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

Author

Day, Felix R, Thompson, Deborah J, Helgason, Hannes, Chasman, Daniel I, Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S, Whalen, Sean, Sarkar, Abhishek K, Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, Caterina M, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J, Karlsson, Robert, Kolcic, Ivana, Loh, Po-Ru, Lunetta, Kathryn L, Mangino, Massimo, Marco, Brumat, McMahon, George, Medland, Sarah E, Nolte, Ilja M, Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M, Schraut, Katharina E, Segrè, Ayellet V, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brüning, Thomas, Buring, Julie E, Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix-Trench, Georgia, Corre, Tanguy, Couch, Fergus J, Cousminer, Diana L, Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, de Geus, Eco JCN, de Mutsert, Renée, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos-Santos-Silva, Isabel, Dunning, Alison M, Eriksson, Johan G, Fasching, Peter A, Fernández-Rhodes, Lindsay, Ferrucci, Luigi, Flesch-Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Guénel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B, Hartman, Catharina A, Heiss, Gerardo, Hooning, Maartje J, Hopper, John L, Hu, Frank, Hunter, David J, Ikram, M Arfan, Im, Hae Kyung, Järvelin, Marjo-Riitta, Joshi, Peter K, Karasik, David, and Kellis, Manolis

Subjects
LifeLines Cohort Study, InterAct Consortium, kConFab/AOCS Investigators, Endometrial Cancer Association Consortium, Ovarian Cancer Association Consortium, PRACTICAL consortium, Humans, Neoplasms, Genetic Predisposition to Disease, Ubiquitin-Protein Ligases, Intercellular Signaling Peptides and Proteins, Calcium-Binding Proteins, Ribonucleoproteins, Membrane Proteins, Body Mass Index, Risk Factors, Age Factors, Genomic Imprinting, Puberty, Menarche, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Databases, Genetic, Adolescent, Female, Male, Genome-Wide Association Study, Aging, Breast Cancer, Biotechnology, Cancer, Human Genome, Genetics, Prostate Cancer, Urologic Diseases, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Published
2017

2. Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease

Author

Crawford, Andrew A., Bankier, Sean, Altmaier, Elisabeth, Barnes, Catriona L. K., Clark, David W., Ermel, Raili, Friedrich, Nele, van der Harst, Pim, Joshi, Peter K., Karhunen, Ville, Lahti, Jari, Mahajan, Anubha, Mangino, Massimo, Nethander, Maria, Neumann, Alexander, Pietzner, Maik, Sukhavasi, Katyayani, Wang, Carol A., Bakker, Stephan J. L., Bjorkegren, Johan L. M., Campbell, Harry, Eriksson, Johan, Gieger, Christian, Hayward, Caroline, Jarvelin, Marjo-Riitta, McLachlan, Stela, Morris, Andrew P., Ohlsson, Claes, Pennell, Craig E., Price, Jackie, Rudan, Igor, Ruusalepp, Arno, Spector, Tim, Tiemeier, Henning, Völzke, Henry, Wilson, James F., Michoel, Tom, Timpson, Nicolas J., Smith, George Davey, and Walker, Brian R.

Published
2021
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3. Radiographic Progression in Sacroiliac Joints in Patients With Axial Spondyloarthritis: Results From a Five‐Year International Observational Study

Author

Poddubnyy, Denis, primary, Sieper, Joachim, additional, Akar, Servet, additional, Muñoz‐Fernández, Santiago, additional, Haibel, Hildrun, additional, Diekhoff, Torsten, additional, Protopopov, Mikhail, additional, Altmaier, Elisabeth, additional, Ganz, Fabiana, additional, and Inman, Robert D., additional

Published
2023
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4. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Author

Day, Felix R, Ruth, Katherine S, Thompson, Deborah J, Lunetta, Kathryn L, Pervjakova, Natalia, Chasman, Daniel I, Stolk, Lisette, Finucane, Hilary K, Sulem, Patrick, Bulik-Sullivan, Brendan, Esko, Tõnu, Johnson, Andrew D, Elks, Cathy E, Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A, Franke, Lude L, Huffman, Jennifer E, Keller, Margaux F, McArdle, Patrick F, Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M, Schick, Ursula M, Smith, Jennifer A, Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke-Jan, Mangino, Massimo, Smith, Albert V, Tanaka, Toshiko, Abecasis, Goncalo, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Arnold, Alice M, Barbieri, Caterina, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J, Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borresen-Dale, Anne-Lise, Boutin, Thibaud S, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J, Chapman, J Ross, Chen, Yii-Der Ida, Chenevix-Trench, Georgia, Couch, Fergus J, Coviello, Andrea D, Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Eicher, John D, Fasching, Peter A, Faul, Jessica D, Figueroa, Jonine, Flesch-Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E, García-Closas, Montserrat, Giles, Graham G, Girotto, Giorgia G, Goldberg, Mark S, González-Neira, Anna, Goodarzi, Mark O, Grove, Megan L, Gudbjartsson, Daniel F, Guénel, Pascal, Guo, Xiuqing, Haiman, Christopher A, Hall, Per, and Hamann, Ute

Subjects
PRACTICAL consortium, kConFab Investigators, AOCS Investigators, Generation Scotland, EPIC-InterAct Consortium, LifeLines Cohort Study, Hypothalamus, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, Genomics, Age Factors, Signal Transduction, DNA Repair, Aging, Reproduction, Menopause, Genotype, Phenotype, Models, Genetic, Adult, Middle Aged, Female, Gene Regulatory Networks, Genetic Variation, Genome-Wide Association Study, Models, Genetic, Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Published
2015

5. Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

Author

Surendran, Praveen, Young, Robin, Barnes, Daniel R., Nielsen, Sune Fallgaard, Rasheed, Asif, Samuel, Maria, Zhao, Wei, Kontto, Jukka, Perola, Markus, Caslake, Muriel, de Craen, Anton J.M., Trompet, Stella, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F., Hoek, Maarten, Vogt, Thomas, Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Alam, Dewan S., Majumder, Abdulla al Shafi, Di Angelantonio, Emanuele, Chowdhury, Rajiv, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrières, Jean, Kee, Frank, Kuulasmaa, Kari, Müller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, EPIC-CVD Consortium, Frossard, Philippe, Nordestgaard, Børge Grønne, Saleheen, Danish, Danesh, John, Butterworth, Adam S., Howson, Joanna M.M., Erzurumluoglu, A. Mesut, Jackson, Victoria E., Melbourne, Carl A., Varga, Tibor V., Warren, Helen R., Tragante, Vinicius, Tachmazidou, Ioanna, Harris, Sarah E., Evangelou, Evangelos, Marten, Jonathan, Zhang, Weihua, Altmaier, Elisabeth, Luan, Jian’an, Langenberg, Claudia, Scott, Robert A., Yaghootkar, Hanieh, Stirrups, Kathleen, Kanoni, Stavroula, Marouli, Eirini, Karpe, Fredrik, Dominiczak, Anna F., Sever, Peter, Poulter, Neil, Rolandsson, Olov, Baumbach, Clemens, Afaq, Saima, Chambers, John C., Kooner, Jaspal S., Wareham, Nicholas J., Renström, Frida, Hallmans, Göran, Marioni, Riccardo E., Corley, Janie, Starr, John M., Verweij, Niek, de Boer, Rudolf A., van der Meer, Peter, Yavas, Ersin, Vaartjes, Ilonca, Bots, Michiel L., Asselbergs, Folkert W., Grabe, Hans J., Völzke, Henry, Nauck, Matthias, Weiss, Stefan, Pharoah, Paul D.P., Dunning, Alison M., Dennis, Joe G., Thompson, Deborah J., Michailidou, Kyriaki, Easton, Douglas F., Antoniou, Antonis C., Tyrrell, Jessica, Mihailov, Evelin, Samani, Nilesh J., Zhou, Kaixin, Neville, Matthew J., Metspalu, Andres, Palmer, Colin N.A., Hall, Ian P., Strachan, David P., Deary, Ian J., Frayling, Tim M., Hayward, Caroline, van der Harst, Pim, Zeggini, Eleftheria, Understanding Society Scientific Group, Munroe, Patricia B., Jansson, Jan-Håkan, Franks, Paul W., Deloukas, Panos, Caulfield, Mark J., Wain, Louise V., Tobin, Martin D., Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valérie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Bertelsen, Sarah, Chou, Yi-Ling, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Kardia, Sharon L.R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, McGue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Weir, David R., Kaprio, Jaakko, Abecasis, Gonçalo R., Liu, Dajiang J., and Vrieze, Scott

Published
2019
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6. Radiographic Progression in Sacroiliac Joints in Patients With Axial Spondyloarthritis: Results From a Five‐Year International Observational Study.

Author

Poddubnyy, Denis, Sieper, Joachim, Akar, Servet, Muñoz‐Fernández, Santiago, Haibel, Hildrun, Diekhoff, Torsten, Protopopov, Mikhail, Altmaier, Elisabeth, Ganz, Fabiana, and Inman, Robert D.

Subjects
SACROILIAC joint radiography, DISEASE progression, SACROILIAC joint, SCIENTIFIC observation, CONFIDENCE intervals, ANKYLOSIS, SPONDYLOARTHROPATHIES, KAPLAN-Meier estimator, DESCRIPTIVE statistics, RESEARCH funding, ODDS ratio, DATA analysis software, LONGITUDINAL method, PROPORTIONAL hazards models
Abstract

Objective: To evaluate progression from nonradiographic (nr‐) to radiographic axial spondyloarthritis (r‐axSpA) over 5 years in patients with recently diagnosed (≤1 year) axSpA fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria. Methods: A prospsective, observational study (Patients with Axial Spondyloarthritis: Multi‐Country Registry of Clinical Characteristics) was conducted in rheumatology practices in 29 countries. Baseline and follow‐up radiographs of sacroiliac joints were centrally evaluated by three readers according to the grading system of the modified New York criteria for patients initially classified as nr‐axSpA. Radiographic progression from nr‐axSpA to r‐axSpA was evaluated by Kaplan‐Meier analysis. Cox proportional regression analyses for progression from nr‐axSpA to r‐axSpA were also conducted. Results: Among 2,165 patients with axSpA, 1,612 (74%) were classified as having r‐axSpA (1,050 [65%]) or nr‐axSpA (562 [35%]) by central reading. Of 246 patients with nr‐axSpA (mean [SD] symptom duration: 4.4 [6.2] years) who had at least one follow‐up sacroiliac joint radiograph, progression from nr‐axSpA to r‐axSpA at any follow‐up visit was observed in 40 patients (16%) over 5 years. Mean time to radiographic progression was 2.4 years (ranging from 0.9 to 5.1 years). Progression to r‐axSpA was associated with male sex (hazard ratio [HR] 3.16 [95% CI 1.22–8.17]), fulfillment of the imaging arm of the ASAS classification criteria (HR 6.64 [1.37–32.25]), and good response to nonsteroidal anti‐inflammatory drugs (HR 4.66 [1.23–17.71]). Conclusion: 16% of patients with nr‐axSpA progressed to r‐axSpA within 5 years. Male sex, fulfillment of the imaging arm of the ASAS criteria, and good response to nonsteroidal anti‐inflammatory drugs were predictors of radiographic progression in patients with recently diagnosed axSpA. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Metabolomic profiles in individuals with negative affectivity and social inhibition: A population-based study of Type D personality

Author

Altmaier, Elisabeth, Emeny, Rebecca T., Krumsiek, Jan, Lacruz, Maria E., Lukaschek, Karoline, Häfner, Sibylle, Kastenmüller, Gabi, Römisch-Margl, Werner, Prehn, Cornelia, Mohney, Robert P., Evans, Anne M., Milburn, Michael V., Illig, Thomas, Adamski, Jerzy, Theis, Fabian, Suhre, Karsten, and Ladwig, Karl-Heinz

Published
2013
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11. Correction: Corrigendum: Rare coding variants and X-linked loci associated with age at menarche

Author

Lunetta, Kathryn L., Day, Felix R., Sulem, Patrick, Ruth, Katherine S., Tung, Joyce Y., Hinds, David A., Esko, Tõnu, Elks, Cathy E., Altmaier, Elisabeth, He, Chunyan, Huffman, Jennifer E., Mihailov, Evelin, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Stolk, Lisette, Teumer, Alexander, Thompson, Deborah J., Traglia, Michela, Wang, Carol A., Yerges-Armstrong, Laura M., Antoniou, Antonis C., Barbieri, Caterina, Coviello, Andrea D., Cucca, Francesco, Demerath, Ellen W., Dunning, Alison M., Gandin, Ilaria, Grove, Megan L., Gudbjartsson, Daniel F., Hocking, Lynne J., Hofman, Albert, Huang, Jinyan, Jackson, Rebecca D., Karasik, David, Kriebel, Jennifer, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Li, Xin, Luan, Jian'an, Mägi, Reedik, Morrison, Alanna C., Padmanabhan, Sandosh, Pirie, Ailith, Polasek, Ozren, Porteous, David, Reiner, Alex P., Rivadeneira, Fernando, Rudan, Igor, Sala, Cinzia F., Schlessinger, David, Scott, Robert A., Stöckl, Doris, Visser, Jenny A., Völker, Uwe, Vozzi, Diego, Wilson, James G., Zygmunt, Marek, Boerwinkle, Eric, Buring, Julie E., Crisponi, Laura, Easton, Douglas F., Hayward, Caroline, Hu, Frank B., Liu, Simin, Metspalu, Andres, Pennell, Craig E., Ridker, Paul M., Strauch, Konstantin, Streeten, Elizabeth A., Toniolo, Daniela, Uitterlinden, André G., Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J., Wellons, Melissa, Franceschini, Nora, Chasman, Daniel I., Thorsteinsdottir, Unnur, Murray, Anna, Stefansson, Kari, Murabito, Joanne M., Ong, Ken K., and Perry, John R. B.

Published
2015
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13. Human metabolic individuality in biomedical and pharmaceutical research

Author

Suhre, Karsten, Shin, So-Youn, Petersen, Ann-Kristin, Mohney, Robert P., Meredith, David, Wagele, Brigitte, Altmaier, Elisabeth, Deloukas, Panos, Erdmann, Jeanette, Grundberg, Elin, Hammond, Christopher J., Angelis, Martin Hrabede, Kastenmuller, Gabi, Kottgen, Anna, Kronenberg, Florian, Mangino, Massimo, Meisinger, Christa, Meitinger, Thomas, Mewes, Hans-Werner, Milburn, Michael V., Prehn, Cornelia, Raffler, Johannes, Ried, Janina S., Romisch-Margl, Werner, Samani, Nilesh J., Small, Kerrin S., Wichmann, H.-Erich, Zhai, Guangju, Illig, Thomas, Spector, Tim D., Adamski, Jerzy, Soranzo, Nicole, and Gieger, Christian

Subjects
Genomes -- Physiological aspects -- Research, Crohn's disease -- Genetic aspects -- Risk factors -- Diagnosis -- Care and treatment -- Research, Metabolomics -- Usage, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research., Understanding the role of genetic predispositions and their interaction with environmental factors in complex chronic diseases is key to the development of safe and efficient therapies, to diagnosis and to [...]

Published
2011
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14. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author

Erzurumluoglu, A Mesut, Liu, Mengzhen, Jackson, Victoria E, Barnes, Daniel R, Datta, Gargi, Melbourne, Carl A, Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C, Asselbergs, Folkert W, Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, de Boer, Rudolf A, de Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Karpe, Fredrik, Nielsen, Sune Fallgaard, Varga, Tibor V, Chen, Fang, Nordestgaard, Børge Grønne, Cardiovascular Centre (CVC), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)

Subjects
RISK, LUNG-CANCER, DATABASE, LD SCORE REGRESSION, BIOLOGICAL INSIGHTS, MENDELIAN RANDOMIZATION, EFFICIENT, CIGARETTE-SMOKING, GENOME-WIDE ASSOCIATION, DISEASE
Abstract

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P

Published
2020
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15. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author

Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L., Brazel, David M., Chambers, John C., Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi Ling, David, Sean P., de Boer, Rudolf A., de Leeuw, Christiaan A., Dennis, Joe G., Dominiczak, Anna F., Dunning, Alison M., Easton, Douglas F., Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D., Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J., Polderman, Tinca J., Posthuma, Danielle, van der Meer, Peter, Verweij, Niek, Jiang, Yu, Zhao, Wei, Chowdhury, Rajiv, Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L., Brazel, David M., Chambers, John C., Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi Ling, David, Sean P., de Boer, Rudolf A., de Leeuw, Christiaan A., Dennis, Joe G., Dominiczak, Anna F., Dunning, Alison M., Easton, Douglas F., Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D., Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J., Polderman, Tinca J., Posthuma, Danielle, van der Meer, Peter, Verweij, Niek, Jiang, Yu, Zhao, Wei, and Chowdhury, Rajiv

Abstract

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10−8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10−8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10−3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Published
2020

18. Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

Author

Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valerie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Barnes, Daniel R., Bertelsen, Sarah, Chou, Yi-Ling, Erzurumluoglu, A. Mesut, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Melbourne, Carl A., Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Zhao, Wei, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Howson, Joanna M. M., Kardia, Sharon L. R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, Mcgue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Tobin, Martin D., Weir, David R., Kaprio, Jaakko, Abecasis, Goncalo R., Liu, Dajiang J., Vrieze, Scott, Surendran, Praveen, Young, Robin, Nielsen, Sune Fallgaard, Rasheed, Asif, Samuel, Maria, Kontto, Jukka, Perola, Markus, Caslake, Muriel, de Craen, Anton J. M., Trompet, Stella, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F., Hoek, Maarten, Vogt, Thomas, Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Alam, Dewan S., Majumder, Abdulla al Shafi, Di Ange-Lantonio, Emanuele, Chowdhury, Rajiv, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrieres, Jean, Kee, Frank, Kuulasmaa, Kari, Mueller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, Frossard, Philippe, Nordestgaard, Borge Gronne, Saleheen, Danish, Danesh, John, Butterworth, Adam S., Jackson, Victoria E., Varga, Tibor V., Warren, Helen R., Tragante, Vinicius, Tachmazidou, Ioanna, Harris, Sarah E., Evangelou, Evangelos, Marten, Jonathan, Zhang, Weihua, Altmaier, Elisabeth, Luan, Jian'an, Langenberg, Claudia, Scott, Robert A., Yaghootkar, Hanieh, Stirrups, Kathleen, Kanoni, Stavroula, Marouli, Eirini, Karpe, Fredrik, Dominiczak, Anna F., Sever, Peter, Poulter, Neil, Rolandsson, Olov, Baumbach, Clemens, Afaq, Saima, Chambers, John C., Kooner, Jaspal S., Wareham, Nicholas J., Renstrom, Frida, Hallmans, Goran, Marioni, Riccardo E., Corley, Janie, Starr, John M., Verweij, Niek, de Boer, Rudolf A., van der Meer, Peter, Yavas, Ersin, Vaartjes, Ilonca, Bots, Michiel L., Asselbergs, Folkert W., Grabe, Hans J., Volzke, Henry, Nauck, Matthias, Weiss, Stefan, Pharoah, Paul D. P., Dunning, Alison M., Dennis, Joe G., Thompson, Deborah J., Michailidou, Kyriaki, Easton, Douglas F., Antoniou, Antonis C., Tyrrell, Jessica, Mihailov, Evelin, Samani, Nilesh J., Zhou, Kaixin, Neville, Matthew J., Metspalu, Andres, Palmer, Colin N. A., Hall, Ian P., Strachan, David P., Deary, Ian J., Frayling, Tim M., Hayward, Caroline, van der Harst, Pim, Zeggini, Eleftheria, Munroe, Patricia B., Jansson, Jan-Hakan, Franks, Paul W., Deloukas, Panos, Caulfield, Mark J., Wain, Louise V., Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valerie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Barnes, Daniel R., Bertelsen, Sarah, Chou, Yi-Ling, Erzurumluoglu, A. Mesut, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Melbourne, Carl A., Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Zhao, Wei, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Howson, Joanna M. M., Kardia, Sharon L. R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, Mcgue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Tobin, Martin D., Weir, David R., Kaprio, Jaakko, Abecasis, Goncalo R., Liu, Dajiang J., Vrieze, Scott, Surendran, Praveen, Young, Robin, Nielsen, Sune Fallgaard, Rasheed, Asif, Samuel, Maria, Kontto, Jukka, Perola, Markus, Caslake, Muriel, de Craen, Anton J. M., Trompet, Stella, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F., Hoek, Maarten, Vogt, Thomas, Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Alam, Dewan S., Majumder, Abdulla al Shafi, Di Ange-Lantonio, Emanuele, Chowdhury, Rajiv, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrieres, Jean, Kee, Frank, Kuulasmaa, Kari, Mueller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, Frossard, Philippe, Nordestgaard, Borge Gronne, Saleheen, Danish, Danesh, John, Butterworth, Adam S., Jackson, Victoria E., Varga, Tibor V., Warren, Helen R., Tragante, Vinicius, Tachmazidou, Ioanna, Harris, Sarah E., Evangelou, Evangelos, Marten, Jonathan, Zhang, Weihua, Altmaier, Elisabeth, Luan, Jian'an, Langenberg, Claudia, Scott, Robert A., Yaghootkar, Hanieh, Stirrups, Kathleen, Kanoni, Stavroula, Marouli, Eirini, Karpe, Fredrik, Dominiczak, Anna F., Sever, Peter, Poulter, Neil, Rolandsson, Olov, Baumbach, Clemens, Afaq, Saima, Chambers, John C., Kooner, Jaspal S., Wareham, Nicholas J., Renstrom, Frida, Hallmans, Goran, Marioni, Riccardo E., Corley, Janie, Starr, John M., Verweij, Niek, de Boer, Rudolf A., van der Meer, Peter, Yavas, Ersin, Vaartjes, Ilonca, Bots, Michiel L., Asselbergs, Folkert W., Grabe, Hans J., Volzke, Henry, Nauck, Matthias, Weiss, Stefan, Pharoah, Paul D. P., Dunning, Alison M., Dennis, Joe G., Thompson, Deborah J., Michailidou, Kyriaki, Easton, Douglas F., Antoniou, Antonis C., Tyrrell, Jessica, Mihailov, Evelin, Samani, Nilesh J., Zhou, Kaixin, Neville, Matthew J., Metspalu, Andres, Palmer, Colin N. A., Hall, Ian P., Strachan, David P., Deary, Ian J., Frayling, Tim M., Hayward, Caroline, van der Harst, Pim, Zeggini, Eleftheria, Munroe, Patricia B., Jansson, Jan-Hakan, Franks, Paul W., Deloukas, Panos, Caulfield, Mark J., and Wain, Louise V.

Published
2019

19. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 1; peer review: 1 approved, 1 approved with reservations]

Author

Jackson, Victoria E., Latourelle, Jeanne C., Wain, Louise V., Smith, Albert V., Grove, Megan L., Bartz, Traci M., Obeidat, Ma’En, Province, Michael A., Gao, Wei, Qaiser, Beenish, Porteous, David J., Cassano, Patricia A., Ahluwalia, Tarunveer S., Grarup, Niels, Li, Jin, Altmaier, Elisabeth, Marten, Jonathan, Harris, Sarah E., Manichaikul, Ani, Pottinger, Tess D., Li-Gao, Ruifang, Lind-Thomsen, Allan, Mahajan, Anubha, Lahousse, Lies, Imboden, Medea, Teumer, Alexander, Prins, Bram, Lyytikäinen, Leo Pekka, Eiriksdottir, Gudny, Franceschini, Nora, Sitlani, Colleen M., Brody, Jennifer A., Bossé, Yohan, Timens, Wim, Kraja, Aldi, Loukola, Anu, Tang, Wenbo, Liu, Yongmei, Bork-Jensen, Jette, Justesen, Johanne M., Linneberg, Allan, Lange, Leslie A., Rawal, Rajesh, Karrasch, Stefan, Huffman, Jennifer E., Brusselle, Guy G., Hansen, Torben, Uitterlinden, André G., Ikram, M. Arfan, Dupuis, Josée, Epidemiology, Erasmus School of Economics, Department of Finance, Internal Medicine, and Radiology & Nuclear Medicine

Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P

Published
2018

20. Meta-analysis of exome array data identifies six novel genetic loci for lung function.

Author

Jackson, Victoria E, Latourelle, Jeanne C, Wain, Louise V, Smith, Albert V, Grove, Megan L, Bartz, Traci M, Obeidat, Ma'en, Province, Michael A, Gao, Wei, Qaiser, Beenish, Porteous, David J, Cassano, Patricia A, Ahluwalia, Tarunveer S, Grarup, Niels, Li, Jin, Altmaier, Elisabeth, Marten, Jonathan, Harris, Sarah E, Manichaikul, Ani, Pottinger, Tess D, Li-Gao, Ruifang, Lind-Thomsen, Allan, Mahajan, Anubha, Lahousse, Lies, Imboden, Medea, Teumer, Alexander, Prins, Bram, Lyytikäinen, Leo-Pekka, Eiriksdottir, Gudny, Franceschini, Nora, Sitlani, Colleen M, Brody, Jennifer A, Bossé, Yohan, Timens, Wim, Kraja, Aldi, Loukola, Anu, Tang, Wenbo, Liu, Yongmei, Bork-Jensen, Jette, Justesen, Johanne M, Linneberg, Allan, Lange, Leslie A, Rawal, Rajesh, Karrasch, Stefan, Huffman, Jennifer E, Smith, Blair H, Davies, Gail, Burkart, Kristin M, Mychaleckyj, Josyf C, Bonten, Tobias N, Enroth, Stefan, Lind, Lars, Brusselle, Guy G, Kumar, Ashish, Stubbe, Beate, Kähönen, Mika, Wyss, Annah B, Psaty, Bruce M, Heckbert, Susan R, Hao, Ke, Rantanen, Taina, Kritchevsky, Stephen B, Lohman, Kurt, Skaaby, Tea, Pisinger, Charlotta, Hansen, Torben, Schulz, Holger, Polasek, Ozren, Campbell, Archie, Starr, John M, Rich, Stephen S, Mook-Kanamori, Dennis O, Johansson, Åsa, Ingelsson, Erik, Uitterlinden, André G, Weiss, Stefan, Raitakari, Olli T, Gudnason, Vilmundur, North, Kari E, Gharib, Sina A, Sin, Don D, Taylor, Kent D, O'Connor, George T, Kaprio, Jaakko, Harris, Tamara B, Pederson, Oluf, Vestergaard, Henrik, Wilson, James G, Strauch, Konstantin, Hayward, Caroline, Kerr, Shona, Deary, Ian J, Barr, R Graham, de Mutsert, Renée, Gyllensten, Ulf, Morris, Andrew P, Ikram, M Arfan, Probst-Hensch, Nicole, Gläser, Sven, Zeggini, Eleftheria, Lehtimäki, Terho, Strachan, David P, Dupuis, Josée, Morrison, Alanna C, Hall, Ian P, Tobin, Martin D, London, Stephanie J, Jackson, Victoria E, Latourelle, Jeanne C, Wain, Louise V, Smith, Albert V, Grove, Megan L, Bartz, Traci M, Obeidat, Ma'en, Province, Michael A, Gao, Wei, Qaiser, Beenish, Porteous, David J, Cassano, Patricia A, Ahluwalia, Tarunveer S, Grarup, Niels, Li, Jin, Altmaier, Elisabeth, Marten, Jonathan, Harris, Sarah E, Manichaikul, Ani, Pottinger, Tess D, Li-Gao, Ruifang, Lind-Thomsen, Allan, Mahajan, Anubha, Lahousse, Lies, Imboden, Medea, Teumer, Alexander, Prins, Bram, Lyytikäinen, Leo-Pekka, Eiriksdottir, Gudny, Franceschini, Nora, Sitlani, Colleen M, Brody, Jennifer A, Bossé, Yohan, Timens, Wim, Kraja, Aldi, Loukola, Anu, Tang, Wenbo, Liu, Yongmei, Bork-Jensen, Jette, Justesen, Johanne M, Linneberg, Allan, Lange, Leslie A, Rawal, Rajesh, Karrasch, Stefan, Huffman, Jennifer E, Smith, Blair H, Davies, Gail, Burkart, Kristin M, Mychaleckyj, Josyf C, Bonten, Tobias N, Enroth, Stefan, Lind, Lars, Brusselle, Guy G, Kumar, Ashish, Stubbe, Beate, Kähönen, Mika, Wyss, Annah B, Psaty, Bruce M, Heckbert, Susan R, Hao, Ke, Rantanen, Taina, Kritchevsky, Stephen B, Lohman, Kurt, Skaaby, Tea, Pisinger, Charlotta, Hansen, Torben, Schulz, Holger, Polasek, Ozren, Campbell, Archie, Starr, John M, Rich, Stephen S, Mook-Kanamori, Dennis O, Johansson, Åsa, Ingelsson, Erik, Uitterlinden, André G, Weiss, Stefan, Raitakari, Olli T, Gudnason, Vilmundur, North, Kari E, Gharib, Sina A, Sin, Don D, Taylor, Kent D, O'Connor, George T, Kaprio, Jaakko, Harris, Tamara B, Pederson, Oluf, Vestergaard, Henrik, Wilson, James G, Strauch, Konstantin, Hayward, Caroline, Kerr, Shona, Deary, Ian J, Barr, R Graham, de Mutsert, Renée, Gyllensten, Ulf, Morris, Andrew P, Ikram, M Arfan, Probst-Hensch, Nicole, Gläser, Sven, Zeggini, Eleftheria, Lehtimäki, Terho, Strachan, David P, Dupuis, Josée, Morrison, Alanna C, Hall, Ian P, Tobin, Martin D, and London, Stephanie J

Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

Published
2018
Full Text
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21. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 1; peer review:1 approved, 1 approved with reservations]

Author

Jackson, Victoria E., Latourelle, Jeanne C., Wain, Louise V., Smith, Albert V., Grove, Megan L., Bartz, Traci M., Obeidat, Ma’En, Province, Michael A., Gao, Wei, Qaiser, Beenish, Porteous, David J., Cassano, Patricia A., Ahluwalia, Tarunveer S., Grarup, Niels, Li, Jin, Altmaier, Elisabeth, Marten, Jonathan, Harris, Sarah E., Manichaikul, Ani, Pottinger, Tess D., Li-Gao, Ruifang, Lind-Thomsen, Allan, Mahajan, Anubha, Lahousse, Lies, Imboden, Medea, Teumer, Alexander, Prins, Bram, Lyytikäinen, Leo Pekka, Eiriksdottir, Gudny, Franceschini, Nora, Sitlani, Colleen M., Brody, Jennifer A., Bossé, Yohan, Timens, Wim, Kraja, Aldi, Loukola, Anu, Tang, Wenbo, Liu, Yongmei, Bork-Jensen, Jette, Justesen, Johanne M., Linneberg, Allan, Lange, Leslie A., Rawal, Rajesh, Karrasch, Stefan, Huffman, Jennifer E., Brusselle, Guy G., Hansen, Torben, Uitterlinden, André G., Ikram, M. Arfan, Dupuis, Josée, Jackson, Victoria E., Latourelle, Jeanne C., Wain, Louise V., Smith, Albert V., Grove, Megan L., Bartz, Traci M., Obeidat, Ma’En, Province, Michael A., Gao, Wei, Qaiser, Beenish, Porteous, David J., Cassano, Patricia A., Ahluwalia, Tarunveer S., Grarup, Niels, Li, Jin, Altmaier, Elisabeth, Marten, Jonathan, Harris, Sarah E., Manichaikul, Ani, Pottinger, Tess D., Li-Gao, Ruifang, Lind-Thomsen, Allan, Mahajan, Anubha, Lahousse, Lies, Imboden, Medea, Teumer, Alexander, Prins, Bram, Lyytikäinen, Leo Pekka, Eiriksdottir, Gudny, Franceschini, Nora, Sitlani, Colleen M., Brody, Jennifer A., Bossé, Yohan, Timens, Wim, Kraja, Aldi, Loukola, Anu, Tang, Wenbo, Liu, Yongmei, Bork-Jensen, Jette, Justesen, Johanne M., Linneberg, Allan, Lange, Leslie A., Rawal, Rajesh, Karrasch, Stefan, Huffman, Jennifer E., Brusselle, Guy G., Hansen, Torben, Uitterlinden, André G., Ikram, M. Arfan, and Dupuis, Josée

Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2•8x10 -7 ) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

Published
2018

22. Variation in the SERPINA6/SERPINA1locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease

Author

Crawford, Andrew A., Bankier, Sean, Altmaier, Elisabeth, Barnes, Catriona L. K., Clark, David W., Ermel, Raili, Friedrich, Nele, van der Harst, Pim, Joshi, Peter K., Karhunen, Ville, Lahti, Jari, Mahajan, Anubha, Mangino, Massimo, Nethander, Maria, Neumann, Alexander, Pietzner, Maik, Sukhavasi, Katyayani, Wang, Carol A., Bakker, Stephan J. L., Bjorkegren, Johan L. M., Campbell, Harry, Eriksson, Johan, Gieger, Christian, Hayward, Caroline, Jarvelin, Marjo-Riitta, McLachlan, Stela, Morris, Andrew P., Ohlsson, Claes, Pennell, Craig E., Price, Jackie, Rudan, Igor, Ruusalepp, Arno, Spector, Tim, Tiemeier, Henning, Völzke, Henry, Wilson, James F., Michoel, Tom, Timpson, Nicolas J., Smith, George Davey, and Walker, Brian R.

Abstract

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1locus influence expression of SERPINA6rather than SERPINA1in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

Published
2021
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23. Rare coding variants and X-linked loci associated with age at menarche

Author

Lunetta, Kathryn L, Day, Felix R, Sulem, Patrick, Ruth, Katherine S, Tung, Joyce Y, Hinds, David A, Esko, Tõnu, Elks, Cathy E, Altmaier, Elisabeth, He, Chunyan, Huffman, Jennifer E, Mihailov, Evelin, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M, Schick, Ursula M, Stolk, Lisette, Teumer, Alexander, Thompson, Deborah J, Traglia, Michela, Wang, Carol A, Yerges Armstrong, Laura M, Antoniou, Antonis C, Barbieri, Caterina, Coviello, Andrea D, Cucca, Francesco, Demerath, Ellen W, Dunning, Alison M, Gandin, Ilaria, Grove, Megan L, Gudbjartsson, Daniel F, Hocking, Lynne J, Hofman, Albert, Huang, Jinyan, Jackson, Rebecca D, Karasik, David, Kriebel, Jennifer, Lange, Ethan M, Lange, Leslie A, Langenberg, Claudia, Li, Xin, Luan, Jian'An, Mägi, Reedik, Morrison, Alanna C, Padmanabhan, Sandosh, Pirie, Ailith, Polasek, Ozren, Porteous, David, Reiner, Alex P, Rivadeneira, Fernando, Rudan, Igor, Sala, Cinzia F, Schlessinger, David, Scott, Robert A, Stöckl, Doris, Visser, Jenny A, Völker, Uwe, Vozzi, Diego, Wilson, James G, Zygmunt, Marek, Boerwinkle, Eric, Buring, Julie E, Crisponi, Laura, Easton, Douglas F, Hayward, Caroline, Hu, Frank B, Liu, Simin, Metspalu, Andres, Pennell, Craig E, Ridker, Paul M, Strauch, Konstantin, Streeten, Elizabeth A, Toniolo, Daniela, Uitterlinden, André G, Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J, Wellons, Melissa, Franceschini, Nora, Chasman, Daniel I, Thorsteinsdottir, Unnur, Murray, Anna, Stefansson, Kari, Murabito, Joanne M, Ong, Ken K, Perry, John R. B., PANICO, SALVATORE, Lunetta, Kathryn L, Day, Felix R, Sulem, Patrick, Ruth, Katherine S, Tung, Joyce Y, Hinds, David A, Esko, Tõnu, Elks, Cathy E, Altmaier, Elisabeth, He, Chunyan, Huffman, Jennifer E, Mihailov, Evelin, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M, Schick, Ursula M, Stolk, Lisette, Teumer, Alexander, Thompson, Deborah J, Traglia, Michela, Wang, Carol A, Yerges Armstrong, Laura M, Antoniou, Antonis C, Barbieri, Caterina, Coviello, Andrea D, Cucca, Francesco, Demerath, Ellen W, Dunning, Alison M, Gandin, Ilaria, Grove, Megan L, Gudbjartsson, Daniel F, Hocking, Lynne J, Hofman, Albert, Huang, Jinyan, Jackson, Rebecca D, Karasik, David, Kriebel, Jennifer, Lange, Ethan M, Lange, Leslie A, Langenberg, Claudia, Li, Xin, Luan, Jian'An, Mägi, Reedik, Morrison, Alanna C, Padmanabhan, Sandosh, Pirie, Ailith, Polasek, Ozren, Porteous, David, Reiner, Alex P, Rivadeneira, Fernando, Rudan, Igor, Sala, Cinzia F, Schlessinger, David, Scott, Robert A, Stöckl, Dori, Visser, Jenny A, Völker, Uwe, Vozzi, Diego, Wilson, James G, Zygmunt, Marek, Boerwinkle, Eric, Buring, Julie E, Crisponi, Laura, Easton, Douglas F, Hayward, Caroline, Hu, Frank B, Liu, Simin, Metspalu, Andre, Pennell, Craig E, Ridker, Paul M, Strauch, Konstantin, Streeten, Elizabeth A, Toniolo, Daniela, Uitterlinden, André G, Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J, Wellons, Melissa, Franceschini, Nora, Chasman, Daniel I, Thorsteinsdottir, Unnur, Murray, Anna, Stefansson, Kari, Murabito, Joanne M, Ong, Ken K, Perry, John R. B., and Panico, Salvatore

Subjects
Adult, Amide, Adolescent, Genotype, European Continental Ancestry Group, Mutation, Missense, Penetrance, RNA-Binding Protein, Young Adult, Gene Frequency, Autoantigen, Genes, X-Linked, Immunoglobulin, Age Factor, Membrane Protein, Aged, Menarche, Chromosomes, Human, X, Hypogonadism, Protein, Genetic Variation, Receptors, Neurokinin-3, Middle Aged, Phenotype, Codon, Nonsense, Female, RNA Interference, Laminin, Energy Metabolism, AMP-Activated Protein Kinase, Fatty Acid, Human, Signal Transduction
Abstract

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P

Published
2015

24. metaP-server: a web-based metabolomics data analysis tool

Author

Kastenmuller, Gabi, Romisch-Margl, Werner, Wagele, Brigitte, Altmaier, Elisabeth, and Suhre, Karsten

Subjects
Physiological aspects, Research, Phenotypes -- Physiological aspects -- Research, Metabolites -- Research, Genomes -- Physiological aspects -- Research, Gene expression -- Research, Phenotype -- Physiological aspects -- Research
Abstract

1. Introduction Metabolomics is an emerging 'omics' technology that focuses on the identification and quantification of all or, in practice, the largest possible set of low-molecular-weight metabolites in a biological [...], Metabolomics is an emerging field that is based on the quantitative measurement of as many small organic molecules occurring in a biological sample as possible. Due to recent technical advances, metabolomics can now be used widely as an analytical high-throughput technology in drug testing and epidemiological metabolome and genome wide association studies. Analogous to chip-based gene expression analyses, the enormous amount of data produced by modern kit-based metabolomics experiments poses new challenges regarding their biological interpretation in the context of various sample phenotypes. We developed metaP-server to facilitate data interpretation. metaP-server provides automated and standardized data analysis for quantitative metabolomics data, covering the following steps from data acquisition to biological interpretation: (i) data quality checks, (ii) estimation of reproducibility and batch effects, (iii) hypothesis tests for multiple categorical phenotypes, (iv) correlation tests for metric phenotypes, (v) optionally including all possible pairs of metabolite concentration ratios, (vi) principal component analysis (PCA), and (vii) mapping of metabolites onto colored KEGG pathway maps. Graphical output is clickable and cross-linked to sample and metabolite identifiers. Interactive coloring of PCA and bar plots by phenotype facilitates on-line data exploration. For users of commercial metabolomics kits, cross-references to the HMDB, LipidMaps, KEGG, PubChem, and CAS databases are provided. metaP-server is freely accessible at http://metabolomics.helmholtz-muenchen.de/metap2/.

Published
2011
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25. Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair EDITORIAL COMMENT

Author

Day, Felix R., Ruth, Katherine S., Thompson, Deborah J., Lunetta, Kathryn L., Pervjakova, Natalia, Chasman, Daniel I., Stolk, Lisette, Finucane, Hilary K., Sulem, Patrick, Bulik-Sullivan, Brendan, Esko, Tonu, Johnson, Andrew D., Elks, Cathy E., Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A., Franke, Lude L., Huffman, Jennifer E., Keller, Margaux F., McArdle, Patrick F., Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Smith, Jennifer A., Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke-Jan, Mangino, Massimo, Smith, Albert V., Tanaka, Toshiko, Abecasis, Goncalo R., Andrulis, Irene L., Anton-Culver, Hoda, Antoniou, Antonis C., Arndt, Volker, Arnold, Alice M., Barbieri, Caterina, Beckmann, Matthias W., Sanna, Serena, Wolffenbuttel, Bruce B. H. R., Alizadeh, Behrooz Z., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Life Course Epidemiology (LCE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)

Published
2015

26. Meta-analysis of exome array data identifies six novel genetic loci for lung function

Author

Jackson, Victoria E, primary, Latourelle, Jeanne C, additional, Wain, Louise V, additional, Smith, Albert V., additional, Grove, Megan L., additional, Bartz, Traci M, additional, Obeidat, Maen, additional, Province, Michael A, additional, Gao, Wei, additional, Qaiser, Beenish, additional, Porteous, David J, additional, Cassano, Patricia A, additional, Ahluwalia, Tarunveer S., additional, Grarup, Niels, additional, Li, Jin, additional, Altmaier, Elisabeth, additional, Marten, Jonathan, additional, Harris, Sarah E, additional, Manichaikul, Ani, additional, Pottinger, Tess D, additional, Li-Gao, Ruifang, additional, Lind-Thomsen, Allan, additional, Mahajan, Anubha, additional, Lahousse, Lies, additional, Imboden, Medea, additional, Teumer, Alexander, additional, Prins, Bram, additional, Lyytikäinen, Leo-Pekka, additional, Eiriksdottir, Gudny, additional, Franceschini, Nora, additional, Sitlani, Colleen M, additional, Brody, Jennifer A, additional, Bossé, Yohan, additional, Timens, Wim, additional, Kraja, Aldi, additional, Loukola, Anu, additional, Tang, Wenbo, additional, Liu, Yongmei, additional, Bork-Jensen, Jette, additional, Justesen, Johanne M., additional, Linneberg, Allan, additional, Lange, Leslie A., additional, Rawal, Rajesh, additional, Karrasch, Stefan, additional, Huffman, Jennifer E, additional, Smith, Blair H, additional, Davies, Gail, additional, Burkart, Kristin M, additional, Mychaleckyj, Josyf C, additional, Bonten, Tobias N., additional, Enroth, Stefan, additional, Lind, Lars, additional, Brusselle, Guy G, additional, Kumar, Ashish, additional, Stubbe, Beate, additional, Kähönen, Mika, additional, Wyss, Annah B., additional, Psaty, Bruce M, additional, Heckbert, Susan R, additional, Hao, Ke, additional, Rantanen, Taina, additional, Kritchevsky, Stephen B, additional, Lohman, Kurt, additional, Skaaby, Tea, additional, Pisinger, Charlotta, additional, Hansen, Torben, additional, Schulz, Holger, additional, Polasek, Ozren, additional, Campbell, Archie, additional, Starr, John M, additional, Rich, Stephen S, additional, Mook-Kanamori, Dennis O., additional, Johansson, Åsa, additional, Ingelsson, Erik, additional, Uitterlinden, André G, additional, Weiss, Stefan, additional, Raitakari, Olli T., additional, Gudnason, Vilmundur, additional, North, Kari E., additional, Gharib, Sina A, additional, Sin, Don D, additional, Taylor, Kent D, additional, O’Connor, George T, additional, Kaprio, Jaakko, additional, Harris, Tamara B, additional, Pedersen, Oluf, additional, Vestergaard, Henrik, additional, Wilson, James G., additional, Strauch, Konstantin, additional, Hayward, Caroline, additional, Kerr, Shona, additional, Deary, Ian J, additional, Barr, R Graham, additional, de Mutsert, Renée, additional, Gyllensten, Ulf, additional, Morris, Andrew P, additional, Ikram, M. Arfan, additional, Probst-Hensch, Nicole M, additional, Gläser, Sven, additional, Zeggini, Eleftheria, additional, Lehtimäki, Terho, additional, Strachan, David P, additional, Dupuis, Josee, additional, Morrison, Alanna C., additional, Hall, Ian P, additional, Tobin, Martin D, additional, and London, Stephanie J, additional

Published
2017
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27. Rare coding variants and X-linked loci associated with age at menarche

Author

Lunetta, Kathryn L., Day, Felix R., Sulem, Patrick, Ruth, Katherine S., Tung, Joyce Y., Hinds, David A., Esko, Tonu, Elks, Cathy E., Altmaier, Elisabeth, He, Chunyan, Huffman, Jennifer E., Mihailov, Evelin, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Stolk, Lisette, Teumer, Alexander, Thompson, Deborah J., Traglia, Michela, Wang, Carol A., Yerges-Armstrong, Laura M., Antoniou, Antonis C., Barbieri, Caterina, Coviello, Andrea D., Cucca, Francesco, Demerath, Ellen W., Dunning, Alison M., Gandin, Ilaria, Grove, Megan L., Gudbjartsson, Daniel F., Hocking, Lynne J., Hofman, Albert, Huang, Jinyan, Jackson, Rebecca D., Karasik, David, Kriebel, Jennifer, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Li, Xin, Luan, Jian'an, Maegi, Reedik, Morrison, Alanna C., Padmanabhan, Sandosh, Pirie, Ailith, Polasek, Ozren, Porteous, David, Reiner, Alex P., and van der Schouw, Yvonne T.

Subjects
SUSCEPTIBILITY LOCI, IDENTIFICATION, MUTATIONS, LAMB2, GENOME-WIDE ASSOCIATION, CANCER, METAANALYSIS
Abstract

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P

Published
2015
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28. Metabolites of milk intake: a metabolomic approach in UK twins with findings replicated in two European cohorts

Author

Pallister, Tess, primary, Haller, Toomas, additional, Thorand, Barbara, additional, Altmaier, Elisabeth, additional, Cassidy, Aedin, additional, Martin, Tiphaine, additional, Jennings, Amy, additional, Mohney, Robert P., additional, Gieger, Christian, additional, MacGregor, Alexander, additional, Kastenmüller, Gabi, additional, Metspalu, Andres, additional, Spector, Tim D., additional, and Menni, Cristina, additional

Published
2016
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29. The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study

Author

Altmaier, Elisabeth, primary, Menni, Cristina, additional, Heier, Margit, additional, Meisinger, Christa, additional, Thorand, Barbara, additional, Quell, Jan, additional, Kobl, Michael, additional, Römisch-Margl, Werner, additional, Valdes, Ana M., additional, Mangino, Massimo, additional, Waldenberger, Melanie, additional, Strauch, Konstantin, additional, Illig, Thomas, additional, Adamski, Jerzy, additional, Spector, Tim, additional, Gieger, Christian, additional, Suhre, Karsten, additional, and Kastenmüller, Gabi, additional

Published
2016
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30. Alterations in Lipid and Inositol Metabolisms in Two Dopaminergic Disorders

Author

Schulte, Eva C., primary, Altmaier, Elisabeth, additional, Berger, Hannah S., additional, Do, Kieu Trinh, additional, Kastenmüller, Gabi, additional, Wahl, Simone, additional, Adamski, Jerzy, additional, Peters, Annette, additional, Krumsiek, Jan, additional, Suhre, Karsten, additional, Haslinger, Bernhard, additional, Ceballos-Baumann, Andres, additional, Gieger, Christian, additional, and Winkelmann, Juliane, additional

Published
2016
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31. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Author

Day, Felix R., Ruth, Katherine S., Thompson, Deborah J., Lunetta, Kathryn L., Pervjakova, Natalia, Chasman, Daniel I., Stolk, Lisette, Finucane, Hilary K., Sulem, Patrick, Bulik-Sullivan, Brendan, Esko, Tonu, Johnson, Andrew D., Elks, Cathy E., Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A., Franke, Lude L., Huffman, Jennifer E., Keller, Margaux F., McArdle, Patrick F., Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Smith, Jennifer A., Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke-Jan, Mangino, Massimo, Smith, Albert V., Tanaka, Toshiko, Abecasis, Goncalo R., Andrulis, Irene L., Anton-Culver, Hoda, Antoniou, Antonis C., Arndt, Volker, Arnold, Alice M., Barbieri, Caterina, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J., Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Borresen-Dale, Anne-Lise, Boutin, Thibaud S., Brauch, Hiltrud, Brenner, Hermann, Bruening, Thomas, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J., Chapman, J. Ross, Chen, Yii-Der Ida, Chenevix-Trench, Georgia, Couch, Fergus J., Coviello, Andrea D., Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Devilee, Peter, Doerk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Eicher, John D., Fasching, Peter A., Faul, Jessica D., Figueroa, Jonine, Flesch-Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E., Garcia-Closas, Montserrat, Giles, Graham G., Girotto, Giorgia G., Goldberg, Mark S., Gonzalez-Neira, Anna, Goodarzi, Mark O., Grove, Megan L., Gudbjartsson, Daniel F., Guenel, Pascal, Guo, Xiuqing, Haiman, Christopher A., Hall, Per, Hamann, Ute, Henderson, Brian E., Hocking, Lynne J., Hofman, Albert, Homuth, Georg, Hooning, Maartje J., Hopper, John L., Hu, Frank B., Huang, Jinyan, Humphreys, Keith, Hunter, David J., Jakubowska, Anna, Jones, Samuel E., Kabisch, Maria, Karasik, David, Knight, Julia A., Kolcic, Ivana, Kooperberg, Charles, Kosma, Veli-Matti, Kriebel, Jennifer, Kristensen, Vessela, Lambrechts, Diether, Langenberg, Claudia, Li, Jingmei, Li, Xin, Lindstroem, Sara, Liu, Yongmei, Luan, Jian'an, Lubinski, Jan, Maegi, Reedik, Mannermaa, Arto, Manz, Judith, Margolin, Sara, Marten, Jonathan, Martin, Nicholas G., Masciullo, Corrado, Meindl, Alfons, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L., Mueller-Nurasyid, Martina, Nalls, Michael, Neale, Benjamin M., Nevanlinna, Heli, Neven, Patrick, Newman, Anne B., Nordestgaard, Borge G., Olson, Janet E., Padmanabhan, Sandosh, Peterlongo, Paolo, Peters, Ulrike, Petersmann, Astrid, Peto, Julian, Pharoah, Paul D. P., Pirastu, Nicola N., Pirie, Ailith, Pistis, Giorgio, Polasek, Ozren, Porteous, David, Psaty, Bruce M., Pylkas, Katri, Radice, Paolo, Raffel, Leslie J., Rivadeneira, Fernando, Rudan, Igor, Rudolph, Anja, Ruggiero, Daniela, Sala, Cinzia F., Sanna, Serena, Sawyer, Elinor J., Schlessinger, David, Schmidt, Marjanka K., Schmidt, Frank, Schmutzler, Rita K., Schoemaker, Minouk J., Scott, Robert A., Seynaeve, Caroline M., Simard, Jacques, Sorice, Rossella, Southey, Melissa C., Stoeckl, Doris, Strauch, Konstantin, Swerdlow, Anthony, Taylor, Kent D., Thorsteinsdottir, Unnur, Toland, Amanda E., Tomlinson, Ian, Truong, Therese, Tryggvadottir, Laufey, Turner, Stephen T., Vozzi, Diego, Wang, Qin, Wellons, Melissa, Willemsen, Gonneke, Wilson, James F., Winqvist, Robert, Wolffenbuttel, Bruce B. H. R., Wright, Alan F., Yannoukakos, Drakoulis, Zemunik, Tatijana, Zheng, Wei, Zygmunt, Marek, Bergmann, Sven, Boomsma, Dorret I., Buring, Julie E., Ferrucci, Luigi, Montgomery, Grant W., Gudnason, Vilmundur, Spector, Tim D., van Duijn, Cornelia M., Alizadeh, Behrooz Z., Ciullo, Marina, Crisponi, Laura, Easton, Douglas F., Gasparini, Paolo P., Gieger, Christian, Harris, Tamara B., Hayward, Caroline, Kardia, Sharon L. R., Kraft, Peter, McKnight, Barbara, Metspalu, Andres, Morrison, Alanna C., Reiner, Alex P., Ridker, Paul M., Rotter, Jerome I., Toniolo, Daniela, Uitterlinden, Andre G., Ulivi, Sheila, Voelzke, Henry, Wareham, Nicholas J., Weir, David R., Yerges-Armstrong, Laura M., Price, Alkes L., Stefansson, Kari, Visser, Jenny A., Ong, Ken K., Chang-Claude, Jenny, Murabito, Joanne M., Perry, John R. B., Murray, Anna, Day, Felix R., Ruth, Katherine S., Thompson, Deborah J., Lunetta, Kathryn L., Pervjakova, Natalia, Chasman, Daniel I., Stolk, Lisette, Finucane, Hilary K., Sulem, Patrick, Bulik-Sullivan, Brendan, Esko, Tonu, Johnson, Andrew D., Elks, Cathy E., Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A., Franke, Lude L., Huffman, Jennifer E., Keller, Margaux F., McArdle, Patrick F., Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Smith, Jennifer A., Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke-Jan, Mangino, Massimo, Smith, Albert V., Tanaka, Toshiko, Abecasis, Goncalo R., Andrulis, Irene L., Anton-Culver, Hoda, Antoniou, Antonis C., Arndt, Volker, Arnold, Alice M., Barbieri, Caterina, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J., Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Borresen-Dale, Anne-Lise, Boutin, Thibaud S., Brauch, Hiltrud, Brenner, Hermann, Bruening, Thomas, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J., Chapman, J. Ross, Chen, Yii-Der Ida, Chenevix-Trench, Georgia, Couch, Fergus J., Coviello, Andrea D., Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Devilee, Peter, Doerk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Eicher, John D., Fasching, Peter A., Faul, Jessica D., Figueroa, Jonine, Flesch-Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E., Garcia-Closas, Montserrat, Giles, Graham G., Girotto, Giorgia G., Goldberg, Mark S., Gonzalez-Neira, Anna, Goodarzi, Mark O., Grove, Megan L., Gudbjartsson, Daniel F., Guenel, Pascal, Guo, Xiuqing, Haiman, Christopher A., Hall, Per, Hamann, Ute, Henderson, Brian E., Hocking, Lynne J., Hofman, Albert, Homuth, Georg, Hooning, Maartje J., Hopper, John L., Hu, Frank B., Huang, Jinyan, Humphreys, Keith, Hunter, David J., Jakubowska, Anna, Jones, Samuel E., Kabisch, Maria, Karasik, David, Knight, Julia A., Kolcic, Ivana, Kooperberg, Charles, Kosma, Veli-Matti, Kriebel, Jennifer, Kristensen, Vessela, Lambrechts, Diether, Langenberg, Claudia, Li, Jingmei, Li, Xin, Lindstroem, Sara, Liu, Yongmei, Luan, Jian'an, Lubinski, Jan, Maegi, Reedik, Mannermaa, Arto, Manz, Judith, Margolin, Sara, Marten, Jonathan, Martin, Nicholas G., Masciullo, Corrado, Meindl, Alfons, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L., Mueller-Nurasyid, Martina, Nalls, Michael, Neale, Benjamin M., Nevanlinna, Heli, Neven, Patrick, Newman, Anne B., Nordestgaard, Borge G., Olson, Janet E., Padmanabhan, Sandosh, Peterlongo, Paolo, Peters, Ulrike, Petersmann, Astrid, Peto, Julian, Pharoah, Paul D. P., Pirastu, Nicola N., Pirie, Ailith, Pistis, Giorgio, Polasek, Ozren, Porteous, David, Psaty, Bruce M., Pylkas, Katri, Radice, Paolo, Raffel, Leslie J., Rivadeneira, Fernando, Rudan, Igor, Rudolph, Anja, Ruggiero, Daniela, Sala, Cinzia F., Sanna, Serena, Sawyer, Elinor J., Schlessinger, David, Schmidt, Marjanka K., Schmidt, Frank, Schmutzler, Rita K., Schoemaker, Minouk J., Scott, Robert A., Seynaeve, Caroline M., Simard, Jacques, Sorice, Rossella, Southey, Melissa C., Stoeckl, Doris, Strauch, Konstantin, Swerdlow, Anthony, Taylor, Kent D., Thorsteinsdottir, Unnur, Toland, Amanda E., Tomlinson, Ian, Truong, Therese, Tryggvadottir, Laufey, Turner, Stephen T., Vozzi, Diego, Wang, Qin, Wellons, Melissa, Willemsen, Gonneke, Wilson, James F., Winqvist, Robert, Wolffenbuttel, Bruce B. H. R., Wright, Alan F., Yannoukakos, Drakoulis, Zemunik, Tatijana, Zheng, Wei, Zygmunt, Marek, Bergmann, Sven, Boomsma, Dorret I., Buring, Julie E., Ferrucci, Luigi, Montgomery, Grant W., Gudnason, Vilmundur, Spector, Tim D., van Duijn, Cornelia M., Alizadeh, Behrooz Z., Ciullo, Marina, Crisponi, Laura, Easton, Douglas F., Gasparini, Paolo P., Gieger, Christian, Harris, Tamara B., Hayward, Caroline, Kardia, Sharon L. R., Kraft, Peter, McKnight, Barbara, Metspalu, Andres, Morrison, Alanna C., Reiner, Alex P., Ridker, Paul M., Rotter, Jerome I., Toniolo, Daniela, Uitterlinden, Andre G., Ulivi, Sheila, Voelzke, Henry, Wareham, Nicholas J., Weir, David R., Yerges-Armstrong, Laura M., Price, Alkes L., Stefansson, Kari, Visser, Jenny A., Ong, Ken K., Chang-Claude, Jenny, Murabito, Joanne M., Perry, John R. B., and Murray, Anna

Abstract

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in similar to 70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (similar to 6% increase in risk per year; P = 3 x 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Published
2015

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

Author

JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Cardiovasculaire Epidemiologie, Lunetta, Kathryn L., Day, Felix R., Sulem, Patrick, Ruth, Katherine S., Tung, Joyce Y., Hinds, David A., Esko, Tonu, Elks, Cathy E., Altmaier, Elisabeth, He, Chunyan, Huffman, Jennifer E., Mihailov, Evelin, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Stolk, Lisette, Teumer, Alexander, Thompson, Deborah J., Traglia, Michela, Wang, Carol A., Yerges-Armstrong, Laura M., Antoniou, Antonis C., Barbieri, Caterina, Coviello, Andrea D., Cucca, Francesco, Demerath, Ellen W., Dunning, Alison M., Gandin, Ilaria, Grove, Megan L., Gudbjartsson, Daniel F., Hocking, Lynne J., Hofman, Albert, Huang, Jinyan, Jackson, Rebecca D., Karasik, David, Kriebel, Jennifer, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Li, Xin, Luan, Jian'an, Maegi, Reedik, Morrison, Alanna C., Padmanabhan, Sandosh, Pirie, Ailith, Polasek, Ozren, Porteous, David, Reiner, Alex P., van der Schouw, Yvonne T., EPIC InterAct Consortium, Generation Scotland, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Cardiovasculaire Epidemiologie, Lunetta, Kathryn L., Day, Felix R., Sulem, Patrick, Ruth, Katherine S., Tung, Joyce Y., Hinds, David A., Esko, Tonu, Elks, Cathy E., Altmaier, Elisabeth, He, Chunyan, Huffman, Jennifer E., Mihailov, Evelin, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Stolk, Lisette, Teumer, Alexander, Thompson, Deborah J., Traglia, Michela, Wang, Carol A., Yerges-Armstrong, Laura M., Antoniou, Antonis C., Barbieri, Caterina, Coviello, Andrea D., Cucca, Francesco, Demerath, Ellen W., Dunning, Alison M., Gandin, Ilaria, Grove, Megan L., Gudbjartsson, Daniel F., Hocking, Lynne J., Hofman, Albert, Huang, Jinyan, Jackson, Rebecca D., Karasik, David, Kriebel, Jennifer, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Li, Xin, Luan, Jian'an, Maegi, Reedik, Morrison, Alanna C., Padmanabhan, Sandosh, Pirie, Ailith, Polasek, Ozren, Porteous, David, Reiner, Alex P., van der Schouw, Yvonne T., EPIC InterAct Consortium, and Generation Scotland

Published
2015

33. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Author

Paternoster, Lavinia, Standl, Marie, Waage, Johannes, Baurecht, Hansjörg, Hotze, Melanie, Strachan, David P, Curtin, John A, Bønnelykke, Klaus, Tian, Chao, Takahashi, Atsushi, Esparza-Gordillo, Jorge, Alves, Alexessander Couto, Thyssen, Jacob P, den Dekker, Herman T, Ferreira, Manuel A, Altmaier, Elisabeth, Sleiman, Patrick M A, Xiao, Feng Li, Gonzalez, Juan R, Marenholz, Ingo, Kalb, Birgit, Pino-Yanes, Maria, Xu, Cheng-Jian, Carstensen, Lisbeth, Groen-Blokhuis, Maria M, Venturini, Cristina, Pennell, Craig E, Barton, Sheila J, Levin, Albert M, Curjuric, Ivan, Bustamante, Mariona, Kreiner-Møller, Eskil, Lockett, Gabrielle A, Bacelis, Jonas, Bunyavanich, Supinda, Myers, Rachel A, Matanovic, Anja, Kumar, Ashish, Tung, Joyce Y, Hirota, Tomomitsu, Kubo, Michiaki, McArdle, Wendy L, Henderson, A John, Kemp, John P, Zheng, Jie, Smith, George Davey, Grarup, Niels, Bisgaard, Hans, Melbye, Mads, Linneberg, Allan, Paternoster, Lavinia, Standl, Marie, Waage, Johannes, Baurecht, Hansjörg, Hotze, Melanie, Strachan, David P, Curtin, John A, Bønnelykke, Klaus, Tian, Chao, Takahashi, Atsushi, Esparza-Gordillo, Jorge, Alves, Alexessander Couto, Thyssen, Jacob P, den Dekker, Herman T, Ferreira, Manuel A, Altmaier, Elisabeth, Sleiman, Patrick M A, Xiao, Feng Li, Gonzalez, Juan R, Marenholz, Ingo, Kalb, Birgit, Pino-Yanes, Maria, Xu, Cheng-Jian, Carstensen, Lisbeth, Groen-Blokhuis, Maria M, Venturini, Cristina, Pennell, Craig E, Barton, Sheila J, Levin, Albert M, Curjuric, Ivan, Bustamante, Mariona, Kreiner-Møller, Eskil, Lockett, Gabrielle A, Bacelis, Jonas, Bunyavanich, Supinda, Myers, Rachel A, Matanovic, Anja, Kumar, Ashish, Tung, Joyce Y, Hirota, Tomomitsu, Kubo, Michiaki, McArdle, Wendy L, Henderson, A John, Kemp, John P, Zheng, Jie, Smith, George Davey, Grarup, Niels, Bisgaard, Hans, Melbye, Mads, and Linneberg, Allan

Abstract

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Published
2015

34. Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality

Author

Raffler, Johannes, primary, Friedrich, Nele, additional, Arnold, Matthias, additional, Kacprowski, Tim, additional, Rueedi, Rico, additional, Altmaier, Elisabeth, additional, Bergmann, Sven, additional, Budde, Kathrin, additional, Gieger, Christian, additional, Homuth, Georg, additional, Pietzner, Maik, additional, Römisch-Margl, Werner, additional, Strauch, Konstantin, additional, Völzke, Henry, additional, Waldenberger, Melanie, additional, Wallaschofski, Henri, additional, Nauck, Matthias, additional, Völker, Uwe, additional, Kastenmüller, Gabi, additional, and Suhre, Karsten, additional

Published
2015
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35. Targeted Metabolomics in Mensch, Maus und Rind: Bioinformatische Methodenentwicklung und Datenanalyse

Author

Suhre, Karsten (Prof. Dr.), Mewes, Hans-Werner (Prof. Dr.), Altmaier, Elisabeth, Suhre, Karsten (Prof. Dr.), Mewes, Hans-Werner (Prof. Dr.), and Altmaier, Elisabeth

Abstract

Diese Arbeit befasst sich mit dem aufstrebenden Gebiet der Metabolomics, das durch neue Technologien in der Tandem-Massenspektrometrie ein quantitatives Screening von mehreren hundert Metaboliten pro Probe erlaubt. Die Menge der dadurch anfallenden Metabolitendaten verlangt nach bioinformatischen Analysemethoden, die hier entwickelt wurden. Deren Anwendung auf die Modellorganismen Mensch, Maus und Rind lassen das Potenzial von Metabolomics für präklinische Medikamententests sowie für ein tieferes Verständnis von metabolischen Stoffwechselvorgängen erkennen., This thesis addresses the upcoming field of metabolomics allowing the quantitative screening of several hundreds of metabolites per sample by using new technologies in tandem mass spectrometry. The amount of the so produced metabolic data requires bioinformatic analysis methods, which have been developed in this thesis. Their application to the model organisms human, mouse and cattle demonstrate the potential of metabolomics for preclinical drug testing as well as for a deeper understanding of metabolic processes.

Published
2009

36. Targeted Metabolomics in Mensch, Maus und Rind: Bioinformatische Methodenentwicklung und Datenanalyse

Author

Mewes, Hans-Werner (Prof. Dr.), Suhre, Karsten (Prof. Dr.), Altmaier, Elisabeth, Mewes, Hans-Werner (Prof. Dr.), Suhre, Karsten (Prof. Dr.), and Altmaier, Elisabeth

Abstract

Diese Arbeit befasst sich mit dem aufstrebenden Gebiet der Metabolomics, das durch neue Technologien in der Tandem-Massenspektrometrie ein quantitatives Screening von mehreren hundert Metaboliten pro Probe erlaubt. Die Menge der dadurch anfallenden Metabolitendaten verlangt nach bioinformatischen Analysemethoden, die hier entwickelt wurden. Deren Anwendung auf die Modellorganismen Mensch, Maus und Rind lassen das Potenzial von Metabolomics für präklinische Medikamententests sowie für ein tieferes Verständnis von metabolischen Stoffwechselvorgängen erkennen., This thesis addresses the upcoming field of metabolomics allowing the quantitative screening of several hundreds of metabolites per sample by using new technologies in tandem mass spectrometry. The amount of the so produced metabolic data requires bioinformatic analysis methods, which have been developed in this thesis. Their application to the model organisms human, mouse and cattle demonstrate the potential of metabolomics for preclinical drug testing as well as for a deeper understanding of metabolic processes.

Published
2009

37. Body Fat Free Mass Is Associated with the Serum Metabolite Profile in a Population-Based Study

Author

Jourdan, Carolin, primary, Petersen, Ann-Kristin, additional, Gieger, Christian, additional, Döring, Angela, additional, Illig, Thomas, additional, Wang-Sattler, Rui, additional, Meisinger, Christa, additional, Peters, Annette, additional, Adamski, Jerzy, additional, Prehn, Cornelia, additional, Suhre, Karsten, additional, Altmaier, Elisabeth, additional, Kastenmüller, Gabi, additional, Römisch-Margl, Werner, additional, Theis, Fabian J., additional, Krumsiek, Jan, additional, Wichmann, H.-Erich, additional, and Linseisen, Jakob, additional

Published
2012
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39. Metabolic Footprint of Diabetes: A Multiplatform Metabolomics Study in an Epidemiological Setting

Author

Suhre, Karsten, primary, Meisinger, Christa, additional, Döring, Angela, additional, Altmaier, Elisabeth, additional, Belcredi, Petra, additional, Gieger, Christian, additional, Chang, David, additional, Milburn, Michael V., additional, Gall, Walter E., additional, Weinberger, Klaus M., additional, Mewes, Hans-Werner, additional, Hrabé de Angelis, Martin, additional, Wichmann, H.-Erich, additional, Kronenberg, Florian, additional, Adamski, Jerzy, additional, and Illig, Thomas, additional

Published
2010
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41. A genome-wide perspective of genetic variation in human metabolism

Author

Illig, Thomas, primary, Gieger, Christian, additional, Zhai, Guangju, additional, Römisch-Margl, Werner, additional, Wang-Sattler, Rui, additional, Prehn, Cornelia, additional, Altmaier, Elisabeth, additional, Kastenmüller, Gabi, additional, Kato, Bernet S, additional, Mewes, Hans-Werner, additional, Meitinger, Thomas, additional, de Angelis, Martin Hrabé, additional, Kronenberg, Florian, additional, Soranzo, Nicole, additional, Wichmann, H-Erich, additional, Spector, Tim D, additional, Adamski, Jerzy, additional, and Suhre, Karsten, additional

Published
2009
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42. Metabolic Profiling Reveals Distinct Variations Linked to Nicotine Consumption in Humans — First Results from the KORA Study

Author

Wang-Sattler, Rui, primary, Yu, Yao, additional, Mittelstrass, Kirstin, additional, Lattka, Eva, additional, Altmaier, Elisabeth, additional, Gieger, Christian, additional, Ladwig, Karl H., additional, Dahmen, Norbert, additional, Weinberger, Klaus M., additional, Hao, Pei, additional, Liu, Lei, additional, Li, Yixue, additional, Wichmann, H.-Erich, additional, Adamski, Jerzy, additional, Suhre, Karsten, additional, and Illig, Thomas, additional

Published
2008
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43. Genetics Meets Metabolomics: A Genome-Wide Association Study of Metabolite Profiles in Human Serum

Author

Gieger, Christian, primary, Geistlinger, Ludwig, additional, Altmaier, Elisabeth, additional, Hrabé de Angelis, Martin, additional, Kronenberg, Florian, additional, Meitinger, Thomas, additional, Mewes, Hans-Werner, additional, Wichmann, H.-Erich, additional, Weinberger, Klaus M., additional, Adamski, Jerzy, additional, Illig, Thomas, additional, and Suhre, Karsten, additional

Published
2008
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44. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Author

Lunetta, Kathryn L, Pervjakova, Natalia, Chasman, Daniel I, Stolk, Lisette, Finucane, Hilary K, Bulik-Sullivan, Brendan, Esko, Tõnu, He, Chunyan, Altmaier, Elisabeth, Huffman, Jennifer E, Porcu, Eleonora, Vuckovic, Dragana, Corre, Tanguy, Mangino, Massimo, Smith, Albert V, Andrulis, Irene L, Barbieri, Caterina, Benitez, Javier, Boerwinkle, Eric, and Bojesen, Stig E

Subjects
MENOPAUSE, BREAST cancer diagnosis, INFERTILITY, HYPOTHALAMIC hormones, MENDEL'S law
Abstract

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10−14), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms. [ABSTRACT FROM AUTHOR]

Published
2015
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45. metaP-Server : A Web-Based Metabolomics Data Analysis Tool.

Author

Kastenmüler, Gabi, Römisch-Margl, Werner, Wägele, Brigitte, Altmaier, Elisabeth, and Suhre, Karsten

Abstract

Metabolomics is an emerging field that is based on the quantitative measurement of as many small organic molecules occurring in a biological sample as possible. Due to recent technical advances, metabolomics can now be used widely as an analytical highthroughput technology in drug testing and epidemiological metabolome and genome wide association studies. Analogous to chipbased gene expression analyses, the enormous amount of data produced by modern kit-based metabolomics experiments poses new challenges regarding their biological interpretation in the context of various sample phenotypes. We developed metaP-server to facilitate data interpretation. metaP-server provides automated and standardized data analysis for quantitative metabolomics data, covering the following steps from data acquisition to biological interpretation: (i) data quality checks, (ii) estimation of reproducibility and batch effects, (iii) hypothesis tests for multiple categorical phenotypes, (iv) correlation tests for metric phenotypes, (v) optionally including all possible pairs of metabolite concentration ratios, (vi) principal component analysis (PCA), and (vii) mapping of metabolites onto colored KEGG pathway maps. Graphical output is clickable and cross-linked to sample and metabolite identifiers. Interactive coloring of PCA and bar plots by phenotype facilitates on-line data exploration. For users of commercial metabolomics kits, cross-references to the HMDB, LipidMaps, KEGG, PubChem, and CAS databases are provided. metaP-server is freely accessible at http://metabolomics.helmholtz-muenchen.de/metap2/. [ABSTRACT FROM AUTHOR]

Published
2011
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46. A genome-wide perspective of genetic variation in human metabolism.

Author

Illig, Thomas, Gieger, Christian, Guangju Zhai, Römisch-Margl, Werner, Wang-Sattler, Rui, Prehn, Cornelia, Altmaier, Elisabeth, Kastenmüller, Gabi, Kato, Bernet S., Mewes, Hans-Werner, Meitinger, Thomas, de Angelis, Martin Hrabé, Kronenberg, Florian, Soranzo, Nicole, Wichmann, H-Erich, Spector, Tim D., Adamski, Jerzy, and Suhre, Karsten

Subjects
HUMAN genetic variation, CARDIOVASCULAR diseases, METABOLIC disorders, GENOMICS, METABOLITES, ENZYMES
Abstract

Serum metabolite concentrations provide a direct readout of biological processes in the human body, and they are associated with disorders such as cardiovascular and metabolic diseases. We present a genome-wide association study (GWAS) of 163 metabolic traits measured in human blood from 1,809 participants from the KORA population, with replication in 422 participants of the TwinsUK cohort. For eight out of nine replicated loci (FADS1, ELOVL2, ACADS, ACADM, ACADL, SPTLC3, ETFDH and SLC16A9), the genetic variant is located in or near genes encoding enzymes or solute carriers whose functions match the associating metabolic traits. In our study, the use of metabolite concentration ratios as proxies for enzymatic reaction rates reduced the variance and yielded robust statistical associations with P values ranging from 3 × 10−24 to 6.5 × 10−179. These loci explained 5.6%–36.3% of the observed variance in metabolite concentrations. For several loci, associations with clinically relevant parameters have been reported previously. [ABSTRACT FROM AUTHOR]

Published
2010
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47. Multi-ethnic genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Author

Paternoster, Lavinia, Standl, Marie, Waage, Johannes, Baurecht, Hansjörg, Hotze, Melanie, Strachan, David P, Curtin, John A, Bønnelykke, Klaus, Tian, Chao, Takahashi, Atsushi, Esparza-Gordillo, Jorge, Alves, Alexessander Couto, Thyssen, Jacob P, den Dekker, Herman T, Ferreira, Manuel A, Altmaier, Elisabeth, Sleiman, Patrick MA, Xiao, Feng Li, Gonzalez, Juan R, Marenholz, Ingo, Kalb, Birgit, Yanes, Maria Pino, Xu, Cheng-Jian, Carstensen, Lisbeth, Groen-Blokhuis, Maria M, Venturini, Cristina, Pennell, Craig E, Barton, Sheila J, Levin, Albert M, Curjuric, Ivan, Bustamante, Mariona, Kreiner-Møller, Eskil, Lockett, Gabrielle A, Bacelis, Jonas, Bunyavanich, Supinda, Myers, Rachel A, Matanovic, Anja, Kumar, Ashish, Tung, Joyce Y, Hirota, Tomomitsu, Kubo, Michiaki, McArdle, Wendy L, Henderson, A J, Kemp, John P, Zheng, Jie, Smith, George Davey, Rüschendorf, Franz, Bauerfeind, Anja, Lee-Kirsch, Min Ae, Arnold, Andreas, Homuth, Georg, Schmidt, Carsten O, Mangold, Elisabeth, Cichon, Sven, Keil, Thomas, Rodríguez, Elke, Peters, Annette, Franke, Andre, Lieb, Wolfgang, Novak, Natalija, Fölster-Holst, Regina, Horikoshi, Momoko, Pekkanen, Juha, Sebert, Sylvain, Husemoen, Lise L, Grarup, Niels, de Jongste, Johan C, Rivadeneira, Fernando, Hofman, Albert, Jaddoe, Vincent WV, Pasmans, Suzanne GMA, Elbert, Niels J, Uitterlinden, André G, Marks, Guy B, Thompson, Philip J, Matheson, Melanie C, Robertson, Colin F, Ried, Janina S, Li, Jin, Zuo, Xian Bo, Zheng, Xiao Dong, Yin, Xian Yong, Sun, Liang Dan, McAleer, Maeve A, O'Regan, Grainne M, Fahy, Caoimhe MR, Campbell, Linda E, Macek, Milan, Kurek, Michael, Hu, Donglei, Eng, Celeste, Postma, Dirkje S, Feenstra, Bjarke, Geller, Frank, Hottenga, Jouke Jan, Middeldorp, Christel M, Hysi, Pirro, Bataille, Veronique, Spector, Tim, Tiesler, Carla MT, Thiering, Elisabeth, Pahukasahasram, Badri, Yang, James J, Imboden, Medea, Huntsman, Scott, Vilor-Tejedor, Natàlia, Relton, Caroline L, Myhre, Ronny, Nystad, Wenche, Custovic, Adnan, Weiss, Scott T, Meyers, Deborah A, Söderhäll, Cilla, Melén, Erik, Ober, Carole, Raby, Benjamin A, Simpson, Angela, Jacobsson, Bo, Holloway, John W, Bisgaard, Hans, Sunyer, Jordi, Hensch, Nicole M Probst, Williams, L Keoki, Godfrey, Keith M, Wang, Carol A, Boomsma, Dorret I, Melbye, Mads, Koppelman, Gerard H, Jarvis, Deborah, McLean, WH Irwin, Irvine, Alan D, Zhang, Xue Jun, Hakonarson, Hakon, Gieger, Christian, Burchard, Esteban G, Martin, Nicholas G, Duijts, Liesbeth, Linneberg, Allan, Jarvelin, Marjo-Riitta, Noethen, Markus M, Lau, Susanne, Hübner, Norbert, Lee, Young-Ae, Tamari, Mayumi, Hinds, David A, Glass, Daniel, Brown, Sara J, Heinrich, Joachim, Evans, David M, and Weidinger, Stephan

Abstract

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified 10 novel risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with novel secondary signals at 4 of these). Notably, the new loci include candidate genes with roles in regulation of innate host defenses and T-cell function, underscoring the important contribution of (auto-)immune mechanisms to atopic dermatitis pathogenesis.

Published
2015
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48. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author

Erzurumluoglu, A Mesut, Liu, Mengzhen, Jackson, Victoria E, Barnes, Daniel R, Datta, Gargi, Melbourne, Carl A, Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C, Asselbergs, Folkert W, Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, De Boer, Rudolf A, De Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul DP, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renström, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, Van Der Leij, Andries R, Van Der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin NA, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, Understanding Society Scientific Group, EPIC-CVD, Van Der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, and Howson, Joanna MM

Subjects
Europe, Male, Databases, Factual, Genetic Loci, Smoking, Humans, Exome, Female, Polymorphism, Single Nucleotide, United Kingdom, 3. Good health, Biological Specimen Banks
Abstract

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

49. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author

Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L., Brazel, David M, Chambers, John C., Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P., De Boer, Rudolf A., De Leeuw, Christiaan A., Dennis, Joe G., Dominiczak, Anna F., Dunning, Alison M., Easton, Douglas F., Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D., Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J., Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R., Harris, Sarah E., Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G., Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L., Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S., Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian’an, Madden, Pamela A. F., Mangino, Massimo, Marioni, Riccardo E., Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G., McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J., Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D. P., Pistis, Giorgio, Polderman, Tinca J., Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renström, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J., Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A., Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A., Starr, John M., Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M., Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J., Tindle, Hilary A., Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, Van Der Leij, Andries R, Van Der Meer, Peter, Varga, Tibor V., Verweij, Niek, Völzke, Henry, Wareham, Nicholas J., Warren, Helen R., Weir, David R., Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J., Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J., Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W., Frayling, Tim M., Frossard, Philippe, Hall, Ian P., Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J. Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B., Nordestgaard, Børge Grønne, Palmer, Colin N. A., Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, Van Der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S., Wain, Louise V., Abecasis, Goncalo R., Danesh, John, Tobin, Martin D., Vrieze, Scott, Liu, Dajiang J., and Howson, Joanna M. M.

Subjects
631/208, 45, 45/43, article, 692/699/476/5, 3. Good health
Abstract

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10−8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10−8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10−3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

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