, Zheng, Yuanting, Ren, Luyao, Yu, Ying, Jaeger, Erich, Schroth, Gary P., Abaan, Ogan D., Talsania, Keyur, Lack, Justin, Shen, Tsai-Wei, Chen, Zhong, Stanbouly, Seta, Tran, Bao, Shetty, Jyoti, Kriga, Yuliya, Meerzaman, Daoud, Nguyen, Cu, Petitjean, Virginie, Sultan, Marc, Cam, Margaret, Mehta, Monika, Hung, Tiffany, Peters, Eric, Kalamegham, Rasika, Sahraeian, Sayed Mohammad Ebrahim, Mohiyuddin, Marghoob, Guo, Yunfei, Yao, Lijing, Song, Lei, Lam, Hugo Y. K., Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Jensen, Roderick, V, Pirooznia, Mehdi, Li, Zhipan, Xiao, Chunlin, Sherry, Stephen T., Kusko, Rebecca, Moos, Malcolm, Donaldson, Eric, Tezak, Zivana, Ning, Baitang, Tong, Weida, Li, Jing, Duerken-Hughes, Penelope, Catalanotti, Claudia, Maheshwari, Shamoni, Shuga, Joe, Liang, Winnie S., Keats, Jonathan, Adkins, Jonathan, Tassone, Erica, Zismann, Victoria, McDaniel, Timothy, Trent, Jeffrey, Foox, Jonathan, Butler, Daniel, Mason, Christopher E., Hong, Huixiao, Shi, Leming, Wang, Charles, and Xiao, Wenming
Abstract: Tumor-normal paired DNA samples from a breast cancer cell line and a matched lymphoblastoid cell line enable calibration of clinical sequencing pipelines and benchmarking 'tumor-only' or 'matched tumor-normal' analyses. The lack of samples for generating standardized DNA datasets for setting up a sequencing pipeline or benchmarking the performance of different algorithms limits the implementation and uptake of cancer genomics. Here, we describe reference call sets obtained from paired tumor-normal genomic DNA (gDNA) samples derived from a breast cancer cell line-which is highly heterogeneous, with an aneuploid genome, and enriched in somatic alterations-and a matched lymphoblastoid cell line. We partially validated both somatic mutations and germline variants in these call sets via whole-exome sequencing (WES) with different sequencing platforms and targeted sequencing with >2,000-fold coverage, spanning 82% of genomic regions with high confidence. Although the gDNA reference samples are not representative of primary cancer cells from a clinical sample, when setting up a sequencing pipeline, they not only minimize potential biases from technologies, assays and informatics but also provide a unique resource for benchmarking 'tumor-only' or 'matched tumor-normal' analyses.
Published: 2021
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12. Whole genome and exome sequencing reference datasets from a multi-center and cross-platform benchmark study

Author: Zhao, Yongmei, Fang, Li Tai, Shen, Tsai-wei, Choudhari, Sulbha, Talsania, Keyur, Chen, Xiongfong, Shetty, Jyoti, Kriga, Yuliya, Tran, Bao, Zhu, Bin, Chen, Zhong, Chen, Wanqiu, Wang, Charles, Jaeger, Erich, Meerzaman, Daoud, Lu, Charles, Idler, Kenneth, Ren, Luyao, Zheng, Yuanting, Shi, Leming, Petitjean, Virginie, Sultan, Marc, Hung, Tiffany, Peters, Eric, Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Foox, Jonathan, Mason, Christopher E., Xiao, Chunlin, Hong, Huixiao, Xiao, Wenming, Zhao, Yongmei, Fang, Li Tai, Shen, Tsai-wei, Choudhari, Sulbha, Talsania, Keyur, Chen, Xiongfong, Shetty, Jyoti, Kriga, Yuliya, Tran, Bao, Zhu, Bin, Chen, Zhong, Chen, Wanqiu, Wang, Charles, Jaeger, Erich, Meerzaman, Daoud, Lu, Charles, Idler, Kenneth, Ren, Luyao, Zheng, Yuanting, Shi, Leming, Petitjean, Virginie, Sultan, Marc, Hung, Tiffany, Peters, Eric, Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Foox, Jonathan, Mason, Christopher E., Xiao, Chunlin, Hong, Huixiao, and Xiao, Wenming
Abstract: With the rapid advancement of sequencing technologies, next generation sequencing (NGS) analysis has been widely applied in cancer genomics research. More recently, NGS has been adopted in clinical oncology to advance personalized medicine. Clinical applications of precision oncology require accurate tests that can distinguish tumor-specific mutations from artifacts introduced during NGS processes or data analysis. Therefore, there is an urgent need to develop best practices in cancer mutation detection using NGS and the need for standard reference data sets for systematically measuring accuracy and reproducibility across platforms and methods. Within the SEQC2 consortium context, we established paired tumor-normal reference samples and generated whole-genome (WGS) and whole-exome sequencing (WES) data using sixteen library protocols, seven sequencing platforms at six different centers. We systematically interrogated somatic mutations in the reference samples to identify factors affecting detection reproducibility and accuracy in cancer genomes. These large cross-platform/site WGS and WES datasets using well-characterized reference samples will represent a powerful resource for benchmarking NGS technologies, bioinformatics pipelines, and for the cancer genomics studies.
Published: 2021
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13. Whole genome and exome sequencing reference datasets from a multi-center and cross-platform benchmark study

Author: Zhao, Yongmei, Fang, Li Tai, Shen, Tsai-wei, Choudhari, Sulbha, Talsania, Keyur, Chen, Xiongfong, Shetty, Jyoti, Kriga, Yuliya, Tran, Bao, Zhu, Bin, Chen, Zhong, Chen, Wanqiu, Wang, Charles, Jaeger, Erich, Meerzaman, Daoud, Lu, Charles, Idler, Kenneth, Ren, Luyao, Zheng, Yuanting, Shi, Leming, Petitjean, Virginie, Sultan, Marc, Hung, Tiffany, Peters, Eric, Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Foox, Jonathan, Mason, Christopher E., Xiao, Chunlin, Hong, Huixiao, Xiao, Wenming, Zhao, Yongmei, Fang, Li Tai, Shen, Tsai-wei, Choudhari, Sulbha, Talsania, Keyur, Chen, Xiongfong, Shetty, Jyoti, Kriga, Yuliya, Tran, Bao, Zhu, Bin, Chen, Zhong, Chen, Wanqiu, Wang, Charles, Jaeger, Erich, Meerzaman, Daoud, Lu, Charles, Idler, Kenneth, Ren, Luyao, Zheng, Yuanting, Shi, Leming, Petitjean, Virginie, Sultan, Marc, Hung, Tiffany, Peters, Eric, Drabek, Jiri, Vojta, Petr, Maestro, Roberta, Gasparotto, Daniela, Koks, Sulev, Reimann, Ene, Scherer, Andreas, Nordlund, Jessica, Liljedahl, Ulrika, Foox, Jonathan, Mason, Christopher E., Xiao, Chunlin, Hong, Huixiao, and Xiao, Wenming
Abstract: With the rapid advancement of sequencing technologies, next generation sequencing (NGS) analysis has been widely applied in cancer genomics research. More recently, NGS has been adopted in clinical oncology to advance personalized medicine. Clinical applications of precision oncology require accurate tests that can distinguish tumor-specific mutations from artifacts introduced during NGS processes or data analysis. Therefore, there is an urgent need to develop best practices in cancer mutation detection using NGS and the need for standard reference data sets for systematically measuring accuracy and reproducibility across platforms and methods. Within the SEQC2 consortium context, we established paired tumor-normal reference samples and generated whole-genome (WGS) and whole-exome sequencing (WES) data using sixteen library protocols, seven sequencing platforms at six different centers. We systematically interrogated somatic mutations in the reference samples to identify factors affecting detection reproducibility and accuracy in cancer genomes. These large cross-platform/site WGS and WES datasets using well-characterized reference samples will represent a powerful resource for benchmarking NGS technologies, bioinformatics pipelines, and for the cancer genomics studies.
Published: 2021
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14. Acute effects of methcathinone and manganese in mice : A dose response study

Author: Asser, Andres, Koks, Sulev, Soomets, Ursel, Terasmaa, Anton, Sauk, Martin, Eltermaa, Mall, Piip, Piret, Ubhayasekera, Kumari, Bergquist, Jonas, Taba, Pille, Asser, Andres, Koks, Sulev, Soomets, Ursel, Terasmaa, Anton, Sauk, Martin, Eltermaa, Mall, Piip, Piret, Ubhayasekera, Kumari, Bergquist, Jonas, and Taba, Pille
Abstract: An intravenously injectable illicit drug made by mixing pseudoephedrine, potassium permanganate, vinegar and water, yielding methcathinone (Mcat) and manganese (Mn), induces an extrapyramidal syndrome with parkinsonism, dystonia, gait and balance disorders similar to manganism. Although the cause of the syndrome is largely attributed to Mn, the interaction of the drug's individual components is not known and the role of Mcat is possibly underestimated. Aim of the present study was to analyze dose-dependent behavioral effects of the mixture and its two main active components Mcat and Mn in an acute setting and determine the lethal doses of each substance. Three groups of C57BL/6 mice were injected intraperitoneally with (1) the drug mixture containing 10, 25, 50, 100 or 150 mg of Mcat and respectively 1.6, 3.8, 6.9, 17.1 and 22.6 mg of Mn per kilogram of body weight; (2) 10, 25, 50, 100, 150, 200 or 300 mg of racemic Mcat/kg of body weight; (3) MnCl2 10, 25 or 50 mg/kg of body weight. Locomotor activity of the animals, various signs and time of death were recorded. Lower doses (10 and 25 mg/kg) of Mcat had a clear motor activity stimulating effect and this was clearly dose-dependent. High doses of Mcat produced epileptic seizures in 74% of the animals and became lethal with the highest doses. Similarly, the mixture had a clear dose-dependent stimulating effect and the higher doses became lethal. The LD50 of the pseudoephedrine mixture was 110.2 mg of Mcat/kg and for pure Mcat 201.7 mg/kg. Mn did not prove to be lethal in doses up to 50 mg/kg, but had a strong dose dependent inhibitory effect on the animals' behavior. Our data reveal that both Mn and Mcat have a significant role in the toxicity of the mixture.
Published: 2019
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15. Acute effects of methcathinone and manganese in mice : A dose response study

Author: Asser, Andres, Koks, Sulev, Soomets, Ursel, Terasmaa, Anton, Sauk, Martin, Eltermaa, Mall, Piip, Piret, Ubhayasekera, Kumari, Bergquist, Jonas, Taba, Pille, Asser, Andres, Koks, Sulev, Soomets, Ursel, Terasmaa, Anton, Sauk, Martin, Eltermaa, Mall, Piip, Piret, Ubhayasekera, Kumari, Bergquist, Jonas, and Taba, Pille
Abstract: An intravenously injectable illicit drug made by mixing pseudoephedrine, potassium permanganate, vinegar and water, yielding methcathinone (Mcat) and manganese (Mn), induces an extrapyramidal syndrome with parkinsonism, dystonia, gait and balance disorders similar to manganism. Although the cause of the syndrome is largely attributed to Mn, the interaction of the drug's individual components is not known and the role of Mcat is possibly underestimated. Aim of the present study was to analyze dose-dependent behavioral effects of the mixture and its two main active components Mcat and Mn in an acute setting and determine the lethal doses of each substance. Three groups of C57BL/6 mice were injected intraperitoneally with (1) the drug mixture containing 10, 25, 50, 100 or 150 mg of Mcat and respectively 1.6, 3.8, 6.9, 17.1 and 22.6 mg of Mn per kilogram of body weight; (2) 10, 25, 50, 100, 150, 200 or 300 mg of racemic Mcat/kg of body weight; (3) MnCl2 10, 25 or 50 mg/kg of body weight. Locomotor activity of the animals, various signs and time of death were recorded. Lower doses (10 and 25 mg/kg) of Mcat had a clear motor activity stimulating effect and this was clearly dose-dependent. High doses of Mcat produced epileptic seizures in 74% of the animals and became lethal with the highest doses. Similarly, the mixture had a clear dose-dependent stimulating effect and the higher doses became lethal. The LD50 of the pseudoephedrine mixture was 110.2 mg of Mcat/kg and for pure Mcat 201.7 mg/kg. Mn did not prove to be lethal in doses up to 50 mg/kg, but had a strong dose dependent inhibitory effect on the animals' behavior. Our data reveal that both Mn and Mcat have a significant role in the toxicity of the mixture.
Published: 2019
Full Text: View/download PDF

16. Acute effects of methcathinone and manganese in mice : A dose response study

Author: Asser, Andres, Koks, Sulev, Soomets, Ursel, Terasmaa, Anton, Sauk, Martin, Eltermaa, Mall, Piip, Piret, Ubhayasekera, Kumari, Bergquist, Jonas, Taba, Pille, Asser, Andres, Koks, Sulev, Soomets, Ursel, Terasmaa, Anton, Sauk, Martin, Eltermaa, Mall, Piip, Piret, Ubhayasekera, Kumari, Bergquist, Jonas, and Taba, Pille
Abstract: An intravenously injectable illicit drug made by mixing pseudoephedrine, potassium permanganate, vinegar and water, yielding methcathinone (Mcat) and manganese (Mn), induces an extrapyramidal syndrome with parkinsonism, dystonia, gait and balance disorders similar to manganism. Although the cause of the syndrome is largely attributed to Mn, the interaction of the drug's individual components is not known and the role of Mcat is possibly underestimated. Aim of the present study was to analyze dose-dependent behavioral effects of the mixture and its two main active components Mcat and Mn in an acute setting and determine the lethal doses of each substance. Three groups of C57BL/6 mice were injected intraperitoneally with (1) the drug mixture containing 10, 25, 50, 100 or 150 mg of Mcat and respectively 1.6, 3.8, 6.9, 17.1 and 22.6 mg of Mn per kilogram of body weight; (2) 10, 25, 50, 100, 150, 200 or 300 mg of racemic Mcat/kg of body weight; (3) MnCl2 10, 25 or 50 mg/kg of body weight. Locomotor activity of the animals, various signs and time of death were recorded. Lower doses (10 and 25 mg/kg) of Mcat had a clear motor activity stimulating effect and this was clearly dose-dependent. High doses of Mcat produced epileptic seizures in 74% of the animals and became lethal with the highest doses. Similarly, the mixture had a clear dose-dependent stimulating effect and the higher doses became lethal. The LD50 of the pseudoephedrine mixture was 110.2 mg of Mcat/kg and for pure Mcat 201.7 mg/kg. Mn did not prove to be lethal in doses up to 50 mg/kg, but had a strong dose dependent inhibitory effect on the animals' behavior. Our data reveal that both Mn and Mcat have a significant role in the toxicity of the mixture.
Published: 2019
Full Text: View/download PDF

17. Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset.

Author: Billingsley, Kimberley J, Billingsley, Kimberley J, Barbosa, Ines A, Bandrés-Ciga, Sara, Quinn, John P, Bubb, Vivien J, Deshpande, Charu, Botia, Juan A, Reynolds, Regina H, Zhang, David, Simpson, Michael A, Blauwendraat, Cornelis, Gan-Or, Ziv, Gibbs, J Raphael, Nalls, Mike A, Singleton, Andrew, International Parkinson’s Disease Genomics Consortium (IPDGC), Ryten, Mina, Koks, Sulev, Billingsley, Kimberley J, Billingsley, Kimberley J, Barbosa, Ines A, Bandrés-Ciga, Sara, Quinn, John P, Bubb, Vivien J, Deshpande, Charu, Botia, Juan A, Reynolds, Regina H, Zhang, David, Simpson, Michael A, Blauwendraat, Cornelis, Gan-Or, Ziv, Gibbs, J Raphael, Nalls, Mike A, Singleton, Andrew, International Parkinson’s Disease Genomics Consortium (IPDGC), Ryten, Mina, and Koks, Sulev
Abstract: Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson's disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial function-associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.
Published: 2019

18. Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset.

Author: Billingsley, Kimberley J, Billingsley, Kimberley J, Barbosa, Ines A, Bandrés-Ciga, Sara, Quinn, John P, Bubb, Vivien J, Deshpande, Charu, Botia, Juan A, Reynolds, Regina H, Zhang, David, Simpson, Michael A, Blauwendraat, Cornelis, Gan-Or, Ziv, Gibbs, J Raphael, Nalls, Mike A, Singleton, Andrew, International Parkinson’s Disease Genomics Consortium (IPDGC), Ryten, Mina, Koks, Sulev, Billingsley, Kimberley J, Billingsley, Kimberley J, Barbosa, Ines A, Bandrés-Ciga, Sara, Quinn, John P, Bubb, Vivien J, Deshpande, Charu, Botia, Juan A, Reynolds, Regina H, Zhang, David, Simpson, Michael A, Blauwendraat, Cornelis, Gan-Or, Ziv, Gibbs, J Raphael, Nalls, Mike A, Singleton, Andrew, International Parkinson’s Disease Genomics Consortium (IPDGC), Ryten, Mina, and Koks, Sulev
Abstract: Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson's disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial function-associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.
Published: 2019

19. Acute effects of methcathinone and manganese in mice : A dose response study

Author: Asser, Andres, Koks, Sulev, Soomets, Ursel, Terasmaa, Anton, Sauk, Martin, Eltermaa, Mall, Piip, Piret, Ubhayasekera, Kumari, Bergquist, Jonas, Taba, Pille, Asser, Andres, Koks, Sulev, Soomets, Ursel, Terasmaa, Anton, Sauk, Martin, Eltermaa, Mall, Piip, Piret, Ubhayasekera, Kumari, Bergquist, Jonas, and Taba, Pille
Abstract: An intravenously injectable illicit drug made by mixing pseudoephedrine, potassium permanganate, vinegar and water, yielding methcathinone (Mcat) and manganese (Mn), induces an extrapyramidal syndrome with parkinsonism, dystonia, gait and balance disorders similar to manganism. Although the cause of the syndrome is largely attributed to Mn, the interaction of the drug's individual components is not known and the role of Mcat is possibly underestimated. Aim of the present study was to analyze dose-dependent behavioral effects of the mixture and its two main active components Mcat and Mn in an acute setting and determine the lethal doses of each substance. Three groups of C57BL/6 mice were injected intraperitoneally with (1) the drug mixture containing 10, 25, 50, 100 or 150 mg of Mcat and respectively 1.6, 3.8, 6.9, 17.1 and 22.6 mg of Mn per kilogram of body weight; (2) 10, 25, 50, 100, 150, 200 or 300 mg of racemic Mcat/kg of body weight; (3) MnCl2 10, 25 or 50 mg/kg of body weight. Locomotor activity of the animals, various signs and time of death were recorded. Lower doses (10 and 25 mg/kg) of Mcat had a clear motor activity stimulating effect and this was clearly dose-dependent. High doses of Mcat produced epileptic seizures in 74% of the animals and became lethal with the highest doses. Similarly, the mixture had a clear dose-dependent stimulating effect and the higher doses became lethal. The LD50 of the pseudoephedrine mixture was 110.2 mg of Mcat/kg and for pure Mcat 201.7 mg/kg. Mn did not prove to be lethal in doses up to 50 mg/kg, but had a strong dose dependent inhibitory effect on the animals' behavior. Our data reveal that both Mn and Mcat have a significant role in the toxicity of the mixture.
Published: 2019
Full Text: View/download PDF

20. Acute effects of methcathinone and manganese in mice : A dose response study

Author: Asser, Andres, Koks, Sulev, Soomets, Ursel, Terasmaa, Anton, Sauk, Martin, Eltermaa, Mall, Piip, Piret, Ubhayasekera, Kumari, Bergquist, Jonas, Taba, Pille, Asser, Andres, Koks, Sulev, Soomets, Ursel, Terasmaa, Anton, Sauk, Martin, Eltermaa, Mall, Piip, Piret, Ubhayasekera, Kumari, Bergquist, Jonas, and Taba, Pille
Abstract: An intravenously injectable illicit drug made by mixing pseudoephedrine, potassium permanganate, vinegar and water, yielding methcathinone (Mcat) and manganese (Mn), induces an extrapyramidal syndrome with parkinsonism, dystonia, gait and balance disorders similar to manganism. Although the cause of the syndrome is largely attributed to Mn, the interaction of the drug's individual components is not known and the role of Mcat is possibly underestimated. Aim of the present study was to analyze dose-dependent behavioral effects of the mixture and its two main active components Mcat and Mn in an acute setting and determine the lethal doses of each substance. Three groups of C57BL/6 mice were injected intraperitoneally with (1) the drug mixture containing 10, 25, 50, 100 or 150 mg of Mcat and respectively 1.6, 3.8, 6.9, 17.1 and 22.6 mg of Mn per kilogram of body weight; (2) 10, 25, 50, 100, 150, 200 or 300 mg of racemic Mcat/kg of body weight; (3) MnCl2 10, 25 or 50 mg/kg of body weight. Locomotor activity of the animals, various signs and time of death were recorded. Lower doses (10 and 25 mg/kg) of Mcat had a clear motor activity stimulating effect and this was clearly dose-dependent. High doses of Mcat produced epileptic seizures in 74% of the animals and became lethal with the highest doses. Similarly, the mixture had a clear dose-dependent stimulating effect and the higher doses became lethal. The LD50 of the pseudoephedrine mixture was 110.2 mg of Mcat/kg and for pure Mcat 201.7 mg/kg. Mn did not prove to be lethal in doses up to 50 mg/kg, but had a strong dose dependent inhibitory effect on the animals' behavior. Our data reveal that both Mn and Mcat have a significant role in the toxicity of the mixture.
Published: 2019
Full Text: View/download PDF

21. Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

Author: Tsoi, Lam C., Stuart, Philip E., Tian, Chao, Gudjonsson, Johann E., Das, Sayantan, Zawistowski, Matthew, Ellinghaus, Eva, Barker, Jonathan N., Chandran, Vinod, Dand, Nick, Callis Duffin, Kristina, Enerbäck, Charlotta, Esko, Tonu, Franke, Andre, Gladman, Dafna D., Hoffmann, Per, Kingo, Kulli, Koks, Sulev, Krueger, Gerald G., Lim, Henry W., Metspalu, Andres, Mrowietz, Ulrich, Mucha, Soren, Rahman, Proton, Reis, Andre, Tejasvi, Trilokraj, Trembath, Richard, Voorhees, John J., Weidinger, Stephan, Weichenthal, Michael, Wen, Xiaoquan, Eriksson, Nicholas, Kang, Hyun M., Hinds, David A., Nair, Rajan P., Abecasis, Goncalo R., Elder, James T., Tsoi, Lam C., Stuart, Philip E., Tian, Chao, Gudjonsson, Johann E., Das, Sayantan, Zawistowski, Matthew, Ellinghaus, Eva, Barker, Jonathan N., Chandran, Vinod, Dand, Nick, Callis Duffin, Kristina, Enerbäck, Charlotta, Esko, Tonu, Franke, Andre, Gladman, Dafna D., Hoffmann, Per, Kingo, Kulli, Koks, Sulev, Krueger, Gerald G., Lim, Henry W., Metspalu, Andres, Mrowietz, Ulrich, Mucha, Soren, Rahman, Proton, Reis, Andre, Tejasvi, Trilokraj, Trembath, Richard, Voorhees, John J., Weidinger, Stephan, Weichenthal, Michael, Wen, Xiaoquan, Eriksson, Nicholas, Kang, Hyun M., Hinds, David A., Nair, Rajan P., Abecasis, Goncalo R., and Elder, James T.
Abstract: Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size amp;gt;39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFkB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8(+) T-cells and CD4(+) T-cells including T(H)0, T(H)1 and T(H)17). The identified loci explain similar to 28% of the genetic heritability and generate a discriminatory genetic risk score (AUC = 0.76 in our sample) that is significantly correlated with age at onset (p = 2 x 10(-89)). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis., Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; Foundation for the National Institutes of Health; Dermatology Foundation; National Psoriasis Foundation; Arthritis National Research Foundation; Ann Arbor Veterans Affairs Hospital; Dawn and Dudley Holmes Foundation; Babcock Memorial Trust; Medical Research Council [MR/L011808/1]; German Ministry of Education and Research (BMBF); Doris Duke Foundation [2013106]; National Institute of Health [K08AR060802, R01AR06907]; Taubman Medical Research Institute; Department of Health via the NIHR comprehensive Biomedical Research Center; Kings College London; KCH NHS Foundation Trust; Barbara and Neal Henschel Charitable Foundation; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); National Human Genome Research Institute of the National Institutes of Health [R44HG006981]; International Psoriasis Council
Published: 2017
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22. Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

Author: Tsoi, Lam C., Stuart, Philip E., Tian, Chao, Gudjonsson, Johann E., Das, Sayantan, Zawistowski, Matthew, Ellinghaus, Eva, Barker, Jonathan N., Chandran, Vinod, Dand, Nick, Callis Duffin, Kristina, Enerbäck, Charlotta, Esko, Tonu, Franke, Andre, Gladman, Dafna D., Hoffmann, Per, Kingo, Kulli, Koks, Sulev, Krueger, Gerald G., Lim, Henry W., Metspalu, Andres, Mrowietz, Ulrich, Mucha, Soren, Rahman, Proton, Reis, Andre, Tejasvi, Trilokraj, Trembath, Richard, Voorhees, John J., Weidinger, Stephan, Weichenthal, Michael, Wen, Xiaoquan, Eriksson, Nicholas, Kang, Hyun M., Hinds, David A., Nair, Rajan P., Abecasis, Goncalo R., Elder, James T., Tsoi, Lam C., Stuart, Philip E., Tian, Chao, Gudjonsson, Johann E., Das, Sayantan, Zawistowski, Matthew, Ellinghaus, Eva, Barker, Jonathan N., Chandran, Vinod, Dand, Nick, Callis Duffin, Kristina, Enerbäck, Charlotta, Esko, Tonu, Franke, Andre, Gladman, Dafna D., Hoffmann, Per, Kingo, Kulli, Koks, Sulev, Krueger, Gerald G., Lim, Henry W., Metspalu, Andres, Mrowietz, Ulrich, Mucha, Soren, Rahman, Proton, Reis, Andre, Tejasvi, Trilokraj, Trembath, Richard, Voorhees, John J., Weidinger, Stephan, Weichenthal, Michael, Wen, Xiaoquan, Eriksson, Nicholas, Kang, Hyun M., Hinds, David A., Nair, Rajan P., Abecasis, Goncalo R., and Elder, James T.
Abstract: Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size amp;gt;39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFkB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8(+) T-cells and CD4(+) T-cells including T(H)0, T(H)1 and T(H)17). The identified loci explain similar to 28% of the genetic heritability and generate a discriminatory genetic risk score (AUC = 0.76 in our sample) that is significantly correlated with age at onset (p = 2 x 10(-89)). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis., Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; Foundation for the National Institutes of Health; Dermatology Foundation; National Psoriasis Foundation; Arthritis National Research Foundation; Ann Arbor Veterans Affairs Hospital; Dawn and Dudley Holmes Foundation; Babcock Memorial Trust; Medical Research Council [MR/L011808/1]; German Ministry of Education and Research (BMBF); Doris Duke Foundation [2013106]; National Institute of Health [K08AR060802, R01AR06907]; Taubman Medical Research Institute; Department of Health via the NIHR comprehensive Biomedical Research Center; Kings College London; KCH NHS Foundation Trust; Barbara and Neal Henschel Charitable Foundation; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); National Human Genome Research Institute of the National Institutes of Health [R44HG006981]; International Psoriasis Council
Published: 2017
Full Text: View/download PDF

23. Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

Author: Tsoi, Lam C., Stuart, Philip E., Tian, Chao, Gudjonsson, Johann E., Das, Sayantan, Zawistowski, Matthew, Ellinghaus, Eva, Barker, Jonathan N., Chandran, Vinod, Dand, Nick, Callis Duffin, Kristina, Enerbäck, Charlotta, Esko, Tonu, Franke, Andre, Gladman, Dafna D., Hoffmann, Per, Kingo, Kulli, Koks, Sulev, Krueger, Gerald G., Lim, Henry W., Metspalu, Andres, Mrowietz, Ulrich, Mucha, Soren, Rahman, Proton, Reis, Andre, Tejasvi, Trilokraj, Trembath, Richard, Voorhees, John J., Weidinger, Stephan, Weichenthal, Michael, Wen, Xiaoquan, Eriksson, Nicholas, Kang, Hyun M., Hinds, David A., Nair, Rajan P., Abecasis, Goncalo R., Elder, James T., Tsoi, Lam C., Stuart, Philip E., Tian, Chao, Gudjonsson, Johann E., Das, Sayantan, Zawistowski, Matthew, Ellinghaus, Eva, Barker, Jonathan N., Chandran, Vinod, Dand, Nick, Callis Duffin, Kristina, Enerbäck, Charlotta, Esko, Tonu, Franke, Andre, Gladman, Dafna D., Hoffmann, Per, Kingo, Kulli, Koks, Sulev, Krueger, Gerald G., Lim, Henry W., Metspalu, Andres, Mrowietz, Ulrich, Mucha, Soren, Rahman, Proton, Reis, Andre, Tejasvi, Trilokraj, Trembath, Richard, Voorhees, John J., Weidinger, Stephan, Weichenthal, Michael, Wen, Xiaoquan, Eriksson, Nicholas, Kang, Hyun M., Hinds, David A., Nair, Rajan P., Abecasis, Goncalo R., and Elder, James T.
Abstract: Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size amp;gt;39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFkB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8(+) T-cells and CD4(+) T-cells including T(H)0, T(H)1 and T(H)17). The identified loci explain similar to 28% of the genetic heritability and generate a discriminatory genetic risk score (AUC = 0.76 in our sample) that is significantly correlated with age at onset (p = 2 x 10(-89)). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis., Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; Foundation for the National Institutes of Health; Dermatology Foundation; National Psoriasis Foundation; Arthritis National Research Foundation; Ann Arbor Veterans Affairs Hospital; Dawn and Dudley Holmes Foundation; Babcock Memorial Trust; Medical Research Council [MR/L011808/1]; German Ministry of Education and Research (BMBF); Doris Duke Foundation [2013106]; National Institute of Health [K08AR060802, R01AR06907]; Taubman Medical Research Institute; Department of Health via the NIHR comprehensive Biomedical Research Center; Kings College London; KCH NHS Foundation Trust; Barbara and Neal Henschel Charitable Foundation; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); National Human Genome Research Institute of the National Institutes of Health [R44HG006981]; International Psoriasis Council
Published: 2017
Full Text: View/download PDF

24. Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

Author: Tsoi, Lam C., Stuart, Philip E., Tian, Chao, Gudjonsson, Johann E., Das, Sayantan, Zawistowski, Matthew, Ellinghaus, Eva, Barker, Jonathan N., Chandran, Vinod, Dand, Nick, Callis Duffin, Kristina, Enerbäck, Charlotta, Esko, Tonu, Franke, Andre, Gladman, Dafna D., Hoffmann, Per, Kingo, Kulli, Koks, Sulev, Krueger, Gerald G., Lim, Henry W., Metspalu, Andres, Mrowietz, Ulrich, Mucha, Soren, Rahman, Proton, Reis, Andre, Tejasvi, Trilokraj, Trembath, Richard, Voorhees, John J., Weidinger, Stephan, Weichenthal, Michael, Wen, Xiaoquan, Eriksson, Nicholas, Kang, Hyun M., Hinds, David A., Nair, Rajan P., Abecasis, Goncalo R., Elder, James T., Tsoi, Lam C., Stuart, Philip E., Tian, Chao, Gudjonsson, Johann E., Das, Sayantan, Zawistowski, Matthew, Ellinghaus, Eva, Barker, Jonathan N., Chandran, Vinod, Dand, Nick, Callis Duffin, Kristina, Enerbäck, Charlotta, Esko, Tonu, Franke, Andre, Gladman, Dafna D., Hoffmann, Per, Kingo, Kulli, Koks, Sulev, Krueger, Gerald G., Lim, Henry W., Metspalu, Andres, Mrowietz, Ulrich, Mucha, Soren, Rahman, Proton, Reis, Andre, Tejasvi, Trilokraj, Trembath, Richard, Voorhees, John J., Weidinger, Stephan, Weichenthal, Michael, Wen, Xiaoquan, Eriksson, Nicholas, Kang, Hyun M., Hinds, David A., Nair, Rajan P., Abecasis, Goncalo R., and Elder, James T.
Abstract: Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size amp;gt;39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFkB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8(+) T-cells and CD4(+) T-cells including T(H)0, T(H)1 and T(H)17). The identified loci explain similar to 28% of the genetic heritability and generate a discriminatory genetic risk score (AUC = 0.76 in our sample) that is significantly correlated with age at onset (p = 2 x 10(-89)). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis., Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; Foundation for the National Institutes of Health; Dermatology Foundation; National Psoriasis Foundation; Arthritis National Research Foundation; Ann Arbor Veterans Affairs Hospital; Dawn and Dudley Holmes Foundation; Babcock Memorial Trust; Medical Research Council [MR/L011808/1]; German Ministry of Education and Research (BMBF); Doris Duke Foundation [2013106]; National Institute of Health [K08AR060802, R01AR06907]; Taubman Medical Research Institute; Department of Health via the NIHR comprehensive Biomedical Research Center; Kings College London; KCH NHS Foundation Trust; Barbara and Neal Henschel Charitable Foundation; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); National Human Genome Research Institute of the National Institutes of Health [R44HG006981]; International Psoriasis Council
Published: 2017
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25. Recent Insights into the Role of Unfolded Protein Response in ER Stress in Health and Disease

Author: Lindholm, Dan, Korhonen, Laura, Eriksson, Ove, Koks, Sulev, Lindholm, Dan, Korhonen, Laura, Eriksson, Ove, and Koks, Sulev
Abstract: Unfolded stress response (UPR) is a conserved cellular pathway involved in protein quality control to maintain homeostasis under different conditions and disease states characterized by cell stress. Although three general schemes of and genes induced by UPR are rather well-established, open questions remain including the precise role of UPR in human diseases and the interactions between different sensor systems during cell stress signaling. Particularly, the issue how the normally adaptive and pro-survival UPR pathway turns into a deleterious process causing sustained endoplasmic reticulum (ER) stress and cell death requires more studies. UPR is also named a friend with multiple personalities that we need to understand better to fully recognize its role in normal physiology and in disease pathology. UPR interacts with other organelles including mitochondria, and with cell stress signals and degradation pathways such as autophagy and the ubiquitin proteasome system. Here we review current concepts and mechanisms of UPR as studied in different cells and model systems and highlight the relevance of UPR and related stress signals in various human diseases.
Published: 2017
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26. Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

Author: Tsoi, Lam C., Stuart, Philip E., Tian, Chao, Gudjonsson, Johann E., Das, Sayantan, Zawistowski, Matthew, Ellinghaus, Eva, Barker, Jonathan N., Chandran, Vinod, Dand, Nick, Callis Duffin, Kristina, Enerbäck, Charlotta, Esko, Tonu, Franke, Andre, Gladman, Dafna D., Hoffmann, Per, Kingo, Kulli, Koks, Sulev, Krueger, Gerald G., Lim, Henry W., Metspalu, Andres, Mrowietz, Ulrich, Mucha, Soren, Rahman, Proton, Reis, Andre, Tejasvi, Trilokraj, Trembath, Richard, Voorhees, John J., Weidinger, Stephan, Weichenthal, Michael, Wen, Xiaoquan, Eriksson, Nicholas, Kang, Hyun M., Hinds, David A., Nair, Rajan P., Abecasis, Goncalo R., Elder, James T., Tsoi, Lam C., Stuart, Philip E., Tian, Chao, Gudjonsson, Johann E., Das, Sayantan, Zawistowski, Matthew, Ellinghaus, Eva, Barker, Jonathan N., Chandran, Vinod, Dand, Nick, Callis Duffin, Kristina, Enerbäck, Charlotta, Esko, Tonu, Franke, Andre, Gladman, Dafna D., Hoffmann, Per, Kingo, Kulli, Koks, Sulev, Krueger, Gerald G., Lim, Henry W., Metspalu, Andres, Mrowietz, Ulrich, Mucha, Soren, Rahman, Proton, Reis, Andre, Tejasvi, Trilokraj, Trembath, Richard, Voorhees, John J., Weidinger, Stephan, Weichenthal, Michael, Wen, Xiaoquan, Eriksson, Nicholas, Kang, Hyun M., Hinds, David A., Nair, Rajan P., Abecasis, Goncalo R., and Elder, James T.
Abstract: Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size amp;gt;39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFkB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8(+) T-cells and CD4(+) T-cells including T(H)0, T(H)1 and T(H)17). The identified loci explain similar to 28% of the genetic heritability and generate a discriminatory genetic risk score (AUC = 0.76 in our sample) that is significantly correlated with age at onset (p = 2 x 10(-89)). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis., Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; Foundation for the National Institutes of Health; Dermatology Foundation; National Psoriasis Foundation; Arthritis National Research Foundation; Ann Arbor Veterans Affairs Hospital; Dawn and Dudley Holmes Foundation; Babcock Memorial Trust; Medical Research Council [MR/L011808/1]; German Ministry of Education and Research (BMBF); Doris Duke Foundation [2013106]; National Institute of Health [K08AR060802, R01AR06907]; Taubman Medical Research Institute; Department of Health via the NIHR comprehensive Biomedical Research Center; Kings College London; KCH NHS Foundation Trust; Barbara and Neal Henschel Charitable Foundation; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); National Human Genome Research Institute of the National Institutes of Health [R44HG006981]; International Psoriasis Council
Published: 2017
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27. Increased striatal VMAT2 binding in mice after chronic administration of methcathinone and manganese

Author: Asser, Andres, Koks, Sulev, Snellman, Anniina, Haaparanta-Solin, Merja, Arponen, Eveliina, Gronroos, Tove, Nairismagi, Jaak, Bergquist, Jonas, Soomets, Ursel, Piip, Piret, Eltermaa, Mall, Sauk, Martin, Lindmae, Hanna, Rinne, Juha O., Taba, Pille, Asser, Andres, Koks, Sulev, Snellman, Anniina, Haaparanta-Solin, Merja, Arponen, Eveliina, Gronroos, Tove, Nairismagi, Jaak, Bergquist, Jonas, Soomets, Ursel, Piip, Piret, Eltermaa, Mall, Sauk, Martin, Lindmae, Hanna, Rinne, Juha O., and Taba, Pille
Abstract: Intravenous use of a psychostimulant drug containing methcathinone (ephedrone) and manganese causes an irreversible extrapyramidal syndrome in drug abusers. We aimed to reproduce the syndrome in mice to evaluate dopaminergic damage. C57/B6 mice were intraperitoneally injected once a day with the study drug or saline for a period of 27 weeks. Motor activity was recorded in an automated motility-box. After 13 and 27 weeks of treatment, ex vivo digital autoradiography was performed using [C-11]dihydrotetrabenazine ([C-11]DTBZ). After 27 weeks of treatment [C-11]DTBZ autoradiography demonstrated a significant increase in the striatum to -cerebellum binding ratio compared with saline treated controls. At the same time point, there was no evident change in motor activity. Increased [C-11]DTBZ binding may indicate vesicular monoamine transporter type 2 (VMAT2) function is altered. The lack of extrapyramidal symptoms in animals could be attributed to low dosing regimen or high metabolic rate.
Published: 2016
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28. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci

Author: Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Jo, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kulli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerbäck, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., Elder, James T., Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Jo, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kulli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerbäck, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., and Elder, James T.
Abstract: Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (Pless than5 x 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies., Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR062382, R01AR065183]; Wellcome Trust; German Research Foundation; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02]; Medical Research Council Stratified Medicine award [MR/L011808/1]; German Ministry of Education and Research (BMBF) through the e:Med sysINFLAME grant; Doris Duke Foundation; Department of Health via the NIHR comprehensive Biomedical Research Center award; Kings College London; KCH NHS Foundation Trust; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); Ann Arbor Veterans Affairs Hospital
Published: 2015
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29. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci

Author: Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Jo, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kulli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerbäck, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., Elder, James T., Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Jo, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kulli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerbäck, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., and Elder, James T.
Abstract: Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (Pless than5 x 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies., Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR062382, R01AR065183]; Wellcome Trust; German Research Foundation; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02]; Medical Research Council Stratified Medicine award [MR/L011808/1]; German Ministry of Education and Research (BMBF) through the e:Med sysINFLAME grant; Doris Duke Foundation; Department of Health via the NIHR comprehensive Biomedical Research Center award; Kings College London; KCH NHS Foundation Trust; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); Ann Arbor Veterans Affairs Hospital
Published: 2015
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30. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci

Author: Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Joanne, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Külli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerback, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., Elder, James T., Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Joanne, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Külli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerback, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., and Elder, James T.
Abstract: Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (P<5 × 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.
Published: 2015

31. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci

Author: Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Jo, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kulli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerbäck, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., Elder, James T., Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Jo, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kulli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerbäck, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., and Elder, James T.
Abstract: Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (Pless than5 x 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies., Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR062382, R01AR065183]; Wellcome Trust; German Research Foundation; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02]; Medical Research Council Stratified Medicine award [MR/L011808/1]; German Ministry of Education and Research (BMBF) through the e:Med sysINFLAME grant; Doris Duke Foundation; Department of Health via the NIHR comprehensive Biomedical Research Center award; Kings College London; KCH NHS Foundation Trust; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); Ann Arbor Veterans Affairs Hospital
Published: 2015
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32. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci

Author: Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Joanne, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Külli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerback, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., Elder, James T., Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Joanne, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Külli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerback, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., and Elder, James T.
Abstract: Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (P<5 × 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.
Published: 2015

33. Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture

Author: Stuart, Philip E., Nair, Rajan P., Tsoi, Lam C., Tejasvi, Trilokraj, Das, Sayantan, Min Kang, Hyun, Ellinghaus, Eva, Chandran, Vinod, Callis-Duffin, Kristina, Ike, Robert, Li, Yanming, Wen, Xiaoquan, Enerbäck, Charlotta, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kuelli, Esko, Tonu, Mrowietz, Ulrich, Reis, Andre, Erich Wichmann, H., Gieger, Christian, Hoffmann, Per, Noethen, Markus M., Winkelmann, Juliane, Kunz, Manfred, Moreta, Elvia G., Mease, Philip J., Ritchlin, Christopher T., Bowcock, Anne M., Krueger, Gerald G., Lim, Henry W., Weidinger, Stephan, Weichenthal, Michael, Voorhees, John J., Rahman, Proton, Gregersen, Peter K., Franke, Andre, Gladman, Dafna D., Abecasis, Goncalo R., Elder, James T., Stuart, Philip E., Nair, Rajan P., Tsoi, Lam C., Tejasvi, Trilokraj, Das, Sayantan, Min Kang, Hyun, Ellinghaus, Eva, Chandran, Vinod, Callis-Duffin, Kristina, Ike, Robert, Li, Yanming, Wen, Xiaoquan, Enerbäck, Charlotta, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kuelli, Esko, Tonu, Mrowietz, Ulrich, Reis, Andre, Erich Wichmann, H., Gieger, Christian, Hoffmann, Per, Noethen, Markus M., Winkelmann, Juliane, Kunz, Manfred, Moreta, Elvia G., Mease, Philip J., Ritchlin, Christopher T., Bowcock, Anne M., Krueger, Gerald G., Lim, Henry W., Weidinger, Stephan, Weichenthal, Michael, Voorhees, John J., Rahman, Proton, Gregersen, Peter K., Franke, Andre, Gladman, Dafna D., Abecasis, Goncalo R., and Elder, James T.
Abstract: Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 x 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 x 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA., Funding Agencies|Barbara and Neal Henschel Charitable Foundation; NIH [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183, R01AR050266]; German Research Foundation; German Ministry of Education and Research (BMBF); Doris Duke Foundation [2013106]; Taubman Medical Research Institute; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); Ann Arbor Veterans Affairs Hospital
Published: 2015
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34. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci

Author: Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Jo, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kulli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerbäck, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., Elder, James T., Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Jo, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kulli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerbäck, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., and Elder, James T.
Abstract: Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (Pless than5 x 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies., Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR062382, R01AR065183]; Wellcome Trust; German Research Foundation; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02]; Medical Research Council Stratified Medicine award [MR/L011808/1]; German Ministry of Education and Research (BMBF) through the e:Med sysINFLAME grant; Doris Duke Foundation; Department of Health via the NIHR comprehensive Biomedical Research Center award; Kings College London; KCH NHS Foundation Trust; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); Ann Arbor Veterans Affairs Hospital
Published: 2015
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35. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci

Author: Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Jo, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kulli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerbäck, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., Elder, James T., Tsoi, Lam C., Spain, Sarah L., Ellinghaus, Eva, Stuart, Philip E., Capon, Francesca, Knight, Jo, Tejasvi, Trilokraj, Kang, Hyun M., Allen, Michael H., Lambert, Sylviane, Stoll, Stefan W., Weidinger, Stephan, Gudjonsson, Johann E., Koks, Sulev, Kingo, Kulli, Esko, Tonu, Das, Sayantan, Metspalu, Andres, Weichenthal, Michael, Enerbäck, Charlotta, Krueger, Gerald G., Voorhees, John J., Chandran, Vinod, Rosen, Cheryl F., Rahman, Proton, Gladman, Dafna D., Reis, Andre, Nair, Rajan P., Franke, Andre, Barker, Jonathan N. W. N., Abecasis, Goncalo R., Trembath, Richard C., and Elder, James T.
Abstract: Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (Pless than5 x 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies., Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR062382, R01AR065183]; Wellcome Trust; German Research Foundation; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02]; Medical Research Council Stratified Medicine award [MR/L011808/1]; German Ministry of Education and Research (BMBF) through the e:Med sysINFLAME grant; Doris Duke Foundation; Department of Health via the NIHR comprehensive Biomedical Research Center award; Kings College London; KCH NHS Foundation Trust; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); Ann Arbor Veterans Affairs Hospital
Published: 2015
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36. Controlling complexity: the clinical relevance of mouse complex genetics.

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Schughart, Klaus, Libert, Claude, Kas, Martien J., Andreux, Penelope, Aransay, Ana Maria, Auwerx, Johan, Balling, Rudi, Banerjee, Sreeparna, Bezerianos, Anastasios, Bragonzi, Alessandra Desj, Brockmann, Gudrun A., Brown, Steve, Campbell-Tofte, Joan, Cendelin, Jan, Chatziioannou, Aristotelis, Chen, Duan, Crusio, Wim, Dimitrakopoulou, Konstantina, Falcon, Juan M., Forejt, Jiri, Franken, Paul, Frohlich, Leopold F., Herault, Yann, Hovatta, Iiris, Iraqi, Fuad A., Jansen, Ritsert C., Kaczmarek, Leszek, Kas, Martien, Knapska, Ewelina, Koks, Sulev, Kolisis, Fragiskos, Korostynski, Michal, Lammert, Frank, Lehrach, Hans, Lengeling, Andreas, Montagutelli, Xavier, Morahan, Grant, Mott, Richard, Panthier, Jean-Jacques, Przewlocki, Ryszard, Ranki, Annamari, Santos, Javier, Severcan, Feride, Schalkwyk, Leonard, Smit, August B., Terasmaa, Anton, Vasar, Eero, Zatloukal, Kurt, Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Schughart, Klaus, Libert, Claude, Kas, Martien J., Andreux, Penelope, Aransay, Ana Maria, Auwerx, Johan, Balling, Rudi, Banerjee, Sreeparna, Bezerianos, Anastasios, Bragonzi, Alessandra Desj, Brockmann, Gudrun A., Brown, Steve, Campbell-Tofte, Joan, Cendelin, Jan, Chatziioannou, Aristotelis, Chen, Duan, Crusio, Wim, Dimitrakopoulou, Konstantina, Falcon, Juan M., Forejt, Jiri, Franken, Paul, Frohlich, Leopold F., Herault, Yann, Hovatta, Iiris, Iraqi, Fuad A., Jansen, Ritsert C., Kaczmarek, Leszek, Kas, Martien, Knapska, Ewelina, Koks, Sulev, Kolisis, Fragiskos, Korostynski, Michal, Lammert, Frank, Lehrach, Hans, Lengeling, Andreas, Montagutelli, Xavier, Morahan, Grant, Mott, Richard, Panthier, Jean-Jacques, Przewlocki, Ryszard, Ranki, Annamari, Santos, Javier, Severcan, Feride, Schalkwyk, Leonard, Smit, August B., Terasmaa, Anton, Vasar, Eero, and Zatloukal, Kurt
Abstract: Experimental animal models are essential to obtain basic knowledge of the underlying biological mechanisms in human diseases. Here, we review major contributions to biomedical research and discoveries that were obtained in the mouse model by using forward genetics approaches and that provided key insights into the biology of human diseases and paved the way for the development of novel therapeutic approaches.
Published: 2013

37. Controlling complexity: the clinical relevance of mouse complex genetics.

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Schughart, Klaus, Libert, Claude, Kas, Martien J., Andreux, Penelope, Aransay, Ana Maria, Auwerx, Johan, Balling, Rudi, Banerjee, Sreeparna, Bezerianos, Anastasios, Bragonzi, Alessandra Desj, Brockmann, Gudrun A., Brown, Steve, Campbell-Tofte, Joan, Cendelin, Jan, Chatziioannou, Aristotelis, Chen, Duan, Crusio, Wim, Dimitrakopoulou, Konstantina, Falcon, Juan M., Forejt, Jiri, Franken, Paul, Frohlich, Leopold F., Herault, Yann, Hovatta, Iiris, Iraqi, Fuad A., Jansen, Ritsert C., Kaczmarek, Leszek, Kas, Martien, Knapska, Ewelina, Koks, Sulev, Kolisis, Fragiskos, Korostynski, Michal, Lammert, Frank, Lehrach, Hans, Lengeling, Andreas, Montagutelli, Xavier, Morahan, Grant, Mott, Richard, Panthier, Jean-Jacques, Przewlocki, Ryszard, Ranki, Annamari, Santos, Javier, Severcan, Feride, Schalkwyk, Leonard, Smit, August B., Terasmaa, Anton, Vasar, Eero, Zatloukal, Kurt, Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Schughart, Klaus, Libert, Claude, Kas, Martien J., Andreux, Penelope, Aransay, Ana Maria, Auwerx, Johan, Balling, Rudi, Banerjee, Sreeparna, Bezerianos, Anastasios, Bragonzi, Alessandra Desj, Brockmann, Gudrun A., Brown, Steve, Campbell-Tofte, Joan, Cendelin, Jan, Chatziioannou, Aristotelis, Chen, Duan, Crusio, Wim, Dimitrakopoulou, Konstantina, Falcon, Juan M., Forejt, Jiri, Franken, Paul, Frohlich, Leopold F., Herault, Yann, Hovatta, Iiris, Iraqi, Fuad A., Jansen, Ritsert C., Kaczmarek, Leszek, Kas, Martien, Knapska, Ewelina, Koks, Sulev, Kolisis, Fragiskos, Korostynski, Michal, Lammert, Frank, Lehrach, Hans, Lengeling, Andreas, Montagutelli, Xavier, Morahan, Grant, Mott, Richard, Panthier, Jean-Jacques, Przewlocki, Ryszard, Ranki, Annamari, Santos, Javier, Severcan, Feride, Schalkwyk, Leonard, Smit, August B., Terasmaa, Anton, Vasar, Eero, and Zatloukal, Kurt
Abstract: Experimental animal models are essential to obtain basic knowledge of the underlying biological mechanisms in human diseases. Here, we review major contributions to biomedical research and discoveries that were obtained in the mouse model by using forward genetics approaches and that provided key insights into the biology of human diseases and paved the way for the development of novel therapeutic approaches.
Published: 2013

38. 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 C A, 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 E M, Reis, Andre, Kere, Juha, Duffin, Kristina Callis, Helms, Cindy, Goldgar, David, Li, Yun, Paschall, Justin, Malloy, Mary J, Pullinger, Clive R, Kane, John P, Gardner, Jennifer, Perlmutter, Amy, Miner, Andrew, Feng, Bing Jian, Hiremagalore, Ravi, Ike, Robert W, Christophers, Enno, Henseler, Tilo, Ruether, Andreas, Schrodi, Steven J, Prahalad, Sampath, Guthery, Stephen L, Fischer, Judith, Liao, Wilson, Kwok, Pui, Menter, Alan, Lathrop, G Mark, Wise, C, Begovich, Ann B, Onoufriadis, Alexandros, Weale, Michael E, Hofer, Angelika, Salmhofer, Wolfgang, Wolf, Peter, Kainu, Kati, Saarialho-Kere, Ulpu, Suomela, Sari, Badorf, Petra, Hüffmeier, Ulrike, Kurrat, Werner, Küster, Wolfgang, Lascorz, Jesús, Mössner, Rotraut, Schürmeier-Horst, Funda, Ständer, Markward, Traupe, Heiko, Bergboer, Judith G M, Heijer, Martin den, van de Kerkhof, Peter C, Zeeuwen, Patrick L J M, Barnes, Louise, Campbell, Linda E, Cusack, Caitriona, Coleman, Ciara, Conroy, Judith, Ennis, Sean, Fitzgerald, Oliver, Gallagher, Phil, Irvine, Alan D, Kirby, Brian, Markham, Trevor, McLean, W H Irwin, McPartlin, Joe, Rogers, Sarah F, Ryan, Anthony W, Zawirska, Agnieszka, Giardina, Emiliano, Lepre, Tiziana, Perricone, Carlo, Martín-Ezquerra, Gemma, Pujol, Ramon M, Riveira-Munoz, Eva, Inerot, Annica, Naluai, Åsa T, Mallbris, Lotus, Wolk, Katarina, Leman, Joyce, Barton, Anne, Warren, Richard B, Young, Helen S, Ricano-Ponce, Isis, Trynka, Gosia, Pellett, Fawnda J, Henschel, Andrew, Aurand, Marin, Bebo, Bruce, Gieger, Christian, Illig, Thomas, Moebus, Susanne, Jöckel, Karl-Heinz, Erbel, Raimund, Donnelly, Peter, Peltonen, Leena, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Craddock, Nicholas, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, McCarthy, Mark I, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Samani, Nilesh, Viswanathan, Ananth C, Wood, Nicholas W, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Su, Zhan, Hunt, Sarah E, Gwilliam, Rhian, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Perez, Marc L, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Nair, Rajan P, Franke, Andre, Barker, Jonathan N W N, Abecasis, Goncalo R, Elder, James T, Trembath, Richard C, 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 C A, 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 E M, Reis, Andre, Kere, Juha, Duffin, Kristina Callis, Helms, Cindy, Goldgar, David, Li, Yun, Paschall, Justin, Malloy, Mary J, Pullinger, Clive R, Kane, John P, Gardner, Jennifer, Perlmutter, Amy, Miner, Andrew, Feng, Bing Jian, Hiremagalore, Ravi, Ike, Robert W, Christophers, Enno, Henseler, Tilo, Ruether, Andreas, Schrodi, Steven J, Prahalad, Sampath, Guthery, Stephen L, Fischer, Judith, Liao, Wilson, Kwok, Pui, Menter, Alan, Lathrop, G Mark, Wise, C, Begovich, Ann B, Onoufriadis, Alexandros, Weale, Michael E, Hofer, Angelika, Salmhofer, Wolfgang, Wolf, Peter, Kainu, Kati, Saarialho-Kere, Ulpu, Suomela, Sari, Badorf, Petra, Hüffmeier, Ulrike, Kurrat, Werner, Küster, Wolfgang, Lascorz, Jesús, Mössner, Rotraut, Schürmeier-Horst, Funda, Ständer, Markward, Traupe, Heiko, Bergboer, Judith G M, Heijer, Martin den, van de Kerkhof, Peter C, Zeeuwen, Patrick L J M, Barnes, Louise, Campbell, Linda E, Cusack, Caitriona, Coleman, Ciara, Conroy, Judith, Ennis, Sean, Fitzgerald, Oliver, Gallagher, Phil, Irvine, Alan D, Kirby, Brian, Markham, Trevor, McLean, W H Irwin, McPartlin, Joe, Rogers, Sarah F, Ryan, Anthony W, Zawirska, Agnieszka, Giardina, Emiliano, Lepre, Tiziana, Perricone, Carlo, Martín-Ezquerra, Gemma, Pujol, Ramon M, Riveira-Munoz, Eva, Inerot, Annica, Naluai, Åsa T, Mallbris, Lotus, Wolk, Katarina, Leman, Joyce, Barton, Anne, Warren, Richard B, Young, Helen S, Ricano-Ponce, Isis, Trynka, Gosia, Pellett, Fawnda J, Henschel, Andrew, Aurand, Marin, Bebo, Bruce, Gieger, Christian, Illig, Thomas, Moebus, Susanne, Jöckel, Karl-Heinz, Erbel, Raimund, Donnelly, Peter, Peltonen, Leena, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Craddock, Nicholas, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, McCarthy, Mark I, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Samani, Nilesh, Viswanathan, Ananth C, Wood, Nicholas W, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Su, Zhan, Hunt, Sarah E, Gwilliam, Rhian, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Perez, Marc L, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Nair, Rajan P, Franke, Andre, Barker, Jonathan N W N, Abecasis, Goncalo R, Elder, James T, and Trembath, Richard C
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

39. 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 C A, 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 E M, Reis, Andre, Kere, Juha, Duffin, Kristina Callis, Helms, Cindy, Goldgar, David, Li, Yun, Paschall, Justin, Malloy, Mary J, Pullinger, Clive R, Kane, John P, Gardner, Jennifer, Perlmutter, Amy, Miner, Andrew, Feng, Bing Jian, Hiremagalore, Ravi, Ike, Robert W, Christophers, Enno, Henseler, Tilo, Ruether, Andreas, Schrodi, Steven J, Prahalad, Sampath, Guthery, Stephen L, Fischer, Judith, Liao, Wilson, Kwok, Pui, Menter, Alan, Lathrop, G Mark, Wise, C, Begovich, Ann B, Onoufriadis, Alexandros, Weale, Michael E, Hofer, Angelika, Salmhofer, Wolfgang, Wolf, Peter, Kainu, Kati, Saarialho-Kere, Ulpu, Suomela, Sari, Badorf, Petra, Hüffmeier, Ulrike, Kurrat, Werner, Küster, Wolfgang, Lascorz, Jesús, Mössner, Rotraut, Schürmeier-Horst, Funda, Ständer, Markward, Traupe, Heiko, Bergboer, Judith G M, Heijer, Martin den, van de Kerkhof, Peter C, Zeeuwen, Patrick L J M, Barnes, Louise, Campbell, Linda E, Cusack, Caitriona, Coleman, Ciara, Conroy, Judith, Ennis, Sean, Fitzgerald, Oliver, Gallagher, Phil, Irvine, Alan D, Kirby, Brian, Markham, Trevor, McLean, W H Irwin, McPartlin, Joe, Rogers, Sarah F, Ryan, Anthony W, Zawirska, Agnieszka, Giardina, Emiliano, Lepre, Tiziana, Perricone, Carlo, Martín-Ezquerra, Gemma, Pujol, Ramon M, Riveira-Munoz, Eva, Inerot, Annica, Naluai, Åsa T, Mallbris, Lotus, Wolk, Katarina, Leman, Joyce, Barton, Anne, Warren, Richard B, Young, Helen S, Ricano-Ponce, Isis, Trynka, Gosia, Pellett, Fawnda J, Henschel, Andrew, Aurand, Marin, Bebo, Bruce, Gieger, Christian, Illig, Thomas, Moebus, Susanne, Jöckel, Karl-Heinz, Erbel, Raimund, Donnelly, Peter, Peltonen, Leena, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Craddock, Nicholas, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, McCarthy, Mark I, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Samani, Nilesh, Viswanathan, Ananth C, Wood, Nicholas W, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Su, Zhan, Hunt, Sarah E, Gwilliam, Rhian, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Perez, Marc L, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Nair, Rajan P, Franke, Andre, Barker, Jonathan N W N, Abecasis, Goncalo R, Elder, James T, Trembath, Richard C, 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 C A, 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 E M, Reis, Andre, Kere, Juha, Duffin, Kristina Callis, Helms, Cindy, Goldgar, David, Li, Yun, Paschall, Justin, Malloy, Mary J, Pullinger, Clive R, Kane, John P, Gardner, Jennifer, Perlmutter, Amy, Miner, Andrew, Feng, Bing Jian, Hiremagalore, Ravi, Ike, Robert W, Christophers, Enno, Henseler, Tilo, Ruether, Andreas, Schrodi, Steven J, Prahalad, Sampath, Guthery, Stephen L, Fischer, Judith, Liao, Wilson, Kwok, Pui, Menter, Alan, Lathrop, G Mark, Wise, C, Begovich, Ann B, Onoufriadis, Alexandros, Weale, Michael E, Hofer, Angelika, Salmhofer, Wolfgang, Wolf, Peter, Kainu, Kati, Saarialho-Kere, Ulpu, Suomela, Sari, Badorf, Petra, Hüffmeier, Ulrike, Kurrat, Werner, Küster, Wolfgang, Lascorz, Jesús, Mössner, Rotraut, Schürmeier-Horst, Funda, Ständer, Markward, Traupe, Heiko, Bergboer, Judith G M, Heijer, Martin den, van de Kerkhof, Peter C, Zeeuwen, Patrick L J M, Barnes, Louise, Campbell, Linda E, Cusack, Caitriona, Coleman, Ciara, Conroy, Judith, Ennis, Sean, Fitzgerald, Oliver, Gallagher, Phil, Irvine, Alan D, Kirby, Brian, Markham, Trevor, McLean, W H Irwin, McPartlin, Joe, Rogers, Sarah F, Ryan, Anthony W, Zawirska, Agnieszka, Giardina, Emiliano, Lepre, Tiziana, Perricone, Carlo, Martín-Ezquerra, Gemma, Pujol, Ramon M, Riveira-Munoz, Eva, Inerot, Annica, Naluai, Åsa T, Mallbris, Lotus, Wolk, Katarina, Leman, Joyce, Barton, Anne, Warren, Richard B, Young, Helen S, Ricano-Ponce, Isis, Trynka, Gosia, Pellett, Fawnda J, Henschel, Andrew, Aurand, Marin, Bebo, Bruce, Gieger, Christian, Illig, Thomas, Moebus, Susanne, Jöckel, Karl-Heinz, Erbel, Raimund, Donnelly, Peter, Peltonen, Leena, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Craddock, Nicholas, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, McCarthy, Mark I, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Samani, Nilesh, Viswanathan, Ananth C, Wood, Nicholas W, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Su, Zhan, Hunt, Sarah E, Gwilliam, Rhian, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Perez, Marc L, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Nair, Rajan P, Franke, Andre, Barker, Jonathan N W N, Abecasis, Goncalo R, Elder, James T, and Trembath, Richard C
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

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39 results on '"Koks, Sulev"'

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