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1. Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

Author: Preeti Gupta, Maryam Hazly Hilmy, Jie Jin Wang, Jiemin Liao, Allan Fong, Maria K. Swift, Johanna M. Colijn, Paul Mitchell, Ya Xing Wang, Anita S Y Chan, Barbara E.K. Klein, Pirro G. Hysi, Jaeyoon Chung, Emily Y. Chew, Wanting Zhao, Yang Shen, Ava Grace Tan, Hengtong Li, Eranga N. Vithana, Gyungah Jun, Wenting Liu, Tin Aung, Qiao Fan, Yuan Shi, Ekaterina Yonova-Doing, Soon-Phaik Chee, Sudha K. Iyengar, Yik Ying Teo, Periasamy Sundaresan, Chiea Chuen Khor, Zheng Li, Kathryn P. Burdon, Miao Ling Chee, Yih Chung Tham, Christopher J Hammond, Xiaoran Chai, Kerrin S. Small, Queenie S. Tan, Jacqueline Chua, Jost B. Jonas, Astrid E. Fletcher, Alexessander Couto Alves, Pieter W.M. Bonnemaijer, Ravilla D. Ravindran, Mei Chin Lee, Milly S. Tedja, Robert P. Igo, Kristine E. Lee, Tien Y Wong, Xinyi Su, Caroline C W Klaver, Xueling Sim, Ching-Yu Cheng, Chaolong Wang, Lars G. Fritsche, Epidemiology, and Ophthalmology
Subjects: 0301 basic medicine, Genotype, genetic structures, QH301-705.5, Medicine (miscellaneous), Genome-wide association study, Disease, Bioinformatics, Polymorphism, Single Nucleotide, Genome-wide association studies, Cataract, Article, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Genetic variation, Humans, Medicine, Genetic Predisposition to Disease, Allele, Biology (General), Alleles, Genetic Association Studies, Genetic association, business.industry, SOXB1 Transcription Factors, Genetic Variation, medicine.disease, eye diseases, 030104 developmental biology, Age-related nuclear cataract, 030221 ophthalmology & optometry, Congenital cataracts, Lens diseases, sense organs, General Agricultural and Biological Sciences, business, Genome-Wide Association Study
Abstract: Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10−19), TMPRSS5 (rs4936279, P = 2.5 × 10−10), LINC01412 (rs16823886, P = 1.3 × 10−9), GLTSCR1 (rs1005911, P = 9.8 × 10−9), and COMMD1 (rs62149908, P = 1.2 × 10−8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye., Here, the authors report a multi-ethnic genome wide association meta-analysis of 12 studies from the International Cataract Genetics Consortium. They find six new loci associated with age-related nuclear cataract, in addition to replicating the association at CRYAA, and suggest a strong genetic link between age-related nuclear and congenital cataracts.
Published: 2020

2. Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores

Author: Marc J. Gunter, Alex Lewin, Karhunen, M-R Jarvelin, Zuber, Debbie A Lawlor, Alexessander Couto Alves, Rebecca C Richmond, Gabriel Cuellar-Partida, Abbas Dehghan, Tom Bond, Maria Carolina Borges, Dan Mason, Paul F. O'Reilly, Tiffany Yang, David M. Evans, Sylvain Sebert, Ioanna Tzoulaki, Bond, Tom A [0000-0002-9298-6860], and Apollo - University of Cambridge Repository
Subjects: CHILDHOOD, CHILDREN, Maternal, Overweight, Body Mass Index, Cohort Studies, 0302 clinical medicine, Pregnancy, Risk Factors, Medicine, 030212 general & internal medicine, Longitudinal Studies, Child, Mendelian randomisation, 11 Medical and Health Sciences, Adiposity, GESTATIONAL WEIGHT-GAIN, 2. Zero hunger, 0303 health sciences, education.field_of_study, Confounding, DOHaD, ASSOCIATION, General Medicine, ALSPAC, BIAS, Child, Preschool, Female, HEALTH, medicine.symptom, Life Sciences & Biomedicine, Research Article, Adolescent, BIRTH, Offspring, Population, 03 medical and health sciences, BMI, Medicine, General & Internal, General & Internal Medicine, Mendelian randomization, Humans, Obesity, education, Alleles, 030304 developmental biology, Science & Technology, business.industry, Infant, INSTRUMENTS, medicine.disease, Confidence interval, United Kingdom, BODY-MASS INDEX, business, Body mass index, Demography
Abstract: Background It has been hypothesised that greater maternal adiposity before or during pregnancy causes greater offspring adiposity in childhood and adulthood, via causal intrauterine or periconceptional mechanisms. Previous Mendelian randomization (MR) estimates were imprecise, with wide confidence intervals that included potentially important protective or adverse effects, and may have been biased by collider effects or imperfect adjustment for genetic inheritance. Here we use an improved MR approach to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal, or are instead due to confounding. Methods and findings We undertook confounder adjusted multivariable (MV) regression and Mendelian randomization (MR) using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB the outcomes were birthweight (BW; N = 9339) and BMI at age 1 (N = 8659) and 4 years (N = 7575), and in ALSPAC only we investigated BMI at 10 (N = 4476) and 15 years (N = 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10– 18 years (N = 2659 to 3855). We compared MR results from several polygenic risk scores (PRS), calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). MV and MR showed a consistent positive association of maternal BMI with BW, but for adiposity at most older ages MR estimates were weaker than MV estimates. In MV regression a one standard deviation (SD) higher maternal BMI was associated with a 0.13 (95% confidence interval [CI]: 0.10, 0.16) SD increase in offspring BW. The corresponding MR estimate from the strongest PRS (including up to 80,939 SNPs) was 0.14 (95% CI: 0.05, 0.23), with no difference between the two estimates (Pdifference = 0.84). For 15 year BMI the MV and MR estimates (80,939 SNPs) were 0.32 (95% CI: 0.29, 0.36) and 0.13 (95% CI: 0.01, 0.24) respectively (Pdifference = 1.0e-3). Results for FMI were similar to those for adolescent BMI. As the number of SNPs included in the PRS increased, the MR confidence intervals narrowed and the effect estimates for adolescent adiposity became closer to the MV estimates. Sensitivity analyses suggested the stronger effects with more SNPs were explained by horizontal pleiotropic bias away from zero. Consequently, the unbiased difference between the MV and MR estimates is probably greater than shown in our main analyses. Furthermore, MR estimates from IVs with fewer SNPs provided no strong evidence for a causal effect on adolescent adiposity. Conclusions Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.
Published: 2022
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3. Epigenetic findings in periodontitis in UK twins: a cross-sectional study

Author: Jordana T. Bell, Mark Ide, Claire J. Steves, Julia S. El-Sayed Moustafa, Kerrin S. Small, Yuko Kurushima, Alexessander Couto Alves, Juan Castillo Fernandez, Pei-Chien Tsai, Caroline I. Le Roy, Tim D. Spector, and Francis J. Hughes
Subjects: 0301 basic medicine, Oncology, Adipose tissue, lcsh:Medicine, Disease, Epigenesis, Genetic, Tooth mobility, 0302 clinical medicine, Medicine, Genetics (clinical), Aged, 80 and over, DNA methylation, Middle Aged, 3. Good health, Phenotype, 030220 oncology & carcinogenesis, Female, Epigenetics, Candidate Gene Analysis, Adult, medicine.medical_specialty, lcsh:QH426-470, 03 medical and health sciences, Internal medicine, Genetics, Diseases in Twins, Humans, Metabolomics, Periodontitis, Molecular Biology, Aged, Epigenome-wide association scan (EWAS), business.industry, Sequence Analysis, RNA, Research, lcsh:R, medicine.disease, Chronic periodontitis, United Kingdom, lcsh:Genetics, 030104 developmental biology, Cross-Sectional Studies, CpG Islands, Gene expression, business, Developmental Biology, Genome-Wide Association Study
Abstract: Background Genetic and environmental risk factors contribute to periodontal disease, but the underlying susceptibility pathways are not fully understood. Epigenetic mechanisms are malleable regulators of gene function that can change in response to genetic and environmental stimuli, thereby providing a potential mechanism for mediating risk effects in periodontitis. The aim of this study is to identify epigenetic changes across tissues that are associated with periodontal disease. Methods Self-reported gingival bleeding and history of gum disease, or tooth mobility, were used as indicators of periodontal disease. DNA methylation profiles were generated using the Infinium HumanMethylation450 BeadChip in whole blood, buccal, and adipose tissue samples from predominantly older female twins (mean age 58) from the TwinsUK cohort. Epigenome-wide association scans (EWAS) of gingival bleeding and tooth mobility were conducted in whole blood in 528 and 492 twins, respectively. Subsequently, targeted candidate gene analysis at 28 genomic regions was carried out testing for phenotype-methylation associations in 41 (tooth mobility) and 43 (gingival bleeding) buccal, and 501 (tooth mobility) and 556 (gingival bleeding) adipose DNA samples. Results Epigenome-wide analyses in blood identified one CpG-site (cg21245277 in ZNF804A) associated with gingival bleeding (FDR = 0.03, nominal p value = 7.17e−8) and 58 sites associated with tooth mobility (FDR
Published: 2019
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4. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author: Joris Deelen, Antonia Trichopoulou, Sara Hägg, Kim Overvad, Elisabete Weiderpass, Iryna O. Fedko, Rudolf Kaaks, Nicola D. Kerrison, Kirsi H. Pietiläinen, Ida Surakka, Veikko Salomaa, Svetlana Stoma, Jaakko Kaprio, Alessandra Allione, Cornelia M. van Duijn, Nicholas G. Martin, Veryan Codd, Olle Melander, Nilesh J. Samani, Josine E. Verhoeven, Anne Tjønneland, Natalia Pervjakova, Domenico Palli, Adam S. Butterworth, Nicholas J. Wareham, María Dolores Chirlaque, P. Eline Slagboom, Massimo Mangino, Pascal P. Arp, Christopher P. Nelson, Brenda W.J.H. Penninx, Jessica L. Buxton, Pietro Ferrari, Tao Jiang, Iiris Hovatta, Taylor K. Loe, N. Charlotte Onland-Moret, Salvatore Panico, Peter Jones, Heiner Boeing, Timothy J. Key, Luca A. Lotta, Miguel Rodríguez-Barranco, Diana van Heemst, Chen Li, Robert A. Scott, Sarah E. Medland, Giuseppe Matullo, Alexessander Couto Alves, Rosario Tumino, Jouke-Jan Hottenga, Ken K. Ong, Vittorio Krogh, Gonneke Willemsen, Andres Metspalu, Eva Albrecht, Elina Sillanpää, Johan G. Eriksson, Najaf Amin, Dale R. Nyholt, Reedik Mägi, Eros Lazzerini Denchi, Peter M. Nilsson, André G. Uitterlinden, Antonio Agudo, Yuri Milaneschi, Ashley van der Spek, Alessia Russo, Linda Broer, Federico Canzian, Marian Beekman, Grant W. Montgomery, Sophie C Warner, Guy Fagherazzi, Markus Perola, Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, Robert Karlsson, Tim D. Spector, Paul W. Franks, H. Eka D. Suchiman, Claudia Langenberg, Liher Imaz, Nancy L. Pedersen, Scott D. Gordon, Stephen E. Hamby, J. Ramón Quirós, Yvonne T. van der Schouw, Concha Moreno, Christian Gieger, Pekka Jousilahti, Dorret I. Boomsma, Marc J. Gunter, Benjamin Miraglio, Gianluca Severi, John Danesh, UNIVERSITY OF OULU, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Personalized Medicine, APH - Methodology, Sociology and Social Gerontology, Li, Chen [0000-0002-6423-6325], Ong, Kenneth [0000-0003-4689-7530], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, University of Helsinki, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, HUS Abdominal Center, Department of Medicine, Endokrinologian yksikkö, Clinicum, Diabetes and Obesity Research Program, Department of General Practice and Primary Health Care, HUS Helsinki and Uusimaa Hospital District, Department of Psychology and Logopedics, Genetics, SLEEPWELL Research Program, Department of Public Health, Mind and Matter, Internal Medicine, and Epidemiology
Subjects: Netherlands Twin Register (NTR), Limfomes, LOCI, Genome-wide association study, Disease, VARIANTS, DISEASE, 0302 clinical medicine, Leukocytes, telomere length, GWAS, Genetics(clinical), Càncer, Mendelian randomisation, Thyroid cancer, Genetics (clinical), 11 Medical and Health Sciences, Cancer, Genetics, Genetics & Heredity, RISK, 0303 health sciences, Telòmer, age-related disease, biological aging, Humans, Nucleotides, Genome-Wide Association Study, Telomere, meta-analyysi, genomiikka, Genomics, CANCER, 3. Good health, 030220 oncology & carcinogenesis, MENDELIAN RANDOMIZATION, Medical genetics, Biomarker (medicine), HEART, Lymphomas, Life Sciences & Biomedicine, Medical Genetics, medicine.medical_specialty, GENES, DATABASE, Age-related Disease, Biological Aging, Mendelian Randomisation, Telomere Length, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Journal Article, 030304 developmental biology, Medicinsk genetik, Science & Technology, 06 Biological Sciences, medicine.disease, Genòmica, ikääntyminen, 1182 Biochemistry, cell and molecular biology, telomeerit, biological
Abstract: Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
Published: 2020
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5. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author: Couto Alves, Alexessander, De Silva, N Maneka G, Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H Rob, Warrington, Nicole M, Lewin, Alexandra M, Kaakinen, Marika, Cousminer, Diana L, Thiering, Elisabeth, Timpson, Nicholas J, Bond, Tom A, Lowry, Estelle, Brown, Christopher D, Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P, Geller, Frank, Speed, Doug, Coin, Lachlan J M, Loh, Marie, Barton, Sheila J, Beilin, Lawrence J, Bisgaard, Hans, Bønnelykke, Klaus, Alili, Rohia, Hatoum, Ida J, Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clément, Karine, Claringbould, Annique A J, Van Duijn, Cornelia M, Moltchanova, Elena, Eriksson, Johan G, Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M, Freathy, Rachel M, Elliott, Paul, Widén, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T, Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W, Hofman, Albert, Hyppönen, Elina, Inskip, Hazel, Kaplan, Lee M, Hedman, Asa K, Läärä, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A, Lawlor, Debbie A, Melbye, Mads, Ahluwalia, Tarunveer S, Marinelli, Marcella, Millwood, Iona Y, Palmer, Lyle J, Pennell, Craig E, Perry, John R, Ring, Susan M, Savolainen, Markku J, Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla M T, Uitterlinden, Andre G, Schierding, William, O'Sullivan, Justin M, Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F, Buxton, Jessica L, Blakemore, Alexandra I F, Ong, Ken K, Jaddoe, Vincent W V, Grant, Struan F A, Sebert, Sylvain, McCarthy, Mark I, Järvelin, Marjo-Riitta, Erasmus MC other, Epidemiology, Internal Medicine, Pediatrics, Medical Research Council (MRC), Sovio, Ulla [0000-0002-0799-1105], Perry, John [0000-0001-6483-3771], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Warrington, Nicole M [0000-0003-4195-775X], Lewin, Alexandra M [0000-0003-0081-7582], Kaakinen, Marika [0000-0002-9228-0462], Cousminer, Diana L [0000-0001-8864-7893], Timpson, Nicholas J [0000-0002-7141-9189], Lowry, Estelle [0000-0002-4655-416X], Brown, Christopher D [0000-0002-3785-5008], Estivill, Xavier [0000-0002-0723-2256], Geller, Frank [0000-0002-9238-3269], Speed, Doug [0000-0002-0096-9765], Coin, Lachlan J M [0000-0002-4300-455X], Loh, Marie [0000-0003-3626-8466], Barton, Sheila J [0000-0003-4963-4242], Alili, Rohia [0000-0002-0158-4250], Schramm, Katharina [0000-0002-8809-3170], Charles, Marie-Aline [0000-0003-4025-4390], Claringbould, Annique A J [0000-0002-9201-6557], van Duijn, Cornelia M [0000-0002-2374-9204], Feenstra, Bjarke [0000-0003-1478-649X], Frayling, Timothy M [0000-0001-8362-2603], Freathy, Rachel M [0000-0003-4152-2238], Widén, Elisabeth [0000-0001-7108-2806], Hakonarson, Hakon [0000-0003-2814-7461], Rodriguez, Alina [0000-0003-1209-8802], Heude, Barbara [0000-0002-1565-1629], Holloway, John W [0000-0001-9998-0464], Hofman, Albert [0000-0002-9865-121X], Hyppönen, Elina [0000-0003-3670-9399], Inskip, Hazel [0000-0001-8897-1749], Kaplan, Lee M [0000-0002-6301-2696], Prokisch, Holger [0000-0003-2379-6286], Lakka, Timo A [0000-0002-9199-2871], Lawlor, Debbie A [0000-0002-6793-2262], Melbye, Mads [0000-0001-8264-6785], Ahluwalia, Tarunveer S [0000-0002-7464-3354], Marinelli, Marcella [0000-0002-5450-3960], Palmer, Lyle J [0000-0002-1628-3055], Pennell, Craig E [0000-0002-0937-6165], Perry, John R [0000-0001-6483-3771], Ring, Susan M [0000-0003-3103-9330], Savolainen, Markku J [0000-0002-2557-6423], Rivadeneira, Fernando [0000-0001-9435-9441], Sunyer, Jordi [0000-0002-2602-4110], Schierding, William [0000-0001-5659-2701], O'Sullivan, Justin M [0000-0003-2927-450X], Prokopenko, Inga [0000-0003-1624-7457], Smith, George Davey [0000-0002-1407-8314], Felix, Janine F [0000-0002-9801-5774], Ong, Ken K [0000-0003-4689-7530], Jaddoe, Vincent W V [0000-0003-2939-0041], Sebert, Sylvain [0000-0001-6681-6983], McCarthy, Mark I [0000-0002-4393-0510], and Järvelin, Marjo-Riitta [0000-0002-2149-0630]
Subjects: Adult, Male, Pharmacogenomic Variants, Quantitative Trait Loci, BLOOD-PRESSURE, 030209 endocrinology & metabolism, Polymorphism, Single Nucleotide, Body Mass Index, EARLY-LIFE, 03 medical and health sciences, AGE, Quantitative Trait, Heritable, 0302 clinical medicine, Humans, Genetic Predisposition to Disease, Longitudinal Studies, 030212 general & internal medicine, GENOME-WIDE ASSOCIATION, METABOLIC RISK, Growth Charts, FTO GENE, Child, Research Articles, Genetic Association Studies, Adaptor Proteins, Signal Transducing, 2. Zero hunger, Science & Technology, BIRTH COHORT, Intracellular Signaling Peptides and Proteins, nutritional and metabolic diseases, SciAdv r-articles, Infant, Human Genetics, Genomics, 3. Good health, Multidisciplinary Sciences, BODY-MASS INDEX, OBESITY, Science & Technology - Other Topics, Receptors, Leptin, ADIPOSITY, Female, biological, Research Article, Genome-Wide Association Study
Abstract: Longitudinal data find a new variant controlling BMI in infancy and reveal genetic differences between infant and adult BMI., Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
Published: 2019

6. Fasting and time of day independently modulate circadian rhythm relevant gene expression in adipose and skin tissue

Author: Couto Alves, Alexessander, Glastonbury, Craig A., El-Sayed Moustafa, Julia S., and Small, Kerrin S.
Subjects: lcsh:QH426-470, Circadian rhythm, Gene x environment, lcsh:Biotechnology, Quantitative Trait Loci, Adipose, Fasting, Middle Aged, eQTL, lcsh:Genetics, Adipose Tissue, Organ Specificity, Risk Factors, lcsh:TP248.13-248.65, Humans, Female, Gene-Environment Interaction, Gene expression, Transcriptome, Research Article, EQTL, Skin
Abstract: Background Intermittent fasting and time-restricted diets are associated with lower risk biomarkers for cardio-metabolic disease. The shared mechanisms underpinning the similar physiological response to these events is not established, but circadian rhythm could be involved. Here we investigated the transcriptional response to fasting in a large cross-sectional study of adipose and skin tissue from healthy volunteers (N = 625) controlling for confounders of circadian rhythm: time of day and season. Results We identified 367 genes in adipose and 79 in skin whose expression levels were associated (FDR
Published: 2018
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7. Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Author: Eugene R. Bleecker, Carlos Flores, Gonneke Willemsen, Kamilla Kjærgaard Jensen, Herman T. den Dekker, Zhanghua Chen, W. James Gauderman, Xingnan Li, Teemu Palviainen, Christian Gieger, Franz Rüschendorf, Dan L. Nicolae, Leon Eyrich Jessen, Hans Bisgaard, Nicole Probst-Hensch, Medea Imboden, Raquel Granell, Ingileif Jonsdottir, Maria Pino-Yanes, Supinda Bunyavanich, Manuel A. R. Ferreira, Michel Georges, Vincent W. V. Jaddoe, Stephan Weidinger, Hongsheng Gui, Esteban G. Burchard, Abdel Abdellaoui, Ivan Curjuric, Johannes Waage, Torben Hansen, Deborah A. Meyers, Rachel A. Myers, Lavinia Paternoster, Ashok Kumar, Ellen A. Nohr, Kari Stefansson, L. Keoki Williams, Andreas Arnold, David P. Strachan, David Torrents, Carol A. Wang, Dorret I. Boomsma, Julia Dmitrieva, Markus J. Ege, Joyce Y. Tung, Jordi Sunyer, Elisabeth Thiering, Nathan Schoettler, Deborah Jarvis, Sílvia Bonàs-Guarch, Joachim Heinrich, Shyamali C. Dharmage, Jaakko Kaprio, Craig E. Pennell, Marie Standl, Philip J. Thompson, Patrick G. Holt, Natalia Hernandez-Pacheco, Angela Simpson, Michael Kabesch, Josep M. Mercader, Marjo-Riitta Järvelin, Andre F.S. Amaral, Tarunveer S. Ahluwalia, Fabián Lorenzo-Díaz, John A. Curtin, Gardar Sveinbjornsson, Susanne Brix, Scott T. Weiss, Chao Tian, Adnan Custovic, David A. Hinds, Amalia Barreto-Luis, John Henderson, Hansjörg Baurecht, Young-Ae Lee, Catharina E. M. van Beijsterveldt, Jonathan Thorsen, Carole Ober, Alexessander Couto Alves, Frank D. Gilliland, Albert M. Levin, Josep M. Antó, Liesbeth Duijts, Erik Melén, Maties Torrent, Klaus Bønnelykke, Göran Pershagen, Epidemiology, Erasmus MC other, Pediatrics, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Health Behaviors & Chronic Diseases
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), HAY-FEVER, Allergy, Genome-wide association study, VARIANTS, Allergic sensitization, 0302 clinical medicine, HLA Antigens, 11 Medical and Health Sciences, Genetics & Heredity, CELL DEVELOPMENT, HERITABILITY, 3. Good health, Phenotype, DISEASES, Hay fever, Life Sciences & Biomedicine, EXPRESSION, Risk, Single-nucleotide polymorphism, Human leukocyte antigen, Biology, DENDRITIC CELLS, 23andMe Research Team, 03 medical and health sciences, Nonallergic rhinitis, SDG 3 - Good Health and Well-being, Genetics, medicine, Humans, Genetic Predisposition to Disease, METAANALYSIS, Science & Technology, RECEPTOR, Genome, Human, AAGC collaborators, Genetic Variation, Allergens, 06 Biological Sciences, medicine.disease, Rhinitis, Allergic, Genetic architecture, 030104 developmental biology, Genetic Loci, Case-Control Studies, Immunology, ASTHMA, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract: Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis. An Author Correction to this article was published on 16 August 2018. https://www.nature.com/articles/s41588-018-0197-6
Published: 2018
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8. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author: Niina Eklund, Robert C. Kaplan, Niek Verweij, Marcus Richards, Nancy L. Heard-Costa, Angelo Tremblay, Lu Qi, Andres Metspalu, Mark A. Sarzynski, Charleston W. K. Chiang, Tõnu Esko, Jaana Lindström, Pirro G. Hysi, Torben Hansen, James F. Wilson, Serena Sanna, Marie-Claude Vohl, Lynda M. Rose, Daniele Cusi, Megan T. Smith, Anne U. Jackson, Jing Hua Zhao, Anubha Mahajan, Nele Friedrich, Marcel Bruinenberg, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Weihua Zhang, Lavinia Paternoster, Jenny van Dongen, Torben Jørgensen, Aarno Palotie, Jana V. van Vliet-Ostaptchouk, Martin Farrall, Konstantin Strauch, Jan Smit, Zoltán Kutalik, Anne E. Justice, Elisabeth Widen, Tuomo Rankinen, Timo A. Lakka, Maria Dimitriou, Louis Pérusse, Peter J. van der Most, Yun Ju Sung, George Dedoussis, Caroline Hayward, Tom Wilsgaard, Peter P. Pramstaller, Maria Karaleftheri, Seppo Koskinen, Clive Osmond, Panos Deloukas, David J. Hunter, Kathleen Stirrups, Nicola Glorioso, Andrew T. Hattersley, Hugh Watkins, Sven Bergmann, Eric Boerwinkle, Catharina A. Hartman, Anke Tönjes, Daniel I. Chasman, May E. Montasser, Alan James, Ben A. Oostra, Nigel W. Rayner, Massimo Mangino, Ron T. Gansevoort, Cristina Barlassina, Johanna Kuusisto, Andrew A. Hicks, Roberto Lorbeer, Tomi Laitinen, Narisu Narisu, Stefan R. Bornstein, Gemma Cadby, Johan G. Eriksson, Gudmar Thorleifsson, Erika Salvi, Jari Lahti, Cornelia M. van Duijn, Janina M. Jeff, Heather M. Stringham, Bruce M. Psaty, Thomas W. Winkler, Paul M. Ridker, Unnur Thorsteinsdottir, Lyle J. Palmer, Alexander Teumer, Jürgen Gräßler, Allan Linneberg, Francesca D'Avila, Markku Heliövaara, Harald Grallert, Ivana Kolcic, Kari E. North, Eleftheria Zeggini, James S. Pankow, Alena Standáková, Marjo-Riitta Järvelin, Ozren Polasek, Krista Fischer, Valeriya Lyssenko, Thorkild I. A. Sørensen, André G. Uitterlinden, Stavroula Kanoni, Caroline S. Fox, Sophie R. Wang, Treva Rice, Maria Grazia Pilia, Olli T. Raitakari, Claudia Langenberg, Thomas Sparsø, Emmanouil Tsafantakis, Irene Pichler, Kathy Ryan, Eero Jokinen, Mika Kähönen, Leif Groop, Irene Mateo Leach, Gabriele Müller, Annette Peters, Peter Vollenweider, Oddgeir L. Holmen, David Schlessinger, Paul Knekt, M. Carola Zillikens, Evelin Mihailov, Erkki Vartiainen, Nicholas J. Wareham, Francis S. Collins, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Joel N. Hirschhorn, Frank B. Hu, Janina S. Ried, Valgerdur Steinthorsdottir, Shapour Jalilzadeh, Peter Kovacs, Anuj Goel, Pim van der Harst, Peter Schwarz, Mathias Gorski, Jorma Viikari, Uwe Völker, Cecilia M. Lindgren, Theodosios Kyriakou, Morris A. Swertz, Inga Prokopenko, Ken K. Ong, Leena Kinnunen, Markus Perola, Kristian Hveem, Matthias Blüher, Rebecca Mills, Albertine J. Oldehinkel, Anders Hamsten, Mattias Lorentzon, Joel Eriksson, Karen L. Mohlke, Rasmus Ribel-Madsen, Pekka Jousilahti, Paolo Manunta, Eva Albrecht, Jeffrey R. O'Connell, Wendy L. McArdle, Amy J. Swift, Dorret I. Boomsma, Harry Campbell, Fracensco Cucca, Aaron Isaacs, Andrew Wong, Georg Homuth, Laura M. Yerges-Armstrong, Carolina Medina-Gomez, Kay-Tee Khaw, Claes Ohlsson, Claude Bouchard, John Blangero, Aliki-Eleni Farmaki, Lorraine Southam, Anette P. Gjesing, Traci M. Bartz, Dabeeru C. Rao, Andrew P. Morris, David P. Strachan, Nita G. Forouhi, Eco J. C. de Geus, Jaakko Tuomilehto, Antti Jula, Ryan W. Walker, Mary F. Feitosa, Reedik Mägi, Aki S. Havulinna, Inger Njølstad, Alan R. Shudiner, Jennifer E. Huffman, Peter Lichtner, Richard N. Bergman, Mariaelisa Graff, Diana Kuh, Tim D. Spector, Robert Luben, Veikko Salomaa, Christian Gieger, Jaspal S. Kooner, Teresa Ferreira, Jennifer L. Bragg-Gresham, Sylvain Sebert, Terho Lehtimäki, Heikki A. Koistinen, Alexandra M. Lewin, Alexessander Couto Alves, Peter S. Chines, Lise Lotte N. Husemoen, Salome Scholtens, Yii-Der Ida Chen, Kati Kristiansson, Barbara McKnight, Sara M. Willems, Rainer Rauramaa, Satu Männistö, Stephan J. L. Bakker, Angela Döring, Audrey Y. Chu, Niels Grarup, Matti Uusitupa, Hannu Puolijoki, L. Adrienne Cupples, Veronique Vitart, Marie Neergaard Harder, Jouke-Jan Hottenga, Kari Stefansson, Alan F. Wright, Igor Rudan, Keri L. Monda, Jian'an Luan, Robert A. Scott, Albert Hofman, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Maija Hassinen, Sarah H. Wild, Iris M. Heid, Brenda W.J.H. Penninx, John C. Chambers, Claire Bellis, Nicholas D. Hastie, Ruth J. F. Loos, Martina Müller-Nurasyid, Johanne Marie Justesen, Gérard Waeber, Jennie Hui, Gonçalo R. Abecasis, Ishminder K. Kooner, Harold Snieder, Judith M. Vonk, Ioanna Tachmazidou, Ronald P. Stolk, Michael Stumvoll, Till Ittermann, Oluf Pedersen, Ingrid B. Borecki, Gonneke Willemsen, Jagvir Grewal, Markku Laakso, Arthur W. Musk, Eero Kajantie, Hans L. Hillege, Michael Boehnke, Cristina Venturini, Lili Milani, John Beilby, Fernando Rivadeneira, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Goel, Anuj [0000-0003-2307-4021], Jackson, Anne U [0000-0002-9672-2547], Kristiansson, Kati [0000-0003-4688-107X], Medina-Gomez, Carolina [0000-0001-7999-5538], Nolte, Ilja M [0000-0001-5047-4077], Prokopenko, Inga [0000-0003-1624-7457], Teumer, Alexander [0000-0002-8309-094X], Wong, Andrew [0000-0003-2079-4779], Beilby, John [0000-0002-4915-2254], Bergmann, Sven [0000-0002-6785-9034], Strachan, David P [0000-0001-7854-1366], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Energy & Sustainability Programme, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Children's Hospital, Lastentautien yksikkö, Clinicum, Institute for Molecular Medicine Finland, Behavioural Sciences, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Department of Medicine, Endokrinologian yksikkö, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, University of Helsinki, Leif Groop Research Group, Quantitative Genetics, HUS Children and Adolescents, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, School of Medicine / Clinical Medicine, School of Medicine / Biomedicine,School of Medicine / Clinical Nutrition, Ried, Janina S., Jeff, Janina M., Chu, Audrey Y., Bragg Gresham, Jennifer L., Van Dongen, Jenny, Huffman, Jennifer E., Ahluwalia, Tarunveer S., Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Toñu, Feitosa, Mary F., Goel, Anuj, Gorski, Mathia, Hayward, Caroline, Heard Costa, Nancy L., Jackson, Anne U., Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'An, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina Gomez, Carolina, Monda, Keri L., Nolte, Ilja M., Pérusse, Loui, Prokopenko, Inga, Qi, Lu, Rose, Lynda M., Salvi, Erika, Smith, Megan T., Snieder, Harold, Standáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, Van Der Harst, Pim, Walker, Ryan W., Wang, Sophie R., Wild, Sarah H., Willems, Sara M., Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan J. L., Barlassina, Cristina, Bartz, Traci M., Beilby, John, Bellis, Claire, Bergman, Richard N., Bergmann, Sven, Blangero, John, Blüher, Matthia, Boerwinkle, Eric, Bonnycastle, Lori L., Bornstein, Stefan R., Bruinenberg, Marcel, Campbell, Harry, Chen, Yii Der Ida, Chiang, Charleston W. K., Chines, Peter S., Collins, Francis S, Cucca, Fracensco, Cupples, L. Adrienne, D'Avila, Francesca, De Geus, Eco J. C., Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G., Farmaki, Aliki Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G., Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niel, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Ander, Harder, Marie Neergaard, Hartman, Catharina A., Hassinen, Maija, Hastie, Nichola, Hattersley, Andrew Tym, Havulinna, Aki S., Heliövaara, Markku, Hillege, Han, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G., Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L., Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E., Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen Kiukaanniemi, Sirkka M., Kinnunen, Leena, Knekt, Paul B., Koistinen, Heikki A., Kolcic, Ivana, Kooner, Ishminder K., Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosio, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M., Lichtner, Peter, Lindgren, Cecilia M., Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattia, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, Mcardle, Wendy L., Mcknight, Barbara, Mohlke, Karen L., Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E., Morris, Andrew P., Müller, Gabriele, Musk, Arthur W., Narisu, Narisu, Ong, Ken K., Oostra, Ben A., Osmond, Clive, Palotie, Aarno, Pankow, James S., Paternoster, Lavinia, Penninx, Brenda W., Pichler, Irene, Pilia, Maria G., Polašek, Ozren, Pramstaller, Peter P., Raitakari, Olli T, Rankinen, Tuomo, Rao, D. C., Rayner, Nigel W., Ribel Madsen, Rasmu, Rice, Treva K., Richards, Marcu, Ridker, Paul M., Rivadeneira, Fernando, Ryan, Kathy A., Sanna, Serena, Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P., Strauch, Konstantin, Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Tönjes, Anke, Tsafantakis, Emmanouil, Van Der Most, Peter J., Van Vliet Ostaptchouk, Jana V., Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie Claude, Vonk, Judith M., Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W., Wright, Alan F., Yerges Armstrong, Laura M., Zhao, Jing Hua, Carola Zillikens, M., Boomsma, Dorret I., Bouchard, Claude, Chambers, John C., Chasman, Daniel I., Cusi, Daniele, Gansevoort, Ron T., Gieger, Christian, Hansen, Torben, Hicks, Andrew A., Hu, Frank, Hveem, Kristian, Jarvelin, Marjo Riitta, Kajantie, Eero, Kooner, Jaspal S., Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Metspalu, Andre, Njølstad, Inger, Ohlsson, Clae, Oldehinkel, Albertine J., Palmer, Lyle J., Pedersen, Oluf, Perola, Marku, Peters, Annette, Psaty, Bruce M., Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E. H., Shudiner, Alan R., Smit, Jan H., Sørensen, Thorkild I. A., Spector, Timothy D., Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J., Watkins, Hugh, Wilson, James F., Zeggini, Eleftheria, Abecasis, Goncalo R., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Pano, Van Duijn, Cornelia M., Fox, Caroline, Groop, Leif C., Heid, Iris M., Hunter, David J., Kaplan, Robert C., Mccarthy, Mark I., North, Kari E., O'Connell, Jeffrey R., Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P., Frayling, Timothy, Hirschhorn, Joel N., Müller Nurasyid, Martina, Loos, Ruth J. F., Internal medicine, Psychiatry, EMGO - Mental health, Public Health, Epidemiology, Surgery, Internal Medicine, Erasmus MC other, and Child and Adolescent Psychiatry / Psychology
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Statistical methods, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Mice, HEIGHT, Body Size, Mass index, 2. Zero hunger, Genetics, Principal Component Analysis, Multidisciplinary, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Anthropometry, Chemistry (all), Phenotype, Common, gene, body, shape, Multidisciplinary Sciences, Principal component analysis, Trait, Science & Technology - Other Topics, DIET-INDUCED OBESITY, Waist, Genotype, 515 Psychology, Science, EARLY-ONSET, Snp, BIOLOGY, HIP RATIO, Genome-wide association studies Statistical methods, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Physics and Astronomy (all), MASS INDEX, DISEASE ASSOCIATIONS, RESOURCE, MD Multidisciplinary, Humans, GENOME-WIDE ASSOCIATION, Biochemistry, Genetics and Molecular Biology (all), Science & Technology, Models, Genetic, ta1184, FAT DISTRIBUTION, General Chemistry, ta3121, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Body mass index, Genome-Wide Association Study
Abstract: Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways., published version, peerReviewed
Published: 2016
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9. Cell-type heterogeneity in adipose tissue is associated with complex traits and reveals disease-relevant cell-specific eQTLs

Author: Craig A. Glastonbury, Alexessander Couto Alves, Kerrin S. Small, and Julia S. El-Sayed Moustafa
Subjects: 0301 basic medicine, Adult, Male, Multifactorial Inheritance, obesity, Cell type, In silico, Quantitative Trait Loci, Adipose tissue, Genomics, Genome-wide association study, Disease, Computational biology, Biology, eQTL, Polymorphism, Single Nucleotide, Article, Transcriptome, transcriptomics, 03 medical and health sciences, 0302 clinical medicine, cell type composition, genomics, Humans, Genetic Predisposition to Disease, genetics, Gene, Genetics (clinical), Aged, 030304 developmental biology, Aged, 80 and over, Inflammation, adipose, 0303 health sciences, Gene Expression Profiling, Middle Aged, interactions, TwinsUK, 030104 developmental biology, Phenotype, Adipose Tissue, 030220 oncology & carcinogenesis, Expression quantitative trait loci, Female, GTEx, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Adipose tissue is an important endocrine organ with a role in many cardiometabolic diseases. It is comprised of a heterogeneous collection of cell types that can differentially impact disease phenotypes. Cellular heterogeneity can also confound -omic analyses but is rarely taken into account in analysis of solid-tissue transcriptomes. Here, we investigate cell-type heterogeneity in two population-level subcutaneous adipose-tissue RNA-seq datasets (TwinsUK, n = 766 and the Genotype-Tissue Expression project [GTEx], n = 326) by estimating the relative proportions of four distinct cell types (adipocytes, macrophages, CD4+ T cells, and micro-vascular endothelial cells). We find significant cellular heterogeneity within and between the TwinsUK and GTEx adipose datasets. We find that adipose cell-type composition is heritable and confirm the positive association between adipose-resident macrophage proportion and obesity (high BMI), but we find a stronger BMI-independent association with dual-energy X-ray absorptiometry (DXA) derived body-fat distribution traits. We benchmark the impact of adipose-tissue cell composition on a range of standard analyses, including phenotype-gene expression association, co-expression networks, and cis-eQTL discovery. Our results indicate that it is critical to account for cell-type composition when combining adipose transcriptome datasets in co-expression analysis and in differential expression analysis with obesity-related traits. We applied gene expression by cell-type proportion interaction models (G × Cell) to identify 26 cell-type-specific expression quantitative trait loci (eQTLs) in 20 genes, including four autoimmune disease genome-wide association study (GWAS) loci. These results identify cell-specific eQTLs and demonstrate the potential of in silico deconvolution of bulk tissue to identify cell-type-restricted regulatory variants.
Published: 2018
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10. Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity

Author: Couto Alves, A, Valcarcel, B, Mäkinen, V-P, Morin-Papunen, L, Sebert, S, Kangas, A J, Soininen, P, Das, S, De Iorio, M, Coin, L, Ala-Korpela, M, and Järvelin, M-R
Subjects: Adult, Obesity, Abdominal/epidemiology, endocrine system diseases, Insulin/metabolism, Waist Circumference/physiology, Finland/epidemiology, nutritional and metabolic diseases, Polycystic Ovary Syndrome/epidemiology, Testosterone/metabolism, Evaluation Studies as Topic, Hyperandrogenism/epidemiology, Humans, Metabolomics, Dyslipidemias/epidemiology, Female, Insulin Resistance/physiology
Abstract: BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with metabolic disturbances including obesity, insulin resistance and diabetes mellitus. Here we investigate whether changes in the metabolic profile of PCOS women are driven by increased tendency to obesity or are specific features of PCOS related to increased testosterone levels.DESIGN AND METHODS: We conducted an NMR metabolomics association study of PCOS cases (n=145) and controls (n=687) nested in a population-based birth cohort (n=3127). Subjects were 31 years old at examination. The main analyses were adjusted for waist circumference (WC) as a proxy measure of central obesity. Subsequently, metabolite concentrations were compared between cases and controls within pre-defined WC strata. In each stratum, additional metabolomics association analyses with testosterone levels were conducted separately among cases and controls.RESULTS: Overall, women with PCOS showed more adverse metabolite profiles than the controls. Four lipid fractions in different subclasses of very low density lipoprotein (VLDL) were associated with PCOS, after adjusting for WC and correction for multiple testing (PCONCLUSIONS: Our findings show that both abdominal obesity and hyperandrogenism contribute to the dyslipidaemia and other metabolic traits of PCOS which all may negatively contribute to the long-term health of women with PCOS.
Published: 2017
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11. Genome-wide association analysis identifies six new loci associated with forced vital capacity

Author: Wenbo Tang, Stephen B. Kritchevsky, Ian P. Hall, Alexessander Couto Alves, Henry Völzke, Kim de Jong, Sina A. Gharib, Louise V. Wain, Adaikalavan Ramasamy, John M. Starr, Tatijana Zemunik, André G. Uitterlinden, Isabelle Pin, A. Bill Musk, Lina Zgaga, Ernst Omenaas, Mi Kyeong Lee, Nadia N. Hansel, Lewis J. Smith, Dana B. Hancock, Anne Viljanen, Anneli Pouta, Erik Melén, Nora Franceschini, Susan Campbell, Alicja R. Rudnicka, Melissa E. Garcia, Jemma B. Wilk, Igor Rudan, John Beilby, Fernando Rivadeneira, Gudny Eiriksdottir, Lenore J. Launer, Kristin M. Burkart, Ozren Polasek, Pieter S. Hiemstra, Regina Hampel, Jerome I. Rotter, Markku Heliövaara, Harald Grallert, Tim D. Spector, Andrew P. Morris, Jennifer E. Huffman, Pau Navarro, Jing Hua Zhao, Robert A. Scott, Bruno H. Stricker, Christopher Oldmeadow, Yeon-Mok Oh, Christian Gieger, Tove Fall, Caroline Hayward, Rodney J. Scott, Mika Kähönen, Vilmundur Gudnason, Guy Brusselle, Stefan Karrasch, Anne B. Newman, Alan James, Ida Surakka, Peter K. Joshi, R. Graham Barr, Fien Verhamme, Alexander Teumer, Ulf Gyllensten, Joohon Sung, Marjolein J. Peters, Ryan L. Minster, Kirsi H. Pietiläinen, Ian J. Deary, Lorna M. Lopez, Matthias Wjst, Myriam Fornage, Susan Redline, Wei Gao, Taina Rantanen, David J. Lederer, Gail Davies, Mary K. Wojczynski, Kari E. North, Beate Koch, Guo Li, George T. O'Connor, Blair H. Smith, Harry Campbell, Wendy B. White, Juha Pekkanen, Eva Albrecht, Sven Gläser, Joyce B. J. van Meurs, Stephen S. Rich, Wendy L. McArdle, Deborah Jarvis, Ani Manichaikul, Pirro G. Hysi, Christopher J Hammond, Erik Ingelsson, Albert V. Smith, John Attia, O. Dale Williams, Tamara B. Harris, Susan R. Heckbert, Josée Dupuis, Bruce M. Psaty, Åsa Johansson, Xin-Qun Wang, Samuli Ripatti, Woo Jin Kim, Patricia A. Cassano, H. Marike Boezen, David J. Porteous, Esteban G. Burchard, Kurt Lohman, Ivana Kolcic, Lies Lahousse, James F. Wilson, Dirkje S. Postma, Holly Trochet, Nicholas J. Wareham, Ana Viñuela, María Soler Artigas, Lars Lind, Jennie Hui, Bharat Thyagarajan, Judith M. Vonk, Marcy F. Petrini, Bonnie R. Joubert, Marjo-Riitta Järvelin, Xiangjun Gu, Claudia Flexeder, Generation Scotland, Sarah H. Wild, Nicholas D. Hastie, Thomas Lumley, Veronique Vitart, Laura R. Loehr, Joachim Heinrich, Yongmei Liu, Akshay Sood, Tess D. Pottinger, Alan F. Wright, Albert Hofman, Rajesh Kumar, Cisca Wijmenga, Elizabeth G. Holliday, Ian Sayers, David P. Strachan, Martin D. Tobin, Stefan Enroth, Thor Aspelund, Leslie A. Lange, Qing Duan, Daan W. Loth, Ken R. Bracke, Nathan C. Gaddis, David Couper, Stephanie J. London, Alanna C. Morrison, Holger Schulz, Jaakko Kaprio, Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Otorhinolaryngology and Head and Neck Surgery, Psychiatry, Epidemiology, Public Health, and Internal Medicine
Subjects: Spirometry, Lung Diseases, Vital capacity, Quantitative Trait Loci, Vital Capacity, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, DISEASE, Pulmonary function testing, Cohort Studies, FEV1/FVC ratio, Idiopathic pulmonary fibrosis, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, Forced Expiratory Volume, Databases, Genetic, Genetics, medicine, Humans, Restrictive lung disease, Lung volumes, Genetic Predisposition to Disease, lung, spriometry, SNP, gene, GENE-EXPRESSION, medicine.diagnostic_test, Genome, Human, HERITABILITY, HEALTHY TWIN, MORTALITY, ta3141, respiratory system, medicine.disease, Prognosis, 3. Good health, Respiratory Function Tests, respiratory tract diseases, FAMILY, LUNG-FUNCTION, Genetic Loci, Immunology, CELLS, IDIOPATHIC PULMONARY-FIBROSIS, TRAITS, Follow-Up Studies, Genome-Wide Association Study
Abstract: Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P
Published: 2014
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12. Telomere Length in Circulating Leukocytes is Associated with Lung Function and Disease

Author: Alexessander Couto Alves, Kirsi H. Pietiläinen, Cornelia M. van Duijn, Pamela A. F. Madden, Massimo Mangino, Iiris Hovatta, Stefan Karrasch, Alexandra I. F. Blakemore, Anjali K. Henders, Marjo-Riitta Järvelin, Ben A. Oostra, Seppo Sarna, Annette Peters, Eco J. C. de Geus, H.-Erich Wichmann, Ana Viñuela, Nilesh J. Samani, Christopher P. Nelson, Linda Broer, Elina Sillanpää, Ida Surakka, Christian Gieger, Konstantin Strauch, Jessica L. Buxton, Markku Peltonen, Taina Rantanen, Sarianna Sipilä, Holger Schulz, Eva Albrecht, Nicholas G. Martin, Veryan Codd, Patrik K. E. Magnusson, Jaakko Kaprio, Melanie Waldenberger, Nancy L. Pedersen, Najaf Amin, Gonneke Willemsen, Dale R. Nyholt, Rudolf A. Jörres, Joachim Heinrich, Dorret I. Boomsma, Juergen Behr, Manuel A. R. Ferreira, Hell M. Backmand, Päivi Piirilä, Tim D. Spector, Aila Rissanen, Tellervo Korhonen, Rudolf M. Huber, Sara Hägg, Epidemiology, Clinical Genetics, Public Health, Biological Psychology, and EMGO+ - Lifestyle, Overweight and Diabetes
Subjects: Lung Diseases, Male, Pulmonary and Respiratory Medicine, Spirometry, Netherlands Twin Register (NTR), Vital capacity, Vital Capacity, ennenaikainen vanheneminen, Disease, Cohort Studies, Pathogenesis, Pulmonary Disease, Chronic Obstructive, Telomere Homeostasis, SDG 3 - Good Health and Well-being, Forced Expiratory Volume, astma, Leukocytes, Humans, COPD, Medicine, keuhkoahtaumatauti, Aged, Asthma, telomeeri, medicine.diagnostic_test, premature aging, business.industry, Smoking, Case-control study, ta3141, Middle Aged, Telomere, spirometria, medicine.disease, biologinen ikä, biological age, 3. Good health, respiratory tract diseases, Europe, Case-Control Studies, Immunology, Regression Analysis, Female, business
Abstract: Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in is (FEV1), forced vital capacity (PVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (beta= -0.0452, p= 0.024) as well as COPD (beta= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07 x 10(-7)), FVC (p=2.07 x 10(-5)), and FEV1/FVC (p =5.27 x 10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.
Published: 2014
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13. A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus

Author: Mark B Y Tang, Michael Poidinger, Zhuang Li, Liangdan Sun, Nurhashikin Yusof, Xuejun Zhang, Liu Jianjun, Linde Meyaard, Marjo-Riitta Järvelin, Julian C. Knight, Doreen Haase, Chin Keh Chuang, Vivek Naranbhai, Alexessander Couto Alves, Astrid Irwanto, Benjamin P. Fairfax, Anand Kumar Andiappan, Geertje H. A. Westerlaken, Olaf Rötzschke, Rossella Melchiotti, Juha Pekkanen, Bernett Lee, Shyam Prabhakar, Josephine Lum, Francesca Zolezzi, Geraldine Koh, E. Birgitte Lane, Dilip Kumar, Joe Yeong, De Yun Wang, Kia Joo Puan, Fook Tim Chew, Shihui Foo, and John E.A. Common
Subjects: Male, 0301 basic medicine, Candidate gene, VSTM1, Neutrophils, Bisulfite sequencing, lcsh:Medicine, Genome-wide association study, Monocytes, Gene expression, HUMAN GENOME, GWAS, Genetics(clinical), TRANSCRIPTION, Receptors, Immunologic, Promoter Regions, Genetic, DNA METHYLATION, Genetics (clinical), Genetics, Regulation of gene expression, Genetics & Heredity, SIGNAL INHIBITORY RECEPTOR, Signal inhibitory receptor on leukocytes-1 (SIRL-1), DNA methylation, Molecular Medicine, Female, Life Sciences & Biomedicine, EXPRESSION, lcsh:QH426-470, Biology, Polymorphism, Single Nucleotide, Dermatitis, Atopic, Young Adult, 03 medical and health sciences, Expression quantitative trait loci (eQTL), Asian People, Journal Article, Humans, LEUKOCYTES-1, Molecular Biology, Atopic dermatitis, 0604 Genetics, Science & Technology, Research, lcsh:R, PU.1, Reactive oxygen species (ROS), Promoter, 1103 Clinical Sciences, lcsh:Genetics, 030104 developmental biology, Gene Expression Regulation, CPG ISLANDS, Expression quantitative trait loci, HUMAN PHAGOCYTES
Abstract: Background Expression quantitative trait loci (eQTL) databases represent a valuable resource to link disease-associated SNPs to specific candidate genes whose gene expression is significantly modulated by the SNP under investigation. We previously identified signal inhibitory receptor on leukocytes-1 (SIRL-1) as a powerful regulator of human innate immune cell function. While it is constitutively high expressed on neutrophils, on monocytes the SIRL-1 surface expression varies strongly between individuals. The underlying mechanism of regulation, its genetic control as well as potential clinical implications had not been explored yet. Methods Whole blood eQTL data of a Chinese cohort was used to identify SNPs regulating the expression of VSTM1, the gene encoding SIRL-1. The genotype effect was validated by flow cytometry (cell surface expression), correlated with electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and bisulfite sequencing (C-methylation) and its functional impact studied the inhibition of reactive oxygen species (ROS). Results We found a significant association of a single CpG-SNP, rs612529T/C, located in the promoter of VSTM1. Through flow cytometry analysis we confirmed that primarily in the monocytes the protein level of SIRL-1 is strongly associated with genotype of this SNP. In monocytes, the T allele of this SNP facilitates binding of the transcription factors YY1 and PU.1, of which the latter has been recently shown to act as docking site for modifiers of DNA methylation. In line with this notion rs612529T associates with a complete demethylation of the VSTM1 promoter correlating with the allele-specific upregulation of SIRL-1 expression. In monocytes, this upregulation strongly impacts the IgA-induced production of ROS by these cells. Through targeted association analysis we found a significant Meta P value of 1.14 × 10–6 for rs612529 for association to atopic dermatitis (AD). Conclusion Low expression of SIRL-1 on monocytes is associated with an increased risk for the manifestation of an inflammatory skin disease. It thus underlines the role of both the cell subset and this inhibitory immune receptor in maintaining immune homeostasis in the skin. Notably, the genetic regulation is achieved by a single CpG-SNP, which controls the overall methylation state of the promoter gene segment. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0404-6) contains supplementary material, which is available to authorized users.
Published: 2017

14. Exome-wide association study of plasma lipids in >300,000 individuals

Author: Asif Rasheed, Mary F. Feitosa, Ian J. Deary, Melissa E. Garcia, Danish Saleheen, Christian Gieger, Andrea Maschio, Lia E. Bang, Cliona Molony, Ivan Brandslund, Dan M. Roden, Ian Ford, Paul M. Ridker, Alisa K. Manning, Giorgio Pistis, Anette Varbo, Alexander P. Reiner, Kathleen Stirrups, David C. Liewald, Tim D. Spector, Paul W. Franks, Cristen J. Willer, Daniel I. Chasman, Jean Ferrières, Vilmundur Gudnason, Tapani Ebeling, Neil Poulter, Magdalena Zoledziewska, Elizabeth K. Speliotes, Eleftheria Zeggini, Megan L. Grove, Hua Tang, Stavroula Kanoni, Peter Weeke, Panos Deloukas, Daniel J. Rader, Amit Khera, Serena Sanna, Dorota Pasko, Gina M. Peloso, Charles Kooperberg, Suthesh Sivapalaratnam, Natalie R. van Zuydam, Christian M. Shaffer, Fredrik Karpe, Naveed Sattar, Pieter Muntendam, Ruth J. F. Loos, Eric Boerwinkle, Wei Gao, Mark J. Caulfield, Matt Neville, Sangeetha Somayajula, Olle Melander, Hayato Tada, Jose M. Ordovas, He Zhang, John D. Rioux, Michael Boehnke, Erwin P. Bottinger, Franco Giulianini, Martina Müller-Nurasyid, Stella Trompet, Connor A. Emdin, Andrew P. Morris, Johanne Marie Justesen, Alan R. Tall, Kari Kuulasmaa, Adam S. Butterworth, Marie-Pierre Dubé, Dajiang J. Liu, Paul L. Auer, Jennifer E. Huffman, Usman Baber, John Danesh, Xiao Wang, Anna F. Dominiczak, Jarmo Virtamo, John M. Starr, Ozren Polasek, Gonçalo R. Abecasis, Timo A. Lakka, Stephen S. Rich, Marco M Ferrario, Marju Orho-Melander, Xueling Sim, Dominique Arveiler, Dermot F. Reilly, Torsten Lauritzen, Gudny Eiriksdottir, Marit E. Jørgensen, Anubha Mahajan, Colin N. A. Palmer, Veikko Salomaa, Nicholas J. Wareham, Dewan S. Alam, Anne Tybjærg-Hansen, Ellen M. Schmidt, Y. Eugene Chen, Heather M. Stringham, Bruce M. Psaty, Christie M. Ballantyne, Nan Wang, Joshua C. Bis, Myriam Fornage, Neil S Zheng, Kristian Hveem, Praveen Surendran, Yingchang Lu, Peter S. Sever, James B. Meigs, Heikki A. Koistinen, Charlotta Pisinger, Tibor V. Varga, Yii-Der Ida Chen, Konstantin Strauch, Timothy M. Frayling, Patricia B. Munroe, Albert V. Smith, Ruth Frikke-Schmidt, Lorraine Southam, Frida Renström, Philippe Amouyel, Nicholas G. D. Masca, Alexessander Couto Alves, Xiangfeng Lu, Andres Metspalu, Anne Langsted, Joanna M. M. Howson, Tamara B. Harris, Leif Groop, Chad A. Cowan, Cramer Christensen, Audrey Y. Chu, Markku Laakso, Torben Hansen, Li-An Lin, John C. Chambers, Jonas B. Nielsen, Niels Grarup, Neil R. Robertson, Kiran Musunuru, Joshua S. Weinstock, Morris J. Brown, Jean-Claude Tardif, Gorm B. Jensen, Jerome I. Rotter, Harald Grallert, Yan Zhang, Kerrin S. Small, Nathan O. Stitziel, Fabio Busonero, Jennifer Wessel, Themistocles L. Assimes, Lenore J. Launer, Lars G. Fritsche, Mark O. Goodarzi, Peter W.F. Wilson, Sekar Kathiresan, Philippe M. Frossard, Emanuele Di Angelantonio, Yanhua Zhou, James G. Wilson, Frank Kee, Scott M. Damrauer, Weihua Zhang, Gail Davies, Oluf Pedersen, Sune F. Nielsen, Alanna C. Morrison, Raquel S. Sevilla, Helen R. Warren, Johanna Kuusisto, Hanieh Yaghootkar, Sandosh Padmanabhan, Philip S. Tsao, Caroline Hayward, Tõnu Esko, Ming Xu, Anders Mälarstig, Anne U. Jackson, Eirini Marouli, Jette Bork-Jensen, Robin Young, C.J. O'Donnell, Yong Huo, Melanie Waldenberger, Jaspal S. Kooner, Pekka Mäntyselkä, Marjo-Riitta Järvelin, Santhi K. Ganesh, Annette Peters, L. Adrienne Cupples, Wei Zhou, Derek Klarin, Markus Perola, Francesco Cucca, Allan Linneberg, Mark I. McCarthy, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, J. Wouter Jukema, Valentin Fuster, Claudia Langenberg, Roxana Mehran, Børge G. Nordestgaard, Jaakko Tuomilehto, Reedik Mägi, Blair H. Smith, Johanna Jakobsdottir, Marianne Benn, Kent D. Taylor, Ani Manichaikul, Igor Rudan, Aniruddh P. Patel, Joshua C. Denny, Oddgeir L. Holmen, John M. C. Connell, Robert A. Scott, Haojie Yu, Rajiv Chowdhury, Sehrish Jabeen, Antonella Mulas, Aliki-Eleni Farmaki, Rainer Rauramaa, George Dedoussis, Vascular Medicine, Nielsen, Jonas B [0000-0002-6654-2852], Kathiresan, Sekar [0000-0002-6724-032X], Apollo - University of Cambridge Repository, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: 0301 basic medicine, Exome/genetics, Genome-wide association study, Type 2 diabetes, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, Charge Diabetes Working Group, Macular Degeneration, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Exome, Macular Degeneration/blood, Genetics & Heredity, Genetic Predisposition to Disease/genetics, CLONAL HEMATOPOIESIS, 11 Medical And Health Sciences, CODING-SEQUENCE VARIANTS, Lipids, Phenotype, CARDIOVASCULAR-DISEASE, VA Million Veteran Program, lipids (amino acids, peptides, and proteins), GOLD Consortium, LOW-FREQUENCY, EPIC-InterAct Consortium, Diabetes Mellitus, Type 2/blood, Life Sciences & Biomedicine, Type 2, medicine.medical_specialty, Genotype, APOBEC-1 COMPLEMENTATION FACTOR, Biology, Lower risk, Article, EPIC-CVD Consortium, GENETIC ARCHITECTURE, 03 medical and health sciences, Coronary Artery Disease/blood, Diabetes mellitus, Internal medicine, Genetics, medicine, Diabetes Mellitus, Journal Article, Lipolysis, Humans, Genetic Predisposition to Disease, Allele, TYROSINE KINASE JAK2, Genetic Association Studies, B MESSENGER-RNA, Science & Technology, MACULAR DEGENERATION, MYELOPROLIFERATIVE DISORDERS, Cholesterol, Lipids/blood, Genetic Variation, 06 Biological Sciences, medicine.disease, cardiovascular diseases, genome wide association studies, Genetic Association Studies/methods, 030104 developmental biology, Endocrinology, chemistry, Diabetes Mellitus, Type 2, TM6SF2, Developmental Biology
Abstract: We screened DNA sequence variants on an exome-focused genotyping array in >300,000 participants with replication in >280,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice revealed lipid changes consistent with the human data. We utilized mapped variants to address four clinically relevant questions and found the following: (1) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease; (2) outside of the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (3) only some mechanisms of lowering LDL-C seemed to increase risk for type 2 diabetes; and (4) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (e.g., TM6SF2, PNPLA3) tracked with higher liver fat, higher risk for type 2 diabetes, and lower risk for coronary artery disease whereas TG-lowering alleles involved in peripheral lipolysis (e.g., LPL, ANGPTL4) had no effect on liver fat but lowered risks for both type 2 diabetes and coronary artery disease.
Published: 2017
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15. Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity

Author: Couto Alves, A. (A), Valcarcel, B. (B), Mäkinen, V.-P. (V-P), Morin-Papunen, L. (L), Sebert, S. (S), Kangas, A. J. (A J), Soininen, P. (P), Das, S. (S), De Iorio, M. (M), Coin, L. (L), Ala-Korpela, M. (M), Järvelin, M.-R. (M-R), Franks, S. (S), School of Pharmacy, Activities, MRC, and Imperial College Healthcare NHS Trust- BRC Funding
Subjects: Adult, endocrine system diseases, SYNDROME PCOS, LOW-DENSITY-LIPOPROTEIN, OLIGOMENORRHEA AND/OR HIRSUTISM, Endocrinology & Metabolism, Humans, Insulin, Metabolomics, Testosterone, Finland, Dyslipidemias, INSULIN-RESISTANCE, Science & Technology, Nutrition & Dietetics, nutritional and metabolic diseases, BIRTH COHORT 1966, 11 Medical And Health Sciences, ANDROGEN LEVELS, CARDIOVASCULAR-DISEASE, Evaluation Studies as Topic, Obesity, Abdominal, CORONARY-ARTERY-DISEASE, Original Article, Female, SELF-REPORTED SYMPTOMS, Insulin Resistance, Waist Circumference, Hyperandrogenism, Life Sciences & Biomedicine, 13 Education, SERUM METABOLOMICS, Polycystic Ovary Syndrome
Abstract: Background: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with metabolic disturbances including obesity, insulin resistance and diabetes mellitus. Here we investigate whether changes in the metabolic profile of PCOS women are driven by increased tendency to obesity or are specific features of PCOS related to increased testosterone levels. Design and methods: We conducted an NMR metabolomics association study of PCOS cases (n=145) and controls (n=687) nested in a population-based birth cohort (n=3127). Subjects were 31 years old at examination. The main analyses were adjusted for waist circumference (WC) as a proxy measure of central obesity. Subsequently, metabolite concentrations were compared between cases and controls within pre-defined WC strata. In each stratum, additional metabolomics association analyses with testosterone levels were conducted separately among cases and controls. Results: Overall, women with PCOS showed more adverse metabolite profiles than the controls. Four lipid fractions in different subclasses of very low density lipoprotein (VLDL) were associated with PCOS, after adjusting for WC and correction for multiple testing (P, published version, peerReviewed
Published: 2017

16. Shared genetic variants suggest common pathways in allergy and autoimmune diseases

Author: Adnan Custovic, David P. Strachan, Joel N. Hirschhorn, Marjo-Riitta Järvelin, Nicholas J. Timpson, Nicole M. Warrington, Hans Bisgaard, Marie Standl, Elaine Fuertes, Lude Franke, John Henderson, Angela Simpson, Manuel A. R. Ferreira, David A. Hinds, Alan James, Tune H. Pers, Carla M. T. Tiesler, Johannes Waage, Joyce Y. Tung, Susanne Brix, Eskil Kreiner, Craig E. Pennell, Gerard H. Koppelman, Alexessander Couto Alves, Dirkje S. Postma, Klaus Bønnelykke, Medical Research Council (MRC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, HAY-FEVER, Allergy, Genetic association studies, genetic association studies, NF-KAPPA-B, Autoimmunity, Genome-wide association study, medicine.disease_cause, Autoimmune Disease, Genetic Association Studies, Single Nucleotide Polymorphism, 0302 clinical medicine, single nucleotide polymorphism, Autoimmune disease, Immunology and Allergy, Genetics, IMMUNE-RESPONSES, autoimmunity, CD4 T-CELLS, MULTIPLE-SCLEROSIS, 3. Good health, 1107 Immunology, Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, Immunology, Single-nucleotide polymorphism, autoimmune disease, Biology, Polymorphism, Single Nucleotide, Autoimmune Diseases, 03 medical and health sciences, Immune system, medicine, Hypersensitivity, SNP, Humans, GENOME-WIDE ASSOCIATION, 1,25-DIHYDROXYVITAMIN D-3, Genetic association, Science & Technology, medicine.disease, RISK LOCI, Single nucleotide polymorphism, RHEUMATOID-ARTHRITIS, 030104 developmental biology, 25-DIHYDROXYVITAMIN D-3, 030215 immunology, Genome-Wide Association Study
Abstract: Background: The relationship between allergy and autoimmune disorders is complex and poorly understood.Objective: We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms.Methods: We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases.Results: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases.Conclusion: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.
Published: 2016
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17. Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity

Author: Julian E. Asher, David Meyre, Philippe Froguel, Robert Sladek, Mario Falchi, Christian Dina, Andrew Walley, Lachlan J. M. Coin, Lena M. S. Carlsson, Hariklia Eleftherohorinou, Leonardo Bottolo, Robin G. Walters, Eleni Hadjigeorgiou, Adam J. de Smith, Alexandra I. F. Blakemore, Johanna C. Andersson-Assarsson, Peter Jacobson, Jessica L. Buxton, Julia S. El-Sayed Moustafa, Sophie Visvikis-Siest, Alexessander Couto Alves, and Lars Sjöström
Subjects: Adult, Context (language use), Minisatellite Repeats, Biology, law.invention, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, law, Genetics, Guanine Nucleotide Exchange Factors, Humans, Genetic Predisposition to Disease, Copy-number variation, Child, Molecular Biology, Gene, Genetics (clinical), Polymerase chain reaction, Sequence Deletion, 030304 developmental biology, Genetic association, 0303 health sciences, Association Studies Articles, Chromosome, General Medicine, Dietary Fats, Phenotype, Obesity, Morbid, 3. Good health, Variable number tandem repeat, Adipose Tissue, Gene Expression Regulation, Case-Control Studies, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 8
Abstract: Variable number tandem repeats (VNTRs) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them. Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms. Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 (DOCK5) gene. The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion, all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects. We have developed a novel VNTR association method named VNTRtest, suitable for association analysis of multi-allelic loci with binary and quantitative outcomes, and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity (P(empirical)= 8.9 × 10(-8) and P= 3.1 × 10(-3), respectively) which we estimate explains ~0.8% of the phenotypic variance. We also identified an independent association between the 3975 base pair (bp) deletion and obesity, explaining a further 0.46% of the variance (P(combined)= 1.6 × 10(-3)). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P= 0.027) and both VNTRs (P(empirical)= 0.015) was also identified in adipose tissue from a Swedish family sample, providing support for a functional effect of the DOCK5 deletion and VNTRs. These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies.
Published: 2012
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18. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Author: Norman Klopp, Chih-Mei Chen, Erik Melén, Dirkje S. Postma, Klaus Bønnelykke, Gerard H. Koppelman, Ivan Curjuric, Massimo Mangino, Nicholas J. Timpson, Alexandra I. F. Blakemore, Stephen B. Montgomery, Marjo-Riitta Järvelin, Anneli Pouta, Dorret I. Boomsma, Melanie C. Matheson, Albert Hofman, Matthias Wjst, Hans Bisgaard, Natalija Novak, Deborah Jarvis, Grant W. Montgomery, Frank Geller, Beate St Pourcain, Craig E. Pennell, Manuel A. R. Ferreira, Andre Franke, Alexessander Couto Alves, Frank D. Mentch, Vincent W. V. Jaddoe, Marie Standl, Nicole M. Warrington, Jouke-Jan Hottenga, Jessica L. Buxton, Peter N. Le Souëf, Bjarke Feenstra, Peter D. Sly, Bo L. Chawes, Martina Mueller-Nurasyid, Angela Simpson, Philip J. Thompson, Jacob P. Thyssen, Patrick G. Holt, Eskil Kreiner-Møller, David L. Duffy, Thomas Illig, Johan C. de Jongste, Bo Jacobsson, Joachim Heinrich, Mads Melbye, Wenche Nystad, H-Erich Wichmann, Medea Imboden, Wendy L. McArdle, Carla M. T. Tiesler, Susan M. Ring, Jeff Murray, Lavinia Paternoster, Torkil Menné, Marjan Kerkhof, John Henderson, Ronny Myhre, Lyle J. Palmer, George Davey Smith, Eva Albrecht, Pamela A. F. Madden, Marika Kaakinen, Hansjoerg Baurecht, Nicole Probst-Hensch, Cecilia Kim, Cornelia M. van Duijin, Panos Deloukas, Patrick M. A. Sleiman, Christian Gieger, John A. Curtin, Adnan Custovic, Daniel Glass, Cilla Söderhäll, Annika Sääf, Elke Rodriguez, Nicholas G. Martin, Stephan Weidinger, Tim D. Spector, Adaikalavan Ramasamy, John P. Kemp, Heather A. Boyd, Elisabeth Thiering, David P. Strachan, Anna-Liisa Hartikainen, Hakon Hakonarson, Allan Linneberg, Ralf J. P. van der Valk, Pirro G. Hysi, David M. Evans, Rain Jögi, Ellen A. Nohr, Liesbeth Duijts, Katharina Heim, Veronique Bataille, Fernando Rivadeneira, Maria M. Groen-Blokhuis, Andrew C. Heath, David Ellinghaus, Michael E. March, Holger Prokisch, Regina Foelster-Holst, André G. Uitterlinden, Emmanouil T. Dermitzakis, Juha Pekkanen, Henriette A. Smit, Medical Research Council (MRC), Dermitzakis, Emmanouil, Montgomery, Stephen, Biological Psychology, EMGO+ - Mental Health, Pediatrics, Surgery, Internal Medicine, Epidemiology, Erasmus MC other, Public Health, Groningen Research Institute of Pharmacy, Faculteit Medische Wetenschappen/UMCG, and Groningen Research Institute for Asthma and COPD (GRIAC)
Subjects: Male, Genetics of Overweight Young Adults (GOYA) Consortium, Netherlands Twin Register (NTR), Epidemiology, Cell Differentiation/genetics Chromosomes, Human, Pair 11/genetics Chromosomes, Human, Pair 20/genetics Chromosomes, Human, Pair 5 Cytokines/genetics DNA-Binding Proteins/genetics Dermatitis, Atopic/*genetics/immunology Epidermis/immunology Female *Genetic Loci Genetic Predisposition to Disease *Genome-Wide Association Study Humans Intermediate Filament Proteins/genetics Kinesin/genetics Male Polymorphism, Single Nucleotide Risk Transcription Factors/genetics, Chromosomes, Human, Pair 20, Kinesins, Genome-wide association study, Filaggrin Proteins, VARIANTS, Chromosomes, Human, Pair 11/genetics, medicine.disease_cause, Genome-wide association studies, DISEASE, 030207 dermatology & venereal diseases, 0302 clinical medicine, Intermediate Filament Proteins, Epidermis/immunology, ddc:576.5, GENETICS & HEREDITY, Genetics, 0303 health sciences, education.field_of_study, PSORIASIS, Cytokines/genetics, Cell Differentiation, Kinesin, 11 Medical And Health Sciences, Atopic dermatitis, 3. Good health, DNA-Binding Proteins, DIFFERENTIATION, Chromosomes, Human, Pair 5, Cytokines, Female, Dermatitis, Atopic/genetics/immunology, Life Sciences & Biomedicine, Kinesin/genetics, Filaggrin, EXPRESSION, Risk, Cell Differentiation/genetics, Population, Transcription Factors/genetics, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Australian Asthma Genetics Consortium (AAGC), Article, MECHANISMS, Dermatitis, Atopic, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, FILAGGRIN, Humans, SPERMATOGENESIS, Genetic Predisposition to Disease, EArly Genetics & Lifecourse Epidemiology (EAGLE) Consortium, education, 030304 developmental biology, Science & Technology, Chromosomes, Human, Pair 11, Odds ratio, 06 Biological Sciences, Immune dysregulation, medicine.disease, Chromosomes, Human, Pair 20/genetics, Genetic Loci, Intermediate Filament Proteins/genetics, Immunology, ASTHMA, Epidermis, CELLULAR MOTILITY, DNA-Binding Proteins/genetics, Genome-Wide Association Study, Transcription Factors, Developmental Biology
Abstract: Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10 -13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10 -9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10 -8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. © 2012 Nature America, Inc. All rights reserved.
Published: 2012
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19. Association of Forced Vital Capacity with the Developmental Gene NCOR2

Author: Cosetta Minelli, Charlotte H. Dean, Matthew Hind, Alexessander Couto Alves, André F. S. Amaral, Valerie Siroux, Ville Huikari, María Soler Artigas, David M. Evans, Daan W. Loth, Yohan Bossé, Dirkje S. Postma, Don Sin, John Thompson, Florence Demenais, John Henderson, Emmanuelle Bouzigon, Deborah Jarvis, Marjo-Riitta Järvelin, Peter Burney, Epidemiology, Medical Research Council (MRC), and Groningen Research Institute for Asthma and COPD (GRIAC)
Subjects: Male, Lung Development, Organogenesis, Gene Expression, Social Sciences, Organic chemistry, DISEASE, Families, Mathematical and Statistical Techniques, Sociology, Consortia, Forced Expiratory Volume, Vitamin A, Children, Lung, HERITABILITY, Genomics, Vitamins, Middle Aged, Chemistry, Physical Sciences, Female, HEALTH, SERPINE2, Statistics (Mathematics), Research Article, EXPRESSION, Adult, General Science & Technology, Quantitative Trait Loci, Research and Analysis Methods, Polymorphism, Single Nucleotide, MECHANISMS, Chemical compounds, Young Adult, REGENERATION, MD Multidisciplinary, Organic compounds, Genome-Wide Association Studies, Genetics, Adults, Humans, Nuclear Receptor Co-Repressor 2, Genes, Developmental, GENOME-WIDE ASSOCIATION, Statistical Methods, Genetic Association Studies, Aged, Gene Expression Profiling, Biology and Life Sciences, Computational Biology, Human Genetics, Genome Analysis, ADULT LUNG-FUNCTION, Age Groups, People and Places, ASTHMA, Population Groupings, Organism Development, Mathematics, Developmental Biology, Meta-Analysis, Genome-Wide Association Study
Abstract: Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p < 0.002; 0.05/25), with a nominal p-value considered as suggestive evidence. For SNPs with evidence of replication, effects on the expression levels of nearby genes in lung tissue were tested in 1,111 lung samples (Lung eQTL consortium), with further functional investigation performed using public epigenomic profiling data (ENCODE). Results NCOR2-rs12708369 showed strong replication in children (p = 0.0002), with replication unavailable in adults due to low imputation quality. This intronic variant is in a strong transcriptional enhancer element in lung fibroblasts, but its eQTL effects could not be tested due to low imputation quality in the eQTL dataset. SERPINE2-rs6754561 replicated at nominal level in both adults (p = 0.036) and children (p = 0.045), while WNT16-rs2707469 replicated at nominal level only in adults (p = 0.026). The eQTL analyses showed association of WNT16-rs2707469 with expression levels of the nearby gene CPED1. We found no statistically significant eQTL effects for SERPINE2-rs6754561. Conclusions We have identified a new gene, NCOR2, in the retinoic acid signalling pathway pointing to a role of vitamin A metabolism in the regulation of FVC. Our findings also support SERPINE2, a COPD gene with weak previous evidence of association with FVC, and suggest WNT16 as a further promising candidate.
Published: 2016

20. Analysis with the exome array identifies multiple new independent variants in lipid loci

Author: George Dedoussis, Stavroula Kanoni, Bengt Sennblad, Patricia B. Munroe, Alice Stanton, Peter S. Braund, John C. Chambers, Angela Matchan, Eleftheria Zeggini, Olov Rolandsson, Céline Besse, Melanie Waldenberger, Tibor V. Varga, Panos Deloukas, Emmanouil Tsafantakis, Kathleen Stirrups, Maciej Tomaszewski, Martina Müller-Nurasyid, Anne Boland, John M. C. Connell, Robert A. Scott, Harald Grallert, Aliki-Eleni Farmaki, Neil R Poulter, Lorraine Southam, Martin D. Tobin, Maria Sabater-Lleal, Alexessander Couto Alves, Helen R. Warren, Rona J. Strawbridge, Nicholas G. D. Masca, Weihua Zhang, Lazaros Lataniotis, Denis C. Shields, Nigel W. Rayner, Stefan A. Escher, Angela Silveira, Christian Gieger, Dorota Pasko, Nicholas J. Wareham, Stephen Franks, Sirkka Keinänen-Kiukaanniemi, Konstantin Strauch, Paul W. Franks, Mark I. McCarthy, Nilesh J. Samani, Nikman An Hashim, Frida Renström, Maria Karaleftheri, Jan-Håkan Jansson, Hanieh Yaghootkar, Jaspal S. Kooner, Peter S. Sever, Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, Annette Peters, Anders Hamsten, Anna F. Dominiczak, Colin N. A. Palmer, Mark J. Caulfield, Timothy M. Frayling, Medical Research Council (MRC), National Institute for Health Research, and MRC
Subjects: 0301 basic medicine, Genome-wide association study, LDL-CHOLESTEROL, BLOOD-LIPIDS, RARE, Gene Frequency, Exome, Child, Genetics (clinical), Genetics & Heredity, Genetics, HERITABILITY, Association Studies Articles, 11 Medical And Health Sciences, General Medicine, Middle Aged, Lipids, CORONARY-ARTERY-DISEASE, LOW-FREQUENCY, Wellcome Trust Case Control Consortium, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, TRAITS, Adult, Biochemistry & Molecular Biology, Adolescent, European Continental Ancestry Group, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Humans, GENOME-WIDE ASSOCIATION, Molecular Biology, Allele frequency, METAANALYSIS, Triglycerides, Aged, Science & Technology, TRANSPORTER, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, 06 Biological Sciences, Heritability, Lipid Metabolism, Genetic architecture, Minor allele frequency, 030104 developmental biology, Genome-Wide Association Study
Abstract: It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF
Published: 2015
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21. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Author: Masato Isono, Jorma Viikari, Jianjun Liu, Xingwang Ye, Hao Peng, James Scott, Nanette R. Lee, Chris Hsu, Woon-Puay Koh, Torben Hansen, Vinicius Tragante, Christian Gieger, Tomohiro Katsuya, Aaron Isaacs, Norihiro Kato, Kjell Nikus, Dingliang Zhu, Tetsuro Miki, Zhirong Guo, Uzma Afzal, Hiroshi Kajio, Mika Kähönen, Terri L. Young, Jer-Yuarn Wu, Terho Lehtimäki, Oscar H. Franco, Niels Grarup, Stella Trompet, Rob M. van Dam, John Danesh, Weihua Zhang, Joanna D. Holbrook, Ryoichi Takayanagi, Miyako Kishimoto, Shuhei Yamaguchi, Jemma CHopewell, Thorkild I. A. Sørensen, André G. Uitterlinden, James Abbott, Cisca Wijmenga, Iris Postmus, Wilko Spiering, Gianluca Campanella, Michela Traglia, Ian J. Deary, Hirotsugu Ueshima, Tanja B. Grammer, Daniel OStram, Panos Deloukas, Huaixing Li, Tatsuaki Matsubara, Koichi Akiyama, Fumihiko Takeuchi, Young Jin Kim, Silke Szymczak, Dirk J. van Veldhuisen, Alexander W. Drong, Yu-Tang Gao, Imke Aits, Mark A. Pereira, Rajkumar Dorajoo, Marc Chadeau-Hyam, Benjamin Lehne, Bastiaan THeijman, Zuan Yu Mok, Timothy R. Braun, Mitsuhiro Yokota, Yechiel Friedlander, David C. Liewald, Pim van der Harst, Mahfuzar Rahman, Takayoshi Ohkubo, Aili Wang, Robert Clarke, Lisette Stolk, Pieter A. Doevendans, Wolfgang Lieb, Rebecca Mills, Sarah Parish, Katsuhiko Kohara, Martina Müller-Nurasyid, Nina Mononen, Steve Franks, Niek Verweij, Johanne Marie Justesen, Tin Aung, Rory Collins, J. Wouter Jukema, M.J. Pinidiyapathirage, Rory P. Wilson, Hong Kiat Ng, Joyce B. J. van Meurs, Yik Ying Teo, Wiek H. van Gilst, Wei Zheng, Robert WKoivula, John C. Chambers, Molly Scannell Bryan, Peng Chen, Gurpreet SWander, Lise Lotte N. Husemoen, David J. Stott, Li Ching Chang, Teresa Nutile, Lude Franke, Jaana Hartiala, Karen L. Mohlke, Folkert W. Asselbergs, Daniela Toniolo, Linda S. Adair, Tõnu Esko, Xueya Zhou, Marja Vääräsmäki, Ralhan Sarju, Hui Cai, Chiea Chuen Khor, Albert Hofman, Marc Jan Bonder, Shikta Das, Väinö Turjanmaa, Ying Wu, Masahiro Nakatochi, Habibul Ahsan, Michelle Ann Rozario, Andrew Bjonnes, Jaspal S. Kooner, Marcus E. Kleber, Rossella Sorice, Lavinia Paternoster, Yumi Matsushita, Tanika NKelly, Quang NNguyen, Stanley L. Hazen, Richa Saxena, Lin Tong, Kenneth Kwek, Keizo Ohnaka, Paolo Vineis, Sahoko Ichihara, Jos C. S. Kleinjans, Irene Mateo Leach, Yonghong Zhang, K. Sangher, Robin Young, Mika Kivimäki, Soterios A. Kyrtopoulos, Ching-Yu Cheng, William R. Scott, Andres Metspalu, Eranga N. Vithana, Ai Ling Teh, Tarunveer S. Ahluwalia, Alexandre F.R. Stewart, John M. Starr, Toru Nabika, Jeannette Lee, Andre Franke, Inês Barroso, Gail Davies, Olov Rolandsson, Wei Huang, Myron D. Gross, Yong-Bing Xiang, Cinzia Sala, Marjo-Riitta Järvelin, W. Frank Paul, Jian'an Luan, Jon White, Robert A. Scott, Torben Jørgensen, Jing He, Tien Yin Wong, Michiya Igase, Yi Zhang, Nur Sabrina Sapari, Simone Wahl, Ron T. Gansevoort, Rasheed Asif, Bruce H W Wolffenbuttel, Alauddin Ahmed, Annette Peters, Silva Kasela, Jiang He, Min Jin Go, Takao Sugiyama, Dongfeng Gu, Jagvir Grewal, Satoshi Umemura, Thomas Sparsø, Anna-Liisa Hartikainen, Hooman Allayee, Xu Wang, Meena Kumari, Eitaro Nakashima, Xu Lin, Harold Snieder, Ananda R. Wickremasinghe, Yun Kyoung Kim, Yuan-Tsong Chen, Chew-Kiat Heng, Alexessander Couto Alves, E. James Ames Hixso, Daniela Ruggiero, Kazuro Shimokawa, Muhammad GKibriya, Jong-Young Lee, Yasuharu Tabara, Oluf Pedersen, Bong Jo Kim, Marie Loh, Lili Milani, Loi D. Do, Dharambir Harambir, Joo Yeon Hwang, Thomas Meitinger, Todd L. Edwards, Danish Saleheen, Anuradhani Kasturiratne, Hiromi Rakugi, Sian Tsung Tan, Paul Elliott, Ken Yamamoto, Chien Hsiun Chen, Abbas Dehghan, Evelin Mihailov, Leo-Pekka Lyytikäinen, Xiao-Ou Shu, Richie Soong, Yiqin Wang, Marina Ciullo, Graciela E. Delgado, Olli TRaitakari, Jian-Min Yuan, Melanie Waldenberger, Jiemin Liao, E. Shyong Tai, Mark I. McCarthy, Winfried März, Nilesh J. Samani, Yap Seng Chong, Son TPham, Sarah E. Harris, Regina Courtney, Allan Linneberg, W.H. Wilson Tang, Epidemiology, Ophthalmology, Medical Microbiology & Infectious Diseases, Cardiology, Radiology & Nuclear Medicine, Internal Medicine, Erasmus MC other, Biochemie, Interne Geneeskunde, Toxicogenomics, RS: GROW - Oncology, RS: GROW - R1 - Prevention, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Male, Vascular smooth muscle, Performance, Research Support, U.S. Gov't, P.H.S, Genome-wide association study, Blood Pressure, Expression, 030204 cardiovascular system & hematology, VARIANTS, P.H.S, genome-wide, 0302 clinical medicine, Risk Factors, Natriuretic Peptide, Brain, Disease, Non-U.S. Gov't, CENTRIC ARRAY, Genetics, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Research Support, Non-U.S. Gov't, 11 Medical And Health Sciences, Middle Aged, REGIONS, Phenotype, CpG site, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, DNA methylation, BIOS-consortium, Regression Analysis, Female, Life Sciences & Biomedicine, Adult, PULMONARY ARTERIAL-HYPERTENSION, Genotype, Population, Single-nucleotide polymorphism, Biology, Research Support, ta3111, Polymorphism, Single Nucleotide, White People, Article, N.I.H, 03 medical and health sciences, KIDNEY, Asian People, Research Support, N.I.H., Extramural, Journal Article, Humans, Genetic Predisposition to Disease, Gene, METAANALYSIS, 030304 developmental biology, Aged, Science & Technology, CARDIo GRAMplusCD, ta1184, Extramural, Genetic Variation, InterAct Consortium, 06 Biological Sciences, DNA Methylation, ta3121, Peptide Fragments, INDIVIDUALS, Blood pressure, Genetic Loci, TISSUE, RISK-FACTORS, U.S. Gov't, LifeLines Cohort Study, Developmental Biology, Genome-Wide Association Study
Abstract: We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 x 10(-11) to 5.0 x 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 x 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
Published: 2015
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22. Integrative pathway genomics of lung function and airflow obstruction

Author: Marjo-Riitta Järvelin, Medea Imboden, Nicole Probst-Hensch, George T. O'Connor, Josée Dupuis, Jing Hua Zhao, Patricia A. Cassano, H. Marike Boezen, Pirro G. Hysi, Vilmundur Gudnason, Mika Kähönen, Daan W. Loth, Stephanie J. London, Adaikalavan Ramasamy, William C. Parks, Timothy P. Birkland, Albert V. Smith, David P. Strachan, Martin D. Tobin, James F. Wilson, Jennifer E. Huffman, Rajesh Rawal, Alexessander Couto Alves, María Soler Artigas, Ida Surakka, Dana B. Hancock, Bruce M. Psaty, Ma'en Obeidat, Susan R. Heckbert, Wenbo Tang, Ian P. Hall, Sina A. Gharib, Kari E. North, Ian J. Deary, Louise V. Wain, Alanna C. Morrison, Holger Schulz, Jemma B. Wilk, Jennifer A. Brody, Jennie Hui, Sven Gläser, David M. Evans, Deborah Jarvis, Ani Manichaikul, R. Graham Barr, Lies Lahousse, Veronique Vitart, Albert Hofman, Caroline Hayward, Groningen Research Institute for Asthma and COPD (GRIAC), Life Course Epidemiology (LCE), and Epidemiology
Subjects: EXPRESSION, Male, Candidate gene, MMP10, MATRIX METALLOPROTEINASES, Population, Genome-wide association study, Genomics, Biology, Polymorphism, Single Nucleotide, White People, Pulmonary function testing, Mice, INFLAMMATION, Genetics, medicine, PULMONARY-DISEASE, WIDE ASSOCIATION, Animals, Humans, Genetic Predisposition to Disease, education, Molecular Biology, Lung, Genetics (clinical), METAANALYSIS, Genetic association, Cell Proliferation, RISK, education.field_of_study, IDENTIFICATION, SET ENRICHMENT ANALYSIS, Association Studies Articles, General Medicine, medicine.disease, Obstructive lung disease, Airway Obstruction, Phenotype, Immune System, GENOMEWIDE ASSOCIATION, Metabolic Networks and Pathways, Genome-Wide Association Study, Signal Transduction
Abstract: Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10' s role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.
Published: 2015

23. Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation

Author: Arthur W. Musk, John P. Kemp, Ioanna Ntalla, Igor Rudan, Suzanne Miller, Anubha Mahajan, Samuli Ripatti, Nicholas J. Wareham, Alan F. Wright, Jennie Hui, Jing Hua Zhao, Jonathan Marten, Olli T. Raitakari, Henry Voelzke, John Beilby, John M. Starr, Robert A. Scott, Harry Campbell, Ma'en Obeidat, Deborah Jarvis, David C. Nickle, Markku Heliövaara, Nick Shrine, Lars Lind, David M. Evans, Richard Hubbard, John Henderson, Ozren Polasek, Panos Deloukas, James F. Wilson, María Soler Artigas, Ian P. Hall, Jennifer E. Huffman, Juan R. González, Joachim Heinrich, Mika Kähönen, Tim D. Spector, Neil C. Thomson, Christopher J Hammond, Marjo-Riitta Järvelin, Erik Ingelsson, Stefan Enroth, Ida Surakka, Andrew P. Morris, Ivana Kolcic, Louise V. Wain, Sarah H. Wild, Lynne J. Hocking, Wendy L. McArdle, Rajesh Rawal, Nina Hutri-Kähönen, Tatijana Zemunik, Åsa Johansson, Terho Lehtimäki, Christian Gieger, Veronique Vitart, Erik Melén, Sarah E. Harris, Medea Imboden, Holly Trochet, Momoko Horikoshi, Don D. Sin, Ian J. Deary, Pau Navarro, Alexessander Couto Alves, Ashok Kumar, Abdul Kader Kheirallah, Caroline Hayward, Stefan Karrasch, Alan James, Alexander Teumer, Ulf Gyllensten, Victoria E. Jackson, Eleftheria Zeggini, Ian D. Pavord, Holger Schulz, Anna-Liisa Hartikainen, Ana Viñuela, Anna Hansell, Nicole Probst-Hensch, Leo-Pekka Lyytikäinen, Pirro G. Hysi, Ian Sayers, Jonathan Marchini, Claudia Flexeder, David P. Strachan, Martin D. Tobin, Raquel Granell, Beate Stubbe, Corry-Anke Brandsma, Sven Glaeser, Janina S. Ried, Eva Albrecht, Yohan Bossé, Peter K. Joshi, Lorna M. Lopez, Sandosh Padmanabhan, Harald Grallert, Medical Research Council (MRC), Groningen Research Institute for Asthma and COPD (GRIAC), Institute for Molecular Medicine Finland, Clinicum, Department of Public Health, Biostatistics Helsinki, and Complex Disease Genetics
Subjects: Lung Diseases, Male, Vital capacity, UK BiLEVE, General Physics and Astronomy, Genome-wide association study, 0302 clinical medicine, Missing heritability problem, MISSING HERITABILITY, Forced Expiratory Volume, Genotype, SEQUENCE VARIANTS, WIDE ASSOCIATION, SUSCEPTIBILITY LOCUS, Lung, GENE-EXPRESSION, Genetics, Aged, 80 and over, 0303 health sciences, ARCHITECTURE, Multidisciplinary, Middle Aged, Aparell respiratori, 3. Good health, ddc, Multidisciplinary Sciences, Science & Technology - Other Topics, Female, Adult, European Continental Ancestry Group, Biology, OBSTRUCTIVE PULMONARY-DISEASE, Polymorphism, Single Nucleotide, White People, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, FEV1/FVC ratio, Young Adult, MD Multidisciplinary, Humans, SMOKING-BEHAVIOR, 1000 Genomes Project, Genetik, METAANALYSIS, 030304 developmental biology, Aged, Science & Technology, spirometry, lung function, genetics, ta1184, General Chemistry, ta3121, Heritability, 030228 respiratory system, 3121 General medicine, internal medicine and other clinical medicine, Pulmons, FORCED VITAL CAPACITY, Imputation (genetics), Genètica, Genome-Wide Association Study
Abstract: Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P, Genetic and environmental factors impact on lung function, important in the diagnosis of pulmonary diseases. Here the authors use imputation of genotypes to the 1000 Genomes Project reference panel to identify novel, low frequency variants associated with lung function.
Published: 2015
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24. Farm environment during infancy and lung function at the age of 31: a prospective birth cohort study in Finland

Author: Adaikalavan Ramasamy, Jussi Lampi, Marjo-Riitta Järvelin, Juha Pekkanen, Anna-Liisa Hartikainen, Alexessander Couto Alves, and Heikki Koskela
Subjects: Male, Pediatrics, Vital capacity, Vital Capacity, Cohort Studies, 0302 clinical medicine, Forced Expiratory Volume, Epidemiology, EPIDEMIOLOGY, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Lung, Finland, 2. Zero hunger, OCCUPATIONAL & INDUSTRIAL MEDICINE, RESPIRATORY-FUNCTION, medicine.diagnostic_test, WOMEN, MEN, Agriculture, General Medicine, Environmental exposure, Pets, respiratory system, PREVALENCE, ATOPY, Animals, Domestic, Female, Life Sciences & Biomedicine, Cohort study, Spirometry, Adult, medicine.medical_specialty, WHEEZE, 1117 Public Health and Health Services, 03 medical and health sciences, FEV1/FVC ratio, Medicine, General & Internal, Dogs, Sex Factors, General & Internal Medicine, medicine, Animals, Humans, EXPOSURE, Risk factor, Occupational and Environmental Medicine, Science & Technology, business.industry, Research, 1103 Clinical Sciences, Environmental Exposure, Protective Factors, Asthma, respiratory tract diseases, 030228 respiratory system, Cats, ENDOTOXIN, RESPIRATORY MEDICINE (see Thoracic Medicine), business, 1199 Other Medical and Health Sciences
Abstract: Objectives Farming as an occupation is considered a risk factor for asthma and reduced lung function. By contrast, living on a farm during infancy has been reported to be associated with lower risk of asthma in adulthood. However, little is known about the association between farming environment during infancy and lung function in adulthood. We aimed to study the prospective longitudinal association between farming environment during infancy and lung function in adulthood. Design A prospective birth cohort study. Setting Northern Finland. Participants 5666 participants born in 1966 were followed up at the age of 31 years. Primary outcome measures Spirometry at the age of 31 years. Results To be born into a farmer’s family was associated with higher forced expiratory volume in 1 s (FEV1) (36 mL; 95% CI 6 to 67 mL) and forced vital capacity (FVC) (40 mL; 95% CI 5 to 75 mL) at the age of 31 years. Contact with farm animals during infancy was associated with higher FEV1. No associations were seen with FEV1/FVC (FEV1/FVC ratio). Having dogs in childhood revealed similar associations. There was a suggestive dose-dependent association with the number of animal species during childhood and higher FEV1 and FVC at adulthood, especially among women. Conclusions Farming environment in early life may have a positive impact on lung function in adulthood.
Published: 2015

25. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Author: Joachim Heinrich, Arthur W. Musk, Dan L. Nicolae, Magnus Wickman, Anita L. Kozyrskyj, George T. O'Connor, Sven Michel, John Beilby, Nicole Probst-Hensch, André G. Uitterlinden, Ulrike Gehring, Eugene R. Bleecker, Markku Heliövaara, Christer Janson, Janine Altmüller, Tatsuhiko Tsunoda, Kathleen C. Barnes, Johan G. Eriksson, Alexey Polonikov, Penelope E. Graves, Andrea von Berg, Philip J. Thompson, Sina A. Gharib, Johan C. de Jongste, Miriam F. Moffatt, Adaikalavan Ramasamy, Kristin M. Burkart, Thomas J. Hudson, Marjo-Riitta Järvelin, Rasika A. Mathias, Kathleen M. Donohue, Gonneke Willemsen, Yuliya Fedorova, Michael Kabesch, Jing Hua Zhao, Ashok Kumar, Kenji Matsumoto, Vivi Schlünssen, Dara G. Torgerson, Terri H. Beaty, Florence Demenais, Julie E. Park, Tari Haahtela, Aarno Palotie, Elisabeth Widen, Hamida Mohamdi, Vladimir P. Ivanov, Tarja Laitinen, Emiko Noguchi, Lewis J. Smith, Valérie Siroux, Christopher E. Brightling, P. A. Selivanova, Frank D. Gilliland, Johannes Waage, Deborah A. Meyers, Unnur Thorsteinsdottir, Melanie C. Matheson, Hiroshi Hirose, Sébastien Letort, Andrew Bush, Alan James, Kari Stefansson, Robert A. Scott, Isabelle Romieu, Mads Melbye, Albert M. Levin, Laura R. Loehr, Guo Li, Veikko Salomaa, Celeste Eng, Esteban G. Burchard, Ralf J. P. van der Valk, Bjarke Feenstra, Daan W. Loth, Atsushi Takahashi, Lies Lahousse, Denise Daley, Stephen S. Rich, Carla M. T. Tiesler, Liming Liang, L. Keoki Williams, Susanne Lau, Nicholas J. Wareham, Erik Melén, Cameron D. Palmer, Medea Imboden, Patricia Margaritte-Jeannin, Unnur S. Bjornsdottir, Ludmila M. Ogorodova, Erika von Mutius, Gerard H. Koppelman, Susan R. Heckbert, Rachel A. Myers, Martin Farrall, Moira Chan-Yeung, Jim Gauderman, Frank Geller, Sailaja Vedantam, Rajesh Kumar, Kian Fan Chung, Jon Genuneit, John Henderson, David B. Kantor, Carole Ober, Alexessander Couto Alves, Craig E. Pennell, Inge M. Wouters, Catherine Laprise, Terho Lehtimäki, Colin F. Robertson, Emmanuelle Bouzigon, Maxim B. Freidin, William O.C.M. Cookson, Bruno H. Stricker, John A. Curtin, Albert Hofman, Muhammad T. Salam, Blanca E. Del-Rio-Navarro, Young-Ae Lee, Liesbeth Duijts, Klaus Bønnelykke, Vincent W. V. Jaddoe, Göran Pershagen, Dirkje S. Postma, Pekka Jousilahti, Hans Bisgaard, Dorret I. Boomsma, Amaury Vaysse, Deborah Jarvis, Maria Solodilova, Gudmar Thorleifsson, James J. Yang, V. P. Puzyrev, Manuel A. R. Ferreira, Maartje A.E. Nieuwenhuis, Jouke J. Hottenga, Ingileif Jonsdottir, Graham Jones, Myriam Brossard, Jennie Hui, Judith M. Vonk, Allan B. Becker, Elza Khusnutdinova, Wendy L. McArdle, Benjamin A. Raby, Olli T. Raitakari, Wendy B. White, Mark Lathrop, Adnan Custovic, Ingo Marenholz, Joel N. Hirschhorn, Fernando J. Martinez, Mikko Kuokkanen, Michiaki Kubo, Patrick G. Holt, Torben Sigsgaard, Eskil Kreiner, Stephanie J. London, Daniel F. Gudbjartsson, Mika Kähönen, Guy Brusselle, Blanca E. Himes, R. Graham Barr, Scott T. Weiss, David P. Strachan, Hamdi Mbarek, Wei Ang, A. S. Karunas, Marie Standl, Angela Simpson, Dick Heederik, Zofia K. Z. Gajdos, Raquel Granell, Ani Manichaikul, Fondation Jean-Dausset-CEPH, INSERM U946, Institut National de la Santé et de la Recherche Médicale (INSERM), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine [Aurora, CO, USA], University of Colorado [Denver], National Heart and Lung Institute (NHLI), Imperial College London, Cologne Center for Genomics (CCG), Cologne Center for Genomics-University of Cologne, Johns Hopkins University (JHU), Pediatrics and Child Health, University of Manitoba [Winnipeg], University of Arizona, King‘s College London, Méthodologie statistique et épidémiologie génétique de maladies multifactorielles, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Respiratory Medicine and Thoracic Surgery, University of Leicester-Institute for Lung Health, Ghent University Hospital, Department of Paediatric Respiratory Medicine, Imperial College London-Royal Brompton Hospital-National Heart and Lung Institute [UK], Airway Disease Section, National Heart and Lung Institute, The Generation R Study group, Erasmus University Medical Centre, Medstar Research Institute, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Université Paris-Sorbonne - Paris 4 - École supérieure du professorat et de l'éducation - Académie de Paris (ESPE Paris), Université Paris-Sorbonne (UP4), Population Genetics Laboratory [Tomsk, Russia], Research Institute for Medical Genetics [Tomsk, Russia], University of Southern California (USC), Utrecht University [Utrecht], Institute of Epidemiology, Universität Ulm - Ulm University [Ulm, Allemagne], MRC Integrative Epidemiology Unit [Bristol, Royaume-Uni] (MRC IEU), University of Bristol [Bristol], Arizona Respiratory Center, Helsinki University Hospital, Division of Occupational and Environmental Health, Institute for Risk Assessment (IRAS), Ludwig Maximilian University [Munich] (LMU), National Institute of Health and Welfare, MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Mathematics, University of Warwick, Warwick Mathematics Institute (WMI), University of Warwick [Coventry]-University of Warwick [Coventry], Sir Charles Gairdner Hospital, Swiss Tropical and Public Health Institute [Basel], The Generation R Study, Pediatrics, Epidemiology, Uppsala University, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Tampere University Hospital, Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Pediatric Pulmonology, Allergology & Epidemiology, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG)-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, National Center for Atmospheric Research [Boulder] (NCAR), Epidemiology & Public Health, Swiss Tropical and Public Health Institute [Basel]-Medical School University of Basel, Department of Respiratory Medicine, Departments of Pulmonary Medicine and Medical Genetics, Université du Québec à Chicoutimi (UQAC), McGill University and Genome Quebec Innovation Centre, Department of Pediatric Pneumology and Immunology, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Laboratoire des interactions plantes micro-organismes (LIPM), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), China Agricultural University (CAU), Harvard School of Public Health, Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, National Institute for Environmental Health Sciences Research Triangle Park, National Institute for Materials Science (NIMS), Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], Institute of Environmental Medicine [Stockholm, Sweden], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Astrid Lindgren Children's Hospital, Center for Human Genomics, Wake Forest University, Université de Tsukuba = University of Tsukuba, Head of Medical Sequencing, Institute of environmental medicine, Karolinska Institute, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centre International de Recherche contre le Cancer (CIRC), Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Aarhus University [Aarhus], Institute of Metabolic Science, MRC, Section of Environment Occupation & Health, University of Manchester [Manchester], Epidémiologie et Biostatistique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), deCODE Genetics, deCODE genetics [Reykjavik], Population Health Sciences and Education, St George's University of London, Drug Safety Unit, Inspectorate for Health Care, Tohoku University [Sendai], Department of Oceanography, University of Hawai‘i [Mānoa] (UHM), University of California [San Francisco] (UCSF), University of California, Asthma and Allergy Department, University Children's Hospital-Ludwig Maximilians University, IT University of Copenhagen, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge [UK] (CAM), Sachs’ Children and Youth Hospital [Stockholm, Sweden], Genetic Epidemiology Unit, Addenbrooke's Hospital, University of Illinois [Chicago] (UIC), University of Illinois System, Titu Maiorescu University Bucharest, Titu Maiorescu University = Universitatea Titu Maiorescu [Buchares] (UTM), Pulmonary Medicine, Erasmus MC other, Internal Medicine, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Vaysse, Amaury, University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), University Children's Hospital-Ludwig-Maximilians University [Munich] (LMU), IT University of Copenhagen (ITU), Groningen Research Institute for Asthma and COPD (GRIAC), Medical Research Council (MRC), National Institute for Health Research, Wellcome Trust, Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, HAY-FEVER, Netherlands Twin Register (NTR), [SDV]Life Sciences [q-bio], Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, VARIANTS, Australian Asthma Genetics Consortium (AAGC) collaborators, Epigenesis, Genetic, 0302 clinical medicine, Pleiotropy, immune system diseases, Leukocytes, Promoter Regions, Genetic, AUTOIMMUNE-DISEASE, 11 Medical and Health Sciences, ComputingMilieux_MISCELLANEOUS, Genetics & Heredity, 3. Good health, Histone Code, [SDV] Life Sciences [q-bio], Enhancer Elements, Genetic, Phenotype, TWINS, Hay fever, POPULATIONS, Life Sciences & Biomedicine, Risk, EXPRESSION, Coronacrisis-Taverne, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Immune system, SDG 3 - Good Health and Well-being, medicine, Genetics, Journal Article, Humans, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, Alleles, METAANALYSIS, Genetic association, Asthma, Autoimmune disease, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Rhinitis, Allergic, Seasonal, 06 Biological Sciences, medicine.disease, GENE, respiratory tract diseases, 030104 developmental biology, 030228 respiratory system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, Immunology, Developmental Biology, Genome-Wide Association Study
Abstract: We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
Published: 2018
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26. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Author: Supinda Bunyavanich, Mayumi Tamari, Ronny Myhre, Birgit Kalb, Benjamin A. Raby, Xuejun Zhang, Wendy L. McArdle, Daniel Glass, Gabrielle A. Lockett, Chao Tian, Adnan Custovic, Frank Geller, Albert M. Levin, Susanne Lau, Nicole Probst-Hensch, Marie Standl, Tim D. Spector, Elke Rodriguez, Badri Pahukasahasram, Craig E. Pennell, Carole Ober, Alexessander Couto Alves, George Davey Smith, Cheng-Jian Xu, James J. Yang, Nicholas G. Martin, Elisabeth Altmaier, Feng Li Xiao, Regina Foelster-Holst, Lise Lotte N. Husemoen, Atsushi Takahashi, Angela Simpson, Markus M. Noethen, Grainne M. O'Regan, Patrick M. A. Sleiman, Anja Bauerfeind, Linda E. Campbell, Jacob P. Thyssen, Caoimhe M. R. Fahy, Ingo Marenholz, André G. Uitterlinden, Jorge Esparza-Gordillo, Albert Hofman, John A. Curtin, John P. Kemp, Jie Zheng, Melanie C. Matheson, Suzanne G.M.A. Pasmans, Christian Gieger, Pirro G. Hysi, Esteban G. Burchard, Eskil Kreiner-Møller, Keith M. Godfrey, Erik Melén, Jin Li, Hans Bisgaard, Michael Kurek, X. Zheng, Min Ae Lee-Kirsch, Lavinia Paternoster, Mads Melbye, Juha Pekkanen, Natalia Vilor-Tejedor, Elisabeth Thiering, Carsten Oliver Schmidt, Anja Matanovic, W.H. Irwin McLean, Wenche Nystad, Carla M. T. Tiesler, Sheila J. Barton, Michiaki Kubo, Klaus Bønnelykke, Guy B. Marks, Stephan Weidinger, Deborah A. Meyers, David P. Strachan, Bjarke Feenstra, Wolfgang Lieb, Thomas Keil, Celeste Eng, Elisabeth Mangold, Christel M. Middeldorp, Cristina Venturini, Niels J. Elbert, Jouke-Jan Hottenga, Xian Bo Zuo, Georg Homuth, L. Keoki Williams, Sylvain Sebert, Maria Pino-Yanes, Mariona Bustamante, Scott T. Weiss, Donglei Hu, Allan Linneberg, Ashok Kumar, Ivan Curjuric, Johannes Waage, Joachim Heinrich, Philip J. Thompson, Johan C. de Jongste, Fernando Rivadeneira, Veronique Bataille, David M. Evans, Joyce Y. Tung, Bo Jacobsson, Natalija Novak, Sara J. Brown, Andre Franke, Medea Imboden, Lisbeth Carstensen, Maeve A. McAleer, Jordi Sunyer, Momoko Horikoshi, Hakon Hakonarson, Liesbeth Duijts, Juan R. González, Scott Huntsman, Xianyong Yin, Melanie Hotze, Niels Grarup, Carol A. Wang, Norbert Huebner, Tomomitsu Hirota, Rachel A. Myers, Milan Macek, Cilla Soederhaell, Maria M. Groen-Blokhuis, Herman T. den Dekker, Dorret I. Boomsma, Franz Rueschendorf, Deborah Jarvis, Alan D. Irvine, Sven Cichon, Manuel A. R. Ferreira, Janina S. Ried, Young-Ae Lee, Andreas Arnold, H. Baurecht, Gerard H. Koppelman, David A. Hinds, Colin F. Robertson, Liangdan Sun, Vincent W. V. Jaddoe, Dirkje S. Postma, Marjo-Riitta Järvelin, Annette Peters, John W. Holloway, Caroline L Relton, A. John Henderson, Jonas Bacelis, Psychiatry, EMGO - Musculoskeletal health, NCA - Neurobiology of mental health, Groningen Research Institute for Asthma and COPD (GRIAC), Epidemiology, Pediatrics, Internal Medicine, Erasmus MC other, Dermatology, Gastroenterology & Hepatology, Child and Adolescent Psychiatry / Psychology, Public Health, Biological Psychology, EMGO+ - Musculoskeletal Health, and Neuroscience Campus Amsterdam - Neurobiology of Mental Health
Subjects: Netherlands Twin Register (NTR), Candidate gene, T-Lymphocytes, Genome-wide association study, VARIANTS, Genome-wide association studies, EArly Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium, Risk Factors, Ethnicity, health care economics and organizations, Genetics & Heredity, Genetics, PSORIASIS, 11 Medical And Health Sciences, Atopic dermatitis, 3. Good health, Life Sciences & Biomedicine, Dermatitis atòpica, Genetic Markers, medicine.medical_specialty, SUSCEPTIBILITY LOCI, education, Biology, Australian Asthma Genetics Consortium (AAGC), Polymorphism, Single Nucleotide, Article, Dermatitis, Atopic, GENETIC ARCHITECTURE, SDG 3 - Good Health and Well-being, Molecular genetics, medicine, Humans, FILAGGRIN, Genetic Predisposition to Disease, JAPANESE POPULATION, Genomes, METAANALYSIS, Genetic association, Science & Technology, Case-control study, Grups ètnics, INTERLEUKIN-7 RECEPTOR, 06 Biological Sciences, medicine.disease, Immunity, Innate, Genetic architecture, Genetic Loci, Genetic marker, Case-Control Studies, Immunology, ASTHMA, Genètica, Developmental Biology, Genome-Wide Association Study, INFLAMMATORY-BOWEL-DISEASE
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. This research was specifically funded by an MRC Population Health Scientist Fellowship awarded to Dr L Paternoster (MR/J012165/1). D.M.E. is supported by an Australian Research Council Future Fellowship (FT130101709) and a Medical Research Council program grant (MC_UU_12013/4)
Published: 2015
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27. Multiple measures of adiposity are associated with mean leukocyte telomere length in the northern Finland birth cohort 1966

Author: Jessica L, Buxton, Shikta, Das, Alina, Rodriguez, Marika, Kaakinen, Alexessander, Couto Alves, Sylvain, Sebert, Iona Y, Millwood, Jaana, Laitinen, Paul F, O'Reilly, Marjo-Riitta, Jarvelin, and Alexandra I F, Blakemore
Subjects: Cell Physiology, Chromosome Structure and Function, Aging, Adolescent, Child Growth, Physiology, Epidemiology, lcsh:Medicine, Pediatrics, Chromosomes, Body Mass Index, Cohort Studies, Child Development, Leukocytes, Medicine and Health Sciences, Humans, Obesity, Child, lcsh:Science, Finland, Adiposity, Chromosome Biology, Body Weight, lcsh:R, Infant, Biology and Life Sciences, nutritional and metabolic diseases, Epidemiology of Aging, Cell Biology, Middle Aged, Telomere, Biomarker Epidemiology, Telomeres, Physiological Parameters, Cell Aging, Child, Preschool, lcsh:Q, Organism Development, Research Article, Developmental Biology
Abstract: Studies of leukocyte telomere length (LTL) and adiposity have produced conflicting results, and the relationship between body mass index (BMI) and telomere length throughout life remains unclear. We therefore tested association of adult LTL measured in 5,598 participants with: i) childhood growth measures (BMI and age at adiposity rebound (AR)); ii) change in BMI from childhood to adulthood and iii) adult BMI, waist-to-hip ratio (WHR), body adiposity index (BAI). Childhood BMI at AR was positively associated with LTL at 31 years in women (P = 0.041). Adult BMI and WHR in both men (P = 0.025 and P = 0.049, respectively) and women (P = 0.029 and P = 0.008, respectively), and BAI in women (P = 0.021) were inversely associated with LTL at 31 years. An increase in standardised BMI between early childhood and adulthood was associated with shorter adult LTL in women (P = 0.008). We show that LTL is inversely associated with multiple measures of adiposity in both men and women. Additionally, BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31, potentially indicating accelerated biological ageing.
Published: 2014

28. Multiple Measures of Adiposity Are Associated with Mean Leukocyte Telomere Length in the Northern Finland Birth Cohort 1966

Author: Buxton, Jessica L., Das, Shikta, Rodriguez, Alina, Kaakinen, Marika, Couto Alves, Alexessander, Sebert, Sylvain, Millwood, Iona Y., Laitinen, Jaana, O'Reilly, Paul F., Jarvelin, Marjo-Riitta, Blakemore, Alexandra I. F., and Medical Research Council (MRC)
Subjects: STRESS, Adolescent, General Science & Technology, ADULTHOOD, DISEASE, Body Mass Index, Cohort Studies, EARLY-LIFE, MD Multidisciplinary, Leukocytes, Humans, Child, Finland, METAANALYSIS, Adiposity, Science & Technology, MULTIDISCIPLINARY SCIENCES, MORTALITY, Infant, nutritional and metabolic diseases, WOMEN, Public Health, Global Health, Social Medicine and Epidemiology, Middle Aged, Telomere, C800 Psychology, BODY-MASS INDEX, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Child, Preschool, OBESITY, Science & Technology - Other Topics, epidemiology, GENDER, biological
Abstract: Studies of leukocyte telomere length (LTL) and adiposity have produced conflicting results, and the relationship between body mass index (BMI) and telomere length throughout life remains unclear. We therefore tested association of adult LTL measured in 5,598 participants with: i) childhood growth measures (BMI and age at adiposity rebound (AR)); ii) change in BMI from childhood to adulthood and iii) adult BMI, waist-to-hip ratio (WHR), body adiposity index (BAI). Childhood BMI at AR was positively associated with LTL at 31 years in women (P = 0.041). Adult BMI and WHR in both men (P = 0.025 and P = 0.049, respectively) and women (P = 0.029 and P = 0.008, respectively), and BAI in women (P = 0.021) were inversely associated with LTL at 31 years. An increase in standardised BMI between early childhood and adulthood was associated with shorter adult LTL in women (P = 0.008). We show that LTL is inversely associated with multiple measures of adiposity in both men and women. Additionally, BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31, potentially indicating accelerated biological ageing.
Published: 2014

29. 1,5 Anhydroglucitol serum concentration as a biomarker for screening gestational diabetes in early pregnancy

Author: Izabella Castilhos Ribeiro dos Santos-Weiss, Alexessander Couto Alves, Rosângela Roginski Réa, Fabiane Gomes de Moraes Rego, Geraldo Picheth, Kátia Cristina Boritza, Emanuel Maltempi de Souza, and Fábio O. Pedrosa
Subjects: medicine.medical_specialty, Clinical Biochemistry, Early pregnancy factor, Deoxyglucose, Gastroenterology, chemistry.chemical_compound, Pregnancy, Internal medicine, medicine, Humans, Mass Screening, biology, business.industry, Biochemistry (medical), General Medicine, Serum concentration, medicine.disease, Gestational diabetes, Diabetes, Gestational, Early Diagnosis, chemistry, biology.protein, Biomarker (medicine), 1,5-Anhydroglucitol, Female, business, Biomarkers
Published: 2013

30. Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

Author: Eva Albrecht, Medea Imboden, Jennifer E. Huffman, James F. Wilson, Eva Reischl, David P. Strachan, Ozren Polasek, Ian P. Hall, Beate Koch, Thierry Rochat, Holger Schulz, Ian J. Deary, Sune F. Nielsen, Ilaria Ferrarotti, Ashok Kumar, Erich W. Russi, Igor Rudan, Margot Haun, Florian Kronenberg, Ivan Curjuric, Gian Andri Thun, Andrew J. Sandford, Marjo-Riitta Järvelin, Morten Dahl, Ke Hao, Ma'en Obeidat, Jennie Hui, Stefan Enroth, Børge G. Nordestgaard, Caroline Hayward, Alan James, Alexander Teumer, Ulf Gyllensten, Maurizio Luisetti, Martin D. Tobin, Victoria E. Jackson, Alexessander Couto Alves, Wim Timens, Nicole Probst-Hensch, Michele Zorzetto, Yohan Bossé, Lorna M. Lopez, Janina S. Ried, Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Medical Research Council (MRC)
Subjects: Cancer Research, Medicin och hälsovetenskap, Pulmonology, Chronic Obstructive Pulmonary Diseases, Epidemiology, Denmark, Genome-wide association study, SUSCEPTIBILITY, gene, serpina, Medical and Health Sciences, AIR-FLOW OBSTRUCTION, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Gene Frequency, MOLECULAR CHARACTERIZATION, Lung, Genetics (clinical), ALPHA(1)-ANTITRYPSIN, POPULATION, Genetics, Genetics & Heredity, 0303 health sciences, education.field_of_study, 3. Good health, DEFICIENCY, LUNG-FUNCTION, RARE VARIANTS, Genetic Epidemiology, Multigene Family, Perspective, Medicine, Life Sciences & Biomedicine, Research Article, lcsh:QH426-470, Genotype, Population, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, OBSTRUCTIVE PULMONARY-DISEASE, 03 medical and health sciences, ALPHA-1-ANTITRYPSIN PHENOTYPES, Genome-Wide Association Studies, SNP, Humans, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, education, Molecular Biology, Allele frequency, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Clinical Genetics, 0604 Genetics, Science & Technology, Computational Biology, Smoking Related Disorders, Human Genetics, AIR-POLLUTION, MZ HETEROZYGOTES, Minor allele frequency, lcsh:Genetics, 030228 respiratory system, alpha 1-Antitrypsin, Genetics of Disease, Genetic Polymorphism, Population Genetics, Genome-Wide Association Study, Developmental Biology
Abstract: Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = −0.068 g/L per minor allele (P = 1.20*10−12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF, Author Summary Low levels of alpha1-antitrypsin (AAT) in the blood are a well-established risk factor for accelerated loss in lung function and chronic obstructive pulmonary disease. While a few infrequent genetic polymorphisms are known to influence the serum levels of this enzyme, the role of common genetic variants has not been examined so far. The present genome-wide scan for associated variants in approximately 1400 Swiss inhabitants revealed a chromosomal locus containing the functionally established variants of AAT deficiency and variants previously associated with lung function and emphysema. We used dense genotyping of this genetic region in more than 5500 individuals and subsequent conditional analyses to unravel which of these associated variants contribute independently to the phenotype's variability. All associations of common variants could be attributed to the rarer functionally established variants, a result which was then replicated in an independent population-based Danish cohort. Hence, this locus represents a textbook example of how a large part of a trait's heritability can be hidden in infrequent genetic polymorphisms. The attempt to transfer these results to lung function furthermore suggests that effects of common variants in this genetic region in ever-smokers may also be explained by rarer variants, but only in individuals with hampered pulmonary health.
Published: 2013
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31. A new scoring system derived from base excess and platelet count at presentation predicts mortality in paediatric meningococcal sepsis

Author: David Inwald, Marieke Emonts, Alexessander Couto-Alves, Padmanabhan Ramnarayan, Jan A. Hazelzet, Ronald de Groot, Taco W. Kuijpers, A. Binder, Werner Zenz, Lachlan J. M. Coin, Michael Levin, Victoria J. Wright, Simon Nadel, Karnan Perumal, Enitan D. Carrol, Pediatrics, AII - Amsterdam institute for Infection and Immunity, and Paediatric Infectious Diseases / Rheumatology / Immunology
Subjects: Male, Pediatrics, medicine.medical_specialty, business.industry, Research, Area under the curve, Retrospective cohort study, Critical Care and Intensive Care Medicine, Severity of Illness Index, Confidence interval, Meningococcal Infections, Predictive value of tests, Sepsis, medicine, Risk of mortality, Humans, Base excess, Female, business, Prospective cohort study, Cohort study
Abstract: INTRODUCTION: The aim of this study was to derive a novel prognostic score for mortality in paediatric meningococcal sepsis (MS) based on readily available laboratory markers. METHODS: A multicentre retrospective cohort study for the consortium set and a single centre retrospective study for replication set. The consortium set were 1,073 children (age 1 week to 17.9 years) referred over a 15-year period (1996 to 2011), who had an admission diagnosis of MS, referred to paediatric intensive care units (PICUs) in six different European centres. The consortium set was split into a development set and validation set to derive the score. The replication set were 134 children with MS (age 2 weeks to 16 years) referred over a 4-year period (2007 to 2011) to PICUs via the Children's Acute Transport Service (CATS), London. RESULTS: A total of 85/1,073 (7.9%) children in the consortium set died. A total of 16/134 (11.9%) children in the replication set died. Children dying in the consortium set had significantly lower base excess, C-reactive protein (CRP), platelet and white cell count, more deranged coagulation and higher lactate than survivors. Paediatric risk of mortality (PRISM) score, Glasgow meningococcal septicaemia prognosis score (GMSPS) and Rotterdam score were also higher. Using the consortium set, a new scoring system using base excess and platelet count at presentation, termed the BEP score, was mathematically developed and validated. BEP predicted mortality with high sensitivity and specificity scores (area under the curve (AUC) in the validation set = 0.86 and in the replication set = 0.96). In the validation set, BEP score performance (AUC = 0.86, confidence interval (CI): 0.80 to 0.91) was better than GMSPS (AUC = 0.77, CI: 0.68, 0.85), similar to Rotterdam (AUC = 0.87, CI: 0.81 to 0.93) and not as good as PRISM (AUC = 0.93, CI: 0.85 to 0.97). CONCLUSIONS: The BEP score, relying on only two variables that are quickly and objectively measurable and readily available at presentation, is highly sensitive and specific in predicting death from MS in childhood
Published: 2013
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32. Correction: Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA

Author: Marjo-Riitta Järvelin, Kay-Tee Khaw, Veikko Salomaa, Colin F. Robertson, Jing Hua Zhao, Guy B. Marks, Adaikalavan Ramasamy, Christer Janson, Tarja Laitinen, Cameron D. Palmer, Grant W. Montgomery, Jaana Laitinen, Melanie C. Matheson, Tari Haahtela, Terho Lehtimäki, Mika Kähönen, Michael J. Abramson, Johan G. Eriksson, George T. O'Connor, Andrew C. Heath, Jorma S. A. Viikari, Manuel A. R. Ferreira, Helen N. Lyon, Philip J. Thompson, Nicholas G. Martin, Lachlan J. M. Coin, Aarno Palotie, Shyamali C. Dharmage, Elisabeth Widen, Juha Pekkanen, Olli T. Raitakari, Nicholas J. Wareham, Joel N. Hirschhorn, Peter N. Le Souëf, Alexessander Couto Alves, Matthew A. Brown, David L. Duffy, Mikko Kuokkanen, Pamela A. F. Madden, David P. Strachan, Zofia K. Z. Gajdos, Matthias Wjst, Sailaja Vedantam, Anneli Pouta, Pekka Jousilahti, Deborah Jarvis, Department of Dermatology, Allergology and Venereology, Clinicum, Institute for Molecular Medicine Finland, Haartman Institute (-2014), Department of Medical and Clinical Genetics, Department of General Practice and Primary Health Care, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, and Medical Research Council (MRC)
Subjects: Medicin och hälsovetenskap, Pulmonology, Population genetics, lcsh:Medicine, Genome-wide association study, VARIANTS, SUSCEPTIBILITY, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, HLA Antigens, Risk Factors, Genetics of the Immune System, lcsh:Science, Genetics, ROR-ALPHA, 0303 health sciences, Multidisciplinary, Allergy and Hypersensitivity, CARDIOVASCULAR RISK, Middle Aged, 3. Good health, Multidisciplinary Sciences, ALLERGY, DISEASES, Science & Technology - Other Topics, HEART, Medicine, HEALTH, Occupational asthma, Research Article, Adult, GENES, General Science & Technology, Quantitative Trait Loci, Immunology, Australian Asthma Genetics Consortium collaborators, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Molecular Genetics, 03 medical and health sciences, Gene interaction, MD Multidisciplinary, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, METAANALYSIS, 030304 developmental biology, Genetic association, Science & Technology, lcsh:R, Correction, Computational Biology, Human Genetics, ta3121, medicine.disease, Human genetics, Asthma, 030228 respiratory system, Genetics of Disease, Clinical Immunology, lcsh:Q, 3111 Biomedicine, LUNG, Population Genetics, Genome-Wide Association Study
Abstract: RATIONALE: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. \ud \ud OBJECTIVES: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations.\ud \ud METHODS: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P
Published: 2012

33. Highly interconnected genes in disease-specific networks are enriched for disease-associated polymorphisms

Author: Sreenivas Chavali, Gary L. Rogers, Marjo-Riitta Järvelin, Hui Wang, Rebecka Jörnsten, Lachlan J. M. Coin, Michael A. Langston, Mikael Benson, Adaikalavan Ramasamy, Alexessander Couto Alves, Fredrik Barrenäs, and Medical Research Council (MRC)
Subjects: Medicin och hälsovetenskap, COEXPRESSION, 05 Environmental Sciences, Gene regulatory network, Genome-wide association study, Medical and Health Sciences, 0302 clinical medicine, Databases, Genetic, Gene Regulatory Networks, Protein Interaction Maps, RNA, Small Interfering, Oligonucleotide Array Sequence Analysis, Genetics & Heredity, Regulation of gene expression, Genetics, 0303 health sciences, Genetic Pleiotropy, DIFFERENTIATION, 030220 oncology & carcinogenesis, Fibroblast Growth Factor 2, Life Sciences & Biomedicine, EXPRESSION, Bioinformatics, INHIBITION, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Sensitivity and Specificity, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Gene, 030304 developmental biology, Inflammation, Science & Technology, Genome, Human, Research, Gene Expression Profiling, Rhinitis, Allergic, Seasonal, 06 Biological Sciences, Human genetics, Gene expression profiling, Biotechnology & Applied Microbiology, Gene Expression Regulation, CELLS, Human genome, 08 Information and Computing Sciences, SYSTEM, Genome-Wide Association Study
Abstract: BACKGROUND: Complex diseases are associated with altered interactions between thousands of genes. We developed a novel method to identify and prioritize disease genes, which was generally applicable to complex diseases. RESULTS: We identified modules of highly interconnected genes in disease-specific networks derived from integrating gene-expression and protein interaction data. We examined if those modules were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies. First, we analyzed publicly available gene expression microarray and genome-wide association study (GWAS) data from 13, highly diverse, complex diseases. In each disease, highly interconnected genes formed modules, which were significantly enriched for genes harboring disease-associated SNPs. To test if such modules could be used to find novel genes for functional studies, we repeated the analyses using our own gene expression microarray and GWAS data from seasonal allergic rhinitis. We identified a novel gene, FGF2, whose relevance was supported by functional studies using combined small interfering RNA-mediated knock-down and gene expression microarrays. The modules in the 13 complex diseases analyzed here tended to overlap and were enriched for pathways related to oncological, metabolic and inflammatory diseases. This suggested that this union of the modules would be associated with a general increase in susceptibility for complex diseases. Indeed, we found that this union was enriched with GWAS genes for 145 other complex diseases. CONCLUSIONS: Modules of highly interconnected complex disease genes were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies. funding agencies|European Community|223367|US National Institutes of Health|R01-AA-0187763P20MD000516-07S1|Swedish Research Council
Published: 2012

34. Dysregulation of Complement System and CD4+ T Cell Activation Pathways Implicated in Allergic Response

Author: Anna-Liisa Hartikainen, Hui Wang, David J. Balding, Mikael Benson, Lachlan J. M. Coin, John W. Holloway, Adaikalavan Ramasamy, Sören Bruhn, Marjo-Riitta Järvelin, and Alexessander Couto Alves
Subjects: CD4-Positive T-Lymphocytes, Medicin och hälsovetenskap, Cellular differentiation, lcsh:Medicine, Lymphocyte Activation, medicine.disease_cause, Medical and Health Sciences, 0302 clinical medicine, Gene expression, lcsh:Science, GENE-EXPRESSION, 0303 health sciences, Multidisciplinary, IMMUNE-RESPONSES, GATA3, Cell Differentiation, Receptors, Complement, 3. Good health, Multidisciplinary Sciences, medicine.anatomical_structure, Allergic response, Science & Technology - Other Topics, Cytokines, Pollen, Research Article, General Science & Technology, T cell, GATA3 Transcription Factor, Biology, MICROARRAY EXPERIMENTS, NETWORK-BASED ANALYSIS, 03 medical and health sciences, medicine, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Science & Technology, Microarray analysis techniques, Gene Expression Profiling, SET ENRICHMENT ANALYSIS, lcsh:R, RHINITIS, Rhinitis, Allergic, Seasonal, Allergens, Complement system, Gene expression profiling, NASAL-MUCOSA, Immunology, T-CELLS, Leukocytes, Mononuclear, ASTHMA, lcsh:Q, 030215 immunology
Abstract: Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens. We delineate a novel disease network linking T cell activation to the complement system that is significantly enriched for genes exhibiting correlated gene expression and protein-protein interactions, suggesting a tight biological coordination that is dysregulated in the disease state in response to pollen allergen but not to diluent. This novel disease network has high predictive power for the gene and protein expression of the Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13) and of the Th2 master regulator (GATA3), suggesting its involvement in the early stages of CD4+ T cell differentiation. Dissection of the complement system gene expression identifies 7 genes specifically associated with atopic response to pollen, including C1QR1, CFD, CFP, ITGB2, ITGAX and confirms the role of C3AR1 and C5AR1. Two of these genes (ITGB2 and C3AR1) are also implicated in the network linking complement system to T cell activation, which comprises 6 differentially expressed genes. C3AR1 is also significantly associated with allergic sensitisation in GWAS data. Funding Agencies|European Commission|223367|Academy of Finland (Centre of Excellence in Complex Disease Genetics and SALVE)|1047811203151292691114194139900/24300796|University Hospital Oulu||Biocenter||University of Oulu|75617|NHLBI through STAMPEED program|5R01HL087679-021RL1MH083268-01|NIH/NIMH|5R01MH63706:02|ENGAGE project|HEALTH-F4-2007-201413|Medical Research Council, UK (PrevMetSyn/SALVE)||Academy of Finland||Biocentrum Helsinki
Published: 2013
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35. A novel common variant in DCST2 is associated with length in early life and height in adulthood

Author: Rj, Valk, Kreiner-Møller E, Mn, Kooijman, Guxens M, Stergiakouli E, Sääf A, Jp, Bradfield, Geller F, Mg, Hayes, Dl, Cousminer, Körner A, Thiering E, Ja, Curtin, Myhre R, Huikari V, Joro R, Kerkhof M, Nm, Warrington, Pitkänen N, Ntalla I, Horikoshi M, Veijola R, Rm, Freathy, Yy, Teo, Sj, Barton, Dm, Evans, Jp, Kemp, St Pourcain B, Sm, Ring, Gd, Smith, Bergström A, Kull I, Hakonarson H, Fd, Mentch, Bisgaard H, Chawes B, Stokholm J, Waage J, Eriksen P, Sevelsted A, Melbye M, Cm, Duijn, Medina-Gomez C, Hofman A, Jc, Jongste, Hr, Taal, Ag, Uitterlinden, Ll, Armstrong, Eriksson J, Palotie A, Bustamante M, Estivill X, Jr, Gonzalez, Llop S, Kiess W, Mahajan A, Flexeder C, Cm, Tiesler, Cs, Murray, Simpson A, Magnus P, Sengpiel V, Al, Hartikainen, Keinanen-Kiukaanniemi S, Lewin A, Da Silva Couto Alves A, Ai, Blakemore, Jl, Buxton, Kaakinen M, Rodriguez A, Sebert S, Vaarasmaki M, Lakka T, Lindi V, Gehring U, Ds, Postma, Ang W, Jp, Newnham, Lp, Lyytikäinen, Pahkala K, Ot, Raitakari, Panoutsopoulou K, Zeggini E, Di, Boomsma, Groen-Blokhuis M, Ilonen J, Franke L, Jn, Hirschhorn, Th, Pers, Liang L, Huang J, Hocher B, Knip M, Sm, Saw, Jw, Holloway, Melén E, Sf, Grant, Feenstra B, Wl, Lowe, Widén E, Sergeyev E, Grallert H, Adnan Custovic, Jacobsson B, Jarvelin MR, Atalay M, Gh, Koppelman, Ce, Pennell, Niinikoski H, Gv, Dedoussis, Mi, Mccarthy, Tm, Frayling, Sunyer J, Nj, Timpson, Rivadeneira F, Bønnelykke K, Vw, Jaddoe, Medical Research Council (MRC), Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Pediatrics, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, Gastroenterology & Hepatology, Epidemiology, Internal Medicine, and Medical Oncology
Subjects: Netherlands Twin Register (NTR), Adult, Biochemistry & Molecular Biology, Genotype, Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Quantitative Trait Loci, LOCI, Polymorphism, Single Nucleotide, DISEASE, Quantitative Trait, Heritable, Early Growth Genetics (EGG) Consortium, Databases, Genetic, Psychology, GLUCOCEREBROSIDASE MUTATIONS, TOOL, Humans, LOW-BIRTH-WEIGHT, GENOME-WIDE ASSOCIATION, DC-STAMP, Alleles, Genetic Association Studies, Medicinsk genetik, Adaptor Proteins, Signal Transducing, Genetics & Heredity, Psykologi, Science & Technology, IMPUTED DATA, Association Studies Articles, Age Factors, Infant, Newborn, Computational Biology, Genetic Variation, Membrane Proteins, Reproducibility of Results, 11 Medical And Health Sciences, 06 Biological Sciences, GENE, Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium, C420 Human Genetics, Body Height, Phenotype, Institut für Ernährungswissenschaft, epidemiology, Medical Genetics, Life Sciences & Biomedicine, biological, GROWTH-RETARDATION
Abstract: Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 x 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
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36. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author: Ried, Janina S, Jeff M, Janina, Chu, Audrey Y, Bragg-Gresham, Jennifer L, Van Dongen, Jenny, Huffman, Jennifer E, Ahluwalia, Tarunveer S, Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Tõnu, Feitosa, Mary F, Goel, Anuj, Gorski, Mathias, Hayward, Caroline, Heard-Costa, Nancy L, Jackson, Anne U, Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'an, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina-Gomez, Carolina, Monda, Keri L, Nolte, Ilja M, Pérusse, Louis, Prokopenko, Inga, Qi, Lu, Rose, Lynda M, Salvi, Erika, Smith, Megan T, Snieder, Harold, Stančáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, Van Der Harst, Pim, Walker, Ryan W, Wang, Sophie R, Wild, Sarah H, Willems, Sara M, Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan JL, Barlassina, Cristina, Bartz, Traci M, Beilby, John, Bellis, Claire, Bergman, Richard N, Bergmann, Sven, Blangero, John, Blüher, Matthias, Boerwinkle, Eric, Bonnycastle, Lori L, Bornstein, Stefan R, Bruinenberg, Marcel, Campbell, Harry, Chen, Yii-Der Ida, Chiang, Charleston WK, Chines, Peter S, Collins, Francis S, Cucca, Fracensco, Cupples, L Adrienne, D'Avila, Francesca, De Geus, Eco JC, Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G, Farmaki, Aliki-Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G, Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Anders, Harder, Marie Neergaard, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew Tym, Havulinna, Aki S, Heliövaara, Markku, Hillege, Hans, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke-Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G, Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L, Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E, Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen-Kiukaanniemi, Sirkka M, Kinnunen, Leena, Knekt, Paul B, Koistinen, Heikki A, Kolcic, Ivana, Kooner, Ishminder K, Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosios, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M, Lichtner, Peter, Lindgren, Cecilia M, Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattias, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, McArdle, Wendy L, Mcknight, Barbara, Mohlke, Karen L, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E, Morris, Andrew P, Müller, Gabriele, Musk, Arthur W, Narisu, Narisu, Ong, Ken K, Oostra, Ben A, Osmond, Clive, Palotie, Aarno, Pankow, James S, Paternoster, Lavinia, Penninx, Brenda W, Pichler, Irene, Pilia, Maria G, Polašek, Ozren, Pramstaller, Peter P, Raitakari, Olli T, Rankinen, Tuomo, Rao, DC, Rayner, Nigel W, Ribel-Madsen, Rasmus, Rice, Treva K, Richards, Marcus, Ridker, Paul M, Rivadeneira, Fernando, Ryan, Kathy A, Sanna, Serena, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P, Strauch, Konstantin, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Tönjes, Anke, Tsafantakis, Emmanouil, Van Der Most, Peter J, Van Vliet-Ostaptchouk, Jana V, Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S, Vitart, Veronique, Vohl, Marie-Claude, Vonk, Judith M, Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W, Wright, Alan F, Yerges-Armstrong, Laura M, Hua Zhao, Jing, Zillikens, M Carola, Boomsma, Dorret I, Bouchard, Claude, Chambers, John C, Chasman, Daniel I, Cusi, Daniele, Gansevoort, Ron T, Gieger, Christian, Hansen, Torben, Hicks, Andrew A, Hu, Frank, Hveem, Kristian, Jarvelin, Marjo-Riitta, Kajantie, Eero, Kooner, Jaspal S, Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Metspalu, Andres, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Palmer, Lyle J, Pedersen, Oluf, Perola, Markus, Peters, Annette, Psaty, Bruce M, Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter EH, Shudiner, Alan R, Smit, Jan H, Sørensen, Thorkild IA, Spector, Timothy D, Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J, Watkins, Hugh, Wilson, James F, Zeggini, Eleftheria, Abecasis, Goncalo R, Boehnke, Michael, Borecki, Ingrid B, Deloukas, Panos, Van Duijn, Cornelia M, Fox, Caroline, Groop, Leif C, Heid, Iris M, Hunter, David J, Kaplan, Robert C, McCarthy, Mark I, North, Kari E, O'Connell, Jeffrey R, Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P, Frayling, Timothy, Hirschhorn, Joel N, Müller-Nurasyid, Martina, and Loos, Ruth JF
Subjects: 2. Zero hunger, Principal Component Analysis, Anthropometry, Genotype, Models, Genetic, Body Size, Humans, Genome-Wide Association Study
Abstract: Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

37. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author: Li, Chen, Stoma, Svetlana, Lotta, Luca A, Warner, Sophie, Albrecht, Eva, Allione, Alessandra, Arp, Pascal P, Broer, Linda, Buxton, Jessica L, Da Silva Couto Alves, Alexessander, Deelen, Joris, Fedko, Iryna O, Gordon, Scott D, Jiang, Tao, Karlsson, Robert, Kerrison, Nicola, Loe, Taylor K, Mangino, Massimo, Milaneschi, Yuri, Miraglio, Benjamin, Pervjakova, Natalia, Russo, Alessia, Surakka, Ida, Van Der Spek, Ashley, Verhoeven, Josine E, Amin, Najaf, Beekman, Marian, Blakemore, Alexandra I, Canzian, Federico, Hamby, Stephen E, Hottenga, Jouke-Jan, Jones, Peter D, Jousilahti, Pekka, Mägi, Reedik, Medland, Sarah E, Montgomery, Grant W, Nyholt, Dale R, Perola, Markus, Pietiläinen, Kirsi H, Salomaa, Veikko, Sillanpää, Elina, Suchiman, H Eka, Van Heemst, Diana, Willemsen, Gonneke, Agudo, Antonio, Boeing, Heiner, Boomsma, Dorret I, Chirlaque, Maria-Dolores, Fagherazzi, Guy, Ferrari, Pietro, Franks, Paul, Gieger, Christian, Eriksson, Johan Gunnar, Gunter, Marc, Hägg, Sara, Hovatta, Iiris, Imaz, Liher, Kaprio, Jaakko, Kaaks, Rudolf, Key, Timothy, Krogh, Vittorio, Martin, Nicholas G, Melander, Olle, Metspalu, Andres, Moreno, Concha, Onland-Moret, N Charlotte, Nilsson, Peter, Ong, Ken K, Overvad, Kim, Palli, Domenico, Panico, Salvatore, Pedersen, Nancy L, Penninx, Brenda WJH, Quirós, J Ramón, Jarvelin, Marjo Riitta, Rodríguez-Barranco, Miguel, Scott, Robert A, Severi, Gianluca, Slagboom, P Eline, Spector, Tim D, Tjonneland, Anne, Trichopoulou, Antonia, Tumino, Rosario, Uitterlinden, André G, Van Der Schouw, Yvonne T, Van Duijn, Cornelia M, Weiderpass, Elisabete, Denchi, Eros Lazzerini, Matullo, Giuseppe, Butterworth, Adam S, Danesh, John, Samani, Nilesh J, Wareham, Nicholas J, Nelson, Christopher P, Langenberg, Claudia, and Codd, Veryan
Subjects: age-related disease, Nucleotides, biological aging, telomere length, Leukocytes, Humans, Telomere, Mendelian randomisation, 3. Good health, Genome-Wide Association Study
Abstract: Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

38. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author: Couto Alves, Alexessander, De Silva, N Maneka G, Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H Rob, Warrington, Nicole M, Lewin, Alexandra M, Kaakinen, Marika, Cousminer, Diana L, Thiering, Elisabeth, Timpson, Nicholas J, Bond, Tom A, Lowry, Estelle, Brown, Christopher D, Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P, Geller, Frank, Speed, Doug, Coin, Lachlan JM, Loh, Marie, Barton, Sheila J, Beilin, Lawrence J, Bisgaard, Hans, Bønnelykke, Klaus, Alili, Rohia, Hatoum, Ida J, Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clément, Karine, Claringbould, Annique AJ, Van Duijn, Cornelia M, Moltchanova, Elena, Eriksson, Johan G, Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M, Freathy, Rachel M, Elliott, Paul, Widén, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T, Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W, Hofman, Albert, Hyppönen, Elina, Inskip, Hazel, Kaplan, Lee M, Hedman, Asa K, Läärä, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A, Lawlor, Debbie A, Melbye, Mads, Ahluwalia, Tarunveer S, Marinelli, Marcella, Millwood, Iona Y, Palmer, Lyle J, Pennell, Craig E, Perry, John R, Ring, Susan M, Savolainen, Markku J, Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla MT, Uitterlinden, Andre G, Schierding, William, O’Sullivan, Justin M, Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F, Buxton, Jessica L, Blakemore, Alexandra IF, Ong, Ken K, Jaddoe, Vincent WV, Grant, Struan FA, Sebert, Sylvain, McCarthy, Mark I, and Järvelin, Marjo-Riitta
Subjects: 2. Zero hunger, Adult, Male, Pharmacogenomic Variants, Quantitative Trait Loci, Intracellular Signaling Peptides and Proteins, Infant, Genomics, Polymorphism, Single Nucleotide, Body Mass Index, Quantitative Trait, Heritable, Humans, Receptors, Leptin, Female, Genetic Predisposition to Disease, Longitudinal Studies, Growth Charts, Child, Genetic Association Studies, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
Abstract: Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

39. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Author: Demenais, Florence, Margaritte-Jeannin, Patricia, Barnes, Kathleen C, Cookson, William OC, Altmüller, Janine, Ang, Wei, Barr, R Graham, Beaty, Terri H, Becker, Allan B, Beilby, John, Bisgaard, Hans, Bjornsdottir, Unnur Steina, Bleecker, Eugene, Bønnelykke, Klaus, Boomsma, Dorret I, Bouzigon, Emmanuelle, Brightling, Christopher E, Brossard, Myriam, Brusselle, Guy G, Burchard, Esteban, Burkart, Kristin M, Bush, Andrew, Chan-Yeung, Moira, Chung, Kian Fan, Couto Alves, Alexessander, Curtin, John A, Custovic, Adnan, Daley, Denise, De Jongste, Johan C, Del-Rio-Navarro, Blanca E, Donohue, Kathleen M, Duijts, Liesbeth, Eng, Celeste, Eriksson, Johan G, Farrall, Martin, Fedorova, Yuliya, Feenstra, Bjarke, Ferreira, Manuel A, Australian Asthma Genetics Consortium (AAGC) Collaborators, Freidin, Maxim B, Gajdos, Zofia, Gauderman, Jim, Gehring, Ulrike, Geller, Frank, Genuneit, Jon, Gharib, Sina A, Gilliland, Frank, Granell, Raquel, Graves, Penelope E, Gudbjartsson, Daniel F, Haahtela, Tari, Heckbert, Susan R, Heederik, Dick, Heinrich, Joachim, Heliövaara, Markku, Henderson, John, Himes, Blanca E, Hirose, Hiroshi, Hirschhorn, Joel N, Hofman, Albert, Holt, Patrick, Hottenga, Jouke, Hudson, Thomas J, Hui, Jennie, Imboden, Medea, Ivanov, Vladimir, Jaddoe, Vincent WV, James, Alan, Janson, Christer, Jarvelin, Marjo-Riitta, Jarvis, Deborah, Jones, Graham, Jonsdottir, Ingileif, Jousilahti, Pekka, Kabesch, Michael, Kähönen, Mika, Kantor, David B, Karunas, Alexandra S, Khusnutdinova, Elza, Koppelman, Gerard H, Kozyrskyj, Anita L, Kreiner, Eskil, Kubo, Michiaki, Kumar, Rajesh, Kumar, Ashish, Kuokkanen, Mikko, Lahousse, Lies, Laitinen, Tarja, Laprise, Catherine, Lathrop, Mark, Lau, Susanne, Lee, Young-Ae, Lehtimäki, Terho, Letort, Sébastien, Levin, Albert M, Li, Guo, Liang, Liming, Loehr, Laura R, London, Stephanie J, Loth, Daan W, Manichaikul, Ani, Marenholz, Ingo, Martinez, Fernando J, Matheson, Melanie C, Mathias, Rasika A, Matsumoto, Kenji, Mbarek, Hamdi, McArdle, Wendy L, Melbye, Mads, Melén, Erik, Meyers, Deborah, Michel, Sven, Mohamdi, Hamida, Musk, Arthur W, Myers, Rachel A, Nieuwenhuis, Maartje AE, Noguchi, Emiko, O'Connor, George T, Ogorodova, Ludmila M, Palmer, Cameron D, Palotie, Aarno, Park, Julie E, Pennell, Craig E, Pershagen, Göran, Polonikov, Alexey, Postma, Dirkje S, Probst-Hensch, Nicole, Puzyrev, Valery P, Raby, Benjamin A, Raitakari, Olli T, Ramasamy, Adaikalavan, Rich, Stephen S, Robertson, Colin F, Romieu, Isabelle, Salam, Muhammad T, Salomaa, Veikko, Schlünssen, Vivi, Scott, Robert, Selivanova, Polina A, Sigsgaard, Torben, Simpson, Angela, Siroux, Valérie, Smith, Lewis J, Solodilova, Maria, Standl, Marie, Stefansson, Kari, Strachan, David P, Stricker, Bruno H, Takahashi, Atsushi, Thompson, Philip J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiesler, Carla MT, Torgerson, Dara G, Tsunoda, Tatsuhiko, Uitterlinden, André G, Van Der Valk, Ralf JP, Vaysse, Amaury, Vedantam, Sailaja, Von Berg, Andrea, Von Mutius, Erika, Vonk, Judith M, Waage, Johannes, Wareham, Nick J, Weiss, Scott T, White, Wendy B, Wickman, Magnus, Widén, Elisabeth, Willemsen, Gonneke, Williams, L Keoki, Wouters, Inge M, Yang, James J, Zhao, Jing Hua, Moffatt, Miriam F, Ober, Carole, and Nicolae, Dan L
Subjects: Risk, Rhinitis, Allergic, Seasonal, Asthma, respiratory tract diseases, 3. Good health, Epigenesis, Genetic, Histone Code, Enhancer Elements, Genetic, Phenotype, immune system diseases, Genetic Loci, Leukocytes, Humans, Genetic Predisposition to Disease, Promoter Regions, Genetic, Alleles, Genome-Wide Association Study
Abstract: We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

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