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1. Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Author

Seyhan Yazar, M. Arfan Ikram, Gonneke Willemsen, Maria Pina Concas, Manfred Kayser, Tim D. Spector, David M. Evans, Nicholas G. Martin, David L. Duffy, Changqing Zeng, Bochao D. Lin, Daniela Toniolo, Pirro G. Hysi, Gibran Hemani, Jouke-Jan Hottenga, Paolo Gasparini, Gu Zhu, Sarah E. Medland, Cornelia M. van Duijn, Mario Falchi, Marco Brumat, Nicholas A. Furlotte, Alessia Visconti, André G. Uitterlinden, Cinzia Sala, George McMahon, David A. Hinds, Dorret I. Boomsma, Ilaria Gandin, Ana M. Valdes, Dragana Vuckovic, Giorgia Girotto, Veronique Bataille, Massimiliano Cocca, David A. Mackey, Susan M. Ring, Fan Liu, Tamar Nijsten, Scott D. Gordon, Yan Chen, George Davey Smith, Merel A. Hamer, Antonietta Robino, Alex W. Hewitt, Genetic Identification, Erasmus MC other, Epidemiology, Internal Medicine, Dermatology, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, Hysi, Pirro G., Valdes, A. M., Liu, Fan, Furlotte, Nicholas A., Evans, David M., Bataille, Veronique, Visconti, Alessia, Hemani, Gibran, Mcmahon, George, Ring, Susan M., Smith, George Davey, Duffy, David L., Zhu, Gu, Gordon, Scott D., Medland, Sarah E., Lin, Bochao D., Willemsen, Gonneke, Jan Hottenga, Jouke, Vuckovic, Dragana, Girotto, Giorgia, Gandin, Ilaria, Sala, Cinzia, Concas, Maria Pina, Brumat, Marco, Gasparini, Paolo, Toniolo, Daniela, Cocca, Massimiliano, Robino, Antonietta, Yazar, Seyhan, Hewitt, Alex W., Chen, Yan, Zeng, Changqing, Uitterlinden, Andre G., Ikram, M. Arfan, Hamer, Merel A., van Duijn, Cornelia M., Nijsten, Tamar, Mackey, David A., Falchi, Mario, Boomsma, Dorret I., Martin, Nicholas G., Hinds, David A., Kayser, Manfred, and Spector, Timothy D.

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, 0302 clinical medicine, Black hair, Genetic variation, Genotype, Genetics, Eye color, otorhinolaryngologic diseases, Journal Article, Humans, Hair Color, Aged, Chromosomes, Human, X, Autosome, integumentary system, Heritability, Middle Aged, 030104 developmental biology, Phenotype, Evolutionary biology, Genetic Loci, Female, sense organs, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

Published
2018

2. Common variation at 16p11.2 is associated with glycosuria in pregnancy: findings from a genome-wide association study in European women

Author

Nicholas J. Timpson, Ville Karhunen, Matthew Lee, David A. Hughes, Kaitlin H Wade, George Davey Smith, Marjo-Riitta Järvelin, George McMahon, Debbie A Lawlor, Laura J Corbin, and UNIVERSITY OF OULU

Subjects
AcademicSubjects/SCI01140, endocrine system diseases, Physiology, Genome-wide association study, Body Mass Index, 0302 clinical medicine, Pregnancy, Association Studies Article, 11 Medical and Health Sciences, Genetics (clinical), Genetics & Heredity, 0303 health sciences, FGFP, General Medicine, ALSPAC, Female, medicine.symptom, Glycosuria, GWAS - genome-wide association study, Adult, endocrine system, Adolescent, Genotype, Offspring, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Sodium-Glucose Transporter 2, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, 030304 developmental biology, Genetic association, nutritional and metabolic diseases, Odds ratio, 06 Biological Sciences, medicine.disease, Pregnancy Complications, Diabetes Mellitus, Type 2, Chromosomes, Human, Pair 16, Genome-Wide Association Study
Abstract

Glycosuria is a condition where glucose is detected in urine at higher concentrations than normal (i.e. not detectable). Glycosuria at some point during pregnancy has an estimated prevalence of 50% and is associated with adverse outcomes in both mothers and offspring. Little is currently known about the genetic contribution to this trait or the extent to which it overlaps with other seemingly related traits, e.g. diabetes. We performed a genome-wide association study (GWAS) for self-reported glycosuria in pregnant mothers from the Avon Longitudinal Study of Parents and Children (cases/controls = 1249/5140). We identified two loci, one of which (lead SNP = rs13337037; chromosome 16; odds ratio of glycosuria per effect allele: 1.42; 95% CI: 1.30, 1.56; P = 1.97 × 10−13) was then validated using an obstetric measure of glycosuria measured in the same cohort (227/6639). We performed a secondary GWAS in the 1986 Northern Finland Birth Cohort (NFBC1986; 747/2991) using midwife-reported glycosuria and offspring genotype as a proxy for maternal genotype. The combined results revealed evidence for a consistent effect on glycosuria at the chromosome 16 locus. In follow-up analyses, we saw little evidence of shared genetic underpinnings with the exception of urinary albumin-to-creatinine ratio (Rg = 0.64; SE = 0.22; P = 0.0042), a biomarker of kidney disease. In conclusion, we identified a genetic association with self-reported glycosuria during pregnancy, with the lead SNP located 15kB upstream of SLC5A2, a target of antidiabetic drugs. The lack of strong genetic correlation with seemingly related traits such as type 2 diabetes suggests different genetic risk factors exist for glycosuria during pregnancy.

Published
2019

3. A genome-wide approach to children's aggressive behavior: The EAGLE consortium

Author

Nicholas J. Timpson, Michel G. Nivard, Craig E. Pennell, Harold Snieder, Gareth E. Davies, Christel M. Middeldorp, Fernando Rivadeneira, Ilkka Seppälä, Carla M. T. Tiesler, Susan M. Ring, Marie Standl, James J. Hudziak, Kelly S. Benke, Viara R. Mileva-Seitz, Fleur P. Velders, George Davey Smith, Christine Power, Alina Rodriguez, John P. Kemp, René Veenstra, Beate St Pourcain, Harald Grallert, Liisa Keltikangas-Järvinen, Maria M. Groen-Blokhuis, Elina Hyppönen, Irene Pappa, David M. Evans, Marian J. Bakermans-Kranenburg, Joachim Heinrich, Marie-Claude Geoffroy, Christian Hakulinen, Albertine J. Oldehinkel, Dorret I. Boomsma, Elisabeth Thiering, Paul Scheet, George McMahon, Ilja M. Nolte, Henning Tiemeier, Alana Cavadino, Ehsan Motazedi, Terho Lehtimäki, Olli T. Raitakari, Andrew J. O. Whitehouse, Life Course Epidemiology (LCE), Sociology/ICS, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, EMGO+ - Mental Health, Child and Adolescent Psychiatry / Psychology, Erasmus MC other, Epidemiology, Internal Medicine, Psychiatry, Pappa, Irene, St, Pourcain Beate, Benke, Kelly, Cavadino, Alana, Hypponen, Elina, and Tiemeier, Henning

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Receptors, Vasopressin, Poison control, Vasopressin/genetics, Genetics, Behavioral/methods, 0302 clinical medicine, Surveys and Questionnaires, Receptors, Psychology, Early childhood, genome-wide complex trait analysis (GCTA), Child, Genetics (clinical), education.field_of_study, HERITABILITY, Genetic Predisposition to Disease/genetics, aggression, Public Health, Global Health, Social Medicine and Epidemiology, ASSOCIATION, Polymorphism, Single Nucleotide/genetics, Justice and Strong Institutions, Aggression, Psychiatry and Mental health, Conduct disorder, DUTCH TWINS, ADOLESCENCE, Meta-analysis, Female, medicine.symptom, Single Nucleotide/genetics, Clinical psychology, SDG 16 - Peace, Adolescent, Population, Aggression/physiology, Single-nucleotide polymorphism, Genetics, Behavioral, Biology, Polymorphism, Single Nucleotide, GENETIC ARCHITECTURE, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, EARLY-CHILDHOOD, education, Receptors, Vasopressin/genetics, Genetic Association Studies, childhood, Behavioral/methods, Behavior, Psykologi, STABILITY, ta1184, SDG 16 - Peace, Justice and Strong Institutions, Genetic Variation, ADULTS, medicine.disease, Genetic architecture, population-based, meta-analysis, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Genetic Association Studies/methods, 030104 developmental biology, TISSUE, CONDUCT DISORDER, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 x 10(-8)). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. (C) 2015 Wiley Periodicals, Inc.

Published
2016

4. Applying polygenic risk scores to postpartum depression

Author

Nicholas G. Martin, Brett Chapman, Dorret I. Boomsma, Samantha Meltzer-Brody, David M. Evans, Brenda W.J.H. Penninx, Paul Lichtenstein, Gerard van Grootheest, Debbie A Lawlor, Enda M. Byrne, Lynn Boschloo, Mikael Landén, Naomi R. Wray, George McMahon, Anjali K. Henders, Pamela A. F. Madden, Hannah M Sallis, Michele L. Pergadia, Andrew C. Heath, Tania Carrillo-Roa, Patrick F. Sullivan, Alexander Viktorin, Patrik K. E. Magnusson, Grant W. Montgomery, Psychiatry, NCA - Neurobiology of mental health, EMGO - Mental health, Functional Genomics, Clinical, Neuro- & Developmental Psychology, APH - Mental Health, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, and EMGO+ - Mental Health

Subjects
Postpartum depression, Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, Bipolar Disorder, Logistic regression, 0302 clinical medicine, Risk Factors, Surveys and Questionnaires, Depression (differential diagnoses), Depression, Bipolar Disorder/genetics, Obstetrics and Gynecology, Major/genetics, Single Nucleotide, Psychiatry and Mental health, Cohort, Major depressive disorder, Female, Psychology, Depressive Disorder, Major/genetics, Postpartum/genetics, Adult, medicine.medical_specialty, Genotype, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Depression, Postpartum, 03 medical and health sciences, Young Adult, SDG 3 - Good Health and Well-being, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, Psychiatry, Retrospective Studies, Depressive Disorder, Major, Depressive Disorder, Genetic Variation, medicine.disease, 030227 psychiatry, Standard error, Depression, Postpartum/genetics, Logistic Models, Etiology, 030217 neurology & neurosurgery, Demography
Abstract

The etiology of major depressive disorder (MDD) is likely to be heterogeneous, but postpartum depression (PPD) is hypothesized to represent a more homogenous subset of MDD. We use genome-wide SNP data to explore this hypothesis. We assembled a total cohort of 1,420 self-report cases of PPD and 9,473 controls with genome-wide genotypes from Australia, The Netherlands, Sweden and the UK. We estimated the total variance attributable to genotyped variants. We used association results from the Psychiatric Genomics Consortia (PGC) of bipolar disorder (BPD) and MDD to create polygenic scores in PPD and related MDD data sets to estimate the genetic overlap between the disorders. We estimated that the percentage of variance on the liability scale explained by common genetic variants to be 0.22 with a standard error of 0.12, p = 0.02. The proportion of variance (R (2)) from a logistic regression of PPD case/control status in all four cohorts on a SNP profile score weighted by PGC-BPD association results was small (0.1 %) but significant (p = 0.004) indicating a genetic overlap between BPD and PPD. The results were highly significant in the Australian and Dutch cohorts (R (2) > 1.1 %, p

Published
2014

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

Author

Emmi Tikkanen, Pascal Guénel, Rico Rueedi, Hamdi Mbarek, Gerardo Heiss, Hilary K. Finucane, Jing Hua Zhao, Peter K. Joshi, Mark I. McCarthy, Frank B. Hu, Stephen J. Chanock, Manjeet K. Bolla, Sandosh Padmanabhan, Vilmundur Gudnason, Chunyan He, Aarno Palotie, Reedik Mägi, Joe Dennis, Nicholas G. Martin, Behrooz Z. Alizadeh, Elisabeth Widen, Caroline Hayward, Penelope A. Lind, Magdalena Zoledziewska, Ayellet V. Segrè, Fergus J. Couch, Massimo Mangino, Melissa C. Southey, Immaculata De Vivo, Yongmei Liu, Ute Hamann, Angela Cox, Maartje J. Hooning, Iffat Rahman, Mitul Shah, Eric Boerwinkle, Matthias W. Beckmann, Catharina A. Hartman, Tanguy Corre, Kathryn L. Lunetta, Thérèse Truong, Anna Marie Mulligan, Caterina Barbieri, Robert Winqvist, Lili Milani, Cristina Menni, Frits R. Rosendaal, Pau Navarro, Christian Gieger, Ken K. Ong, Stig E. Bojesen, Susan M. Ring, Marjanka K. Schmidt, George McMahon, Deborah J. Thompson, Robert Karlsson, Nicholas J. Timpson, M. Arfan Ikram, Alexander Teumer, Jingmei Li, Christa Meisinger, Diana L. Cousminer, Doris Stöckl, Heli Nevanlinna, Teresa Nutile, Tim D. Spector, Eva Albrecht, Murielle Bochud, Linda Broer, Felix R. Day, Sven Bergmann, Renée de Mutsert, Nicholas J. Wareham, Marjo-Riitta Järvelin, Marzyeh Amini, Elisabeth Altmaier, Isabel dos-Santos-Silva, Peter Vollenweider, Douglas F. Easton, Tamara B. Harris, Ellen A. Nohr, Paul D.P. Pharoah, David J. Porteous, Jenny A. Visser, Ilja M. Nolte, Genevieve Lachance, Thomas Meitinger, Archie Campbell, Thomas Brüning, Graham G. Giles, Johan G. Eriksson, Nancy L. Pedersen, George Davey Smith, Gonneke Willemsen, Joanne M. Murabito, Francesco Cucca, Daniel I. Chasman, Eleonora Porcu, Nora Franceschini, Thibaud Boutin, Ulla Sovio, Roger L. Milne, Annette Peters, Lisette Stolk, Paul M. Ridker, Claudia Langenberg, Patrick Sulem, Toshiko Tanaka, Marike Gabrielson, Judith S. Brand, Unnur Thorsteindottir, Alison M. Dunning, Marina Ciullo, Julie E. Buring, Harold Snieder, Lude Franke, Meir J. Stampfer, Po-Ru Loh, Julian Peto, Ellen W. Demerath, Sheila Ulivi, Ivana Kolcic, Maristella Steri, Jouke J. Hottenga, Amanda B. Spurdle, Tõnu Esko, Katherine S. Pollard, Eulalia Catamo, Anneli Pouta, Kyriaki Michailidou, Dieter Flesch-Janys, James F. Wilson, Kamila Czene, Sean Whalen, Diether Lambrechts, Abhishek Sarkar, Laura Crisponi, Jonathan Tyrer, Antonietta Robino, Sara Lindström, Harald Grallert, Stefania Lenarduzzi, Peter Kraft, Patrik K. E. Magnusson, Lavinia Paternoster, Digna R. Velez Edwards, Mike A. Nalls, Per Hall, Joyce Y. Tung, Cinzia Sala, Lindsay Fernández-Rhodes, Ayush Giri, Hiltrud Brauch, André G. Uitterlinden, Alkes L. Price, Tracy A. O'Mara, Lynda M. Rose, John L. Hopper, David A. Hinds, Katherine S. Ruth, Arto Mannermaa, Uwe Völker, Rossella Sorice, Zoltán Kutalik, Debbie A Lawlor, Georgia Chenevix-Trench, Anna Murray, Albertine J. Oldehinkel, Bruce H. R. Wolffenbuttel, Hae Kyung Im, Dale R. Nyholt, Lenore J. Launer, Andres Metspalu, Irene L. Andrulis, Konstantin Strauch, Albert V. Smith, Daniela Toniolo, Eco J. C. de Geus, Jenny Chang-Claude, Marek Zygmunt, Dorret I. Boomsma, Harry Campbell, Peter Devilee, Henry Völzke, Daniela Ruggiero, Dennis O. Mook-Kanamori, John R. B. Perry, Javier Benitez, Grant W. Montgomery, David J. Hunter, David Karasik, Luigi Ferrucci, Emily Hallberg, Stefania Bandinelli, Hermann Brenner, Raymond Noordam, Sarah E. Medland, Peter A. Fasching, Qin Wang, Ilaria Gandin, Manolis Kellis, Hannes Helgason, Igor Rudan, Paolo Radice, Michela Traglia, Jian'an Luan, Robert A. Scott, Brumat Marco, Veronique Vitart, Kari Stefansson, Katharina E. Schraut, Ko Willems van Dijk, Ozren Polasek, Daniel F. Gudbjartsson, Natalia Perjakova, Joop S.E. Laven, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Art and Culture, History, Antiquity, Day, Felix R., Thompson, Deborah J., Helgason, Hanne, Chasman, Daniel I., Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S., Whalen, Sean, Sarkar, Abhishek K., Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, CATERINA MARIA, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J., Karlsson, Robert, Kolcic, Ivana, Loh, Po Ru, Lunetta, Kathryn L., Mangino, Massimo, Brumat, Marco, Mcmahon, George, Medland, Sarah E., Nolte, Ilja M., Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M., Schraut, Katharina E., Segrã¨, Ayellet V., Smith, Albert V., Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L., Bandinelli, Stefania, Beckmann, Matthias W., Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brã¼ning, Thoma, Buring, Julie E., Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix Trench, Georgia, Corre, Tanguy, Couch, Fergus J., Cousminer, Diana L., Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, De Geus, Eco J. C. N., De Mutsert, Renã©e, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos Santos Silva, Isabel, Dunning, Alison M., Eriksson, Johan G., Fasching, Peter A., Fernández Rhodes, Lindsay, Ferrucci, Luigi, Flesch Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Guã©nel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B., Hartman, Catharina A., Heiss, Gerardo, Hooning, Maartje J., Hopper, John L., Hu, Frank, Hunter, David J., Ikram, M. Arfan, Im, Hae Kyung, Jã¤rvelin, Marjo Riitta, Joshi, Peter K., Karasik, David, Kellis, Manoli, Kutalik, Zoltan, Lachance, Genevieve, Lambrechts, Diether, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lenarduzzi, Stefania, Li, Jingmei, Lind, Penelope A., Lindstrom, Sara, Liu, Yongmei, Luan, Jian'An, Mã¤gi, Reedik, Mannermaa, Arto, Mbarek, Hamdi, Mccarthy, Mark I., Meisinger, Christa, Meitinger, Thoma, Menni, Cristina, Metspalu, Andre, Michailidou, Kyriaki, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mulligan, Anna M., Nalls, Mike A., Navarro, Pau, Nevanlinna, Heli, Nyholt, Dale R., Oldehinkel, Albertine J., O'Mara, Tracy A., Padmanabhan, Sandosh, Palotie, Aarno, Pedersen, Nancy, Peters, Annette, Peto, Julian, Pharoah, Paul D. P., Pouta, Anneli, Radice, Paolo, Rahman, Iffat, Ring, Susan M., Robino, Antonietta, Rosendaal, Frits R., Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Schmidt, Marjanka K., Scott, Robert A., Shah, Mitul, Sorice, Rossella, Southey, Melissa C., Sovio, Ulla, Stampfer, Meir, Steri, Maristella, Strauch, Konstantin, Tanaka, Toshiko, Tikkanen, Emmi, Timpson, Nicholas J., Traglia, Michela, Truong, Thã©rã¨se, Tyrer, Jonathan P., Uitterlinden, André G., Edwards, Digna R. Velez, Vitart, Veronique, Vã¶lker, Uwe, Vollenweider, Peter, Wang, Qin, Widen, Elisabeth, Van Dijk, Ko Willem, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R., Zhao, Jing Hua, Zoledziewska, Magdalena, Zygmunt, Marek, Alizadeh, Behrooz Z., Boomsma, Dorret I., Ciullo, Marina, Cucca, Francesco, Esko, Tãµnu, Franceschini, Nora, Gieger, Christian, Gudnason, Vilmundur, Hayward, Caroline, Kraft, Peter, Lawlor, Debbie A., Magnusson, Patrik K. E., Martin, Nicholas G., Mook Kanamori, Dennis O., Nohr, Ellen A., Polasek, Ozren, Porteous, David, Price, Alkes L., Ridker, Paul M., Snieder, Harold, Spector, Tim D., Stã¶ckl, Dori, Toniolo, Daniela, Ulivi, Sheila, Visser, Jenny A., Vã¶lzke, Henry, Wareham, Nicholas J., Wilson, James F., LifeLines Cohort, Study, Interact, Consortium, Kconfab/aocs, Investigator, Endometrial Cancer Association, Consortium, Ovarian Cancer Association, Consortium, Practical, Consortium, Spurdle, Amanda B., Thorsteindottir, Unnur, Pollard, Katherine S., Easton, Douglas F., Tung, Joyce Y., Chang Claude, Jenny, Hinds, David, Murray, Anna, Murabito, Joanne M., Stefansson, Kari, Ong, Ken K., Perry, John R. B., Internal Medicine, Erasmus MC other, Medical Oncology, Epidemiology, Obstetrics & Gynecology, Day, Felix [0000-0003-3789-7651], Thompson, Deborah [0000-0003-1465-5799], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Pharoah, Paul [0000-0001-8494-732X], Sovio, Ulla [0000-0002-0799-1105], Tyrer, Jonathan [0000-0003-3724-4757], Zhao, Jing Hua [0000-0003-4930-3582], Wareham, Nicholas [0000-0003-1422-2993], Easton, Douglas [0000-0003-2444-3247], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Massachusetts Institute of Technology. Department of Mathematics, and Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Ovarian Cancer Association Consortium, LOCI, Genome-wide association study, cancer risk, Menarche/genetics, Bioinformatics, GWAS, menarche, puberty, Body Mass Index, Risk Factors, Neoplasms, Databases, Genetic, WIDE ASSOCIATION, Endometrial Cancer Association Consortium, Ribonucleoproteins/genetics, 2. Zero hunger, Genetics, Age Factors, Genetics GWAS menarche, reproductive disorders, Neoplasms/genetics, 3. Good health, Ribonucleoproteins, Menarche, MENDELIAN RANDOMIZATION, Intercellular Signaling Peptides and Proteins, GROWTH, Female, TRAITS, Population variance, Intercellular Signaling Peptides and Proteins/genetics, Adolescent, Ubiquitin-Protein Ligases, kConFab/AOCS Investigators, Quantitative Trait Loci, Quantitative trait locus, Biology, METABOLISM, INHERITANCE, Polymorphism, Single Nucleotide, PRACTICAL consortium, 03 medical and health sciences, Genomic Imprinting, SDG 3 - Good Health and Well-being, Mendelian randomization, REGRESSION, medicine, Journal Article, Humans, cancer, Genetic Predisposition to Disease, 1000 Genomes Project, Membrane Proteins/genetics, METAANALYSIS, Puberty, Calcium-Binding Proteins, Membrane Proteins, Cancer, InterAct Consortium, Heritability, medicine.disease, BODY-MASS INDEX, 030104 developmental biology, genome-wide association studies, Puberty/genetics, LifeLines Cohort Study, Genome-Wide Association Study
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P

Published
2017

6. A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci

Author

George McMahon, Beate St Pourcain, Susan M. Ring, Chuong B. Do, Nicholas Eriksson, George Davey-Smith, Uta Francke, David A. Hinds, David M. Evans, Amy K. Kiefer, Joanna L. Mountain, Nicholas J. Timpson, and Joyce Y. Tung

Subjects
Adult, Male, Allergy, Locus (genetics), Genome-wide association study, Disease, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Hypersensitivity, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Aged, 030304 developmental biology, Autoimmune disease, 0303 health sciences, Pyroglyphidae, Allergens, Middle Aged, medicine.disease, 3. Good health, Genetic Loci, TLR6, Immunology, Cats, Female, Self Report, Genome-Wide Association Study, 030215 immunology
Abstract

Allergic disease is very common and carries substantial public-health burdens. We conducted a meta-analysis of genome-wide associations with self-reported cat, dust-mite and pollen allergies in 53,862 individuals. We used generalized estimating equations to model shared and allergy-specific genetic effects. We identified 16 shared susceptibility loci with association P

Published
2013

7. Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women

Author

Kristina Åkesson, Fiona E. McGuigan, John Blangero, Melanie A. Carless, Ching-Ti Liu, Candace M. Kammerer, François Rousseau, Dongbing Lai, Munro Peacock, Audrey C. Choh, Sylvie Giroux, David Karasik, Tatiana Foroud, Beate St Pourcain, Bradford Towne, David M. Evans, Howard J. Edenberg, Jonathan H Tobias, John P. Kemp, Braxton D. Mitchell, Daniel L. Koller, Debbie A Lawlor, J. Brent Richards, Tim D. Spector, George McMahon, David Goltzman, Laura M. Yerges-Armstrong, Jerilynn C. Prior, Christopher S. Kovacs, Stefan A. Czerwinski, Douglas P. Kiel, Michael J. Econs, Nicholas J. Timpson, and Hou-Feng Zheng

Subjects
Oncology, Peak bone mass, musculoskeletal diseases, medicine.medical_specialty, Bone density, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Genome-wide association study, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Bone Density, Internal medicine, medicine, SNP, Humans, Orthopedics and Sports Medicine, 030304 developmental biology, Femoral neck, Genetic association, Bone mineral, 0303 health sciences, business.industry, Estrogen Receptor alpha, Wnt Proteins, Endocrinology, medicine.anatomical_structure, Premenopause, Female, business, Genome-Wide Association Study
Abstract

Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n=4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p=1.7x109) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p=1.3x108) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5597 for femoral neck; n=4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3x1011; ESR1/C6orf97 joint p=1.4x1010). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p

Published
2013
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8. Genetic variants linked to education predict longevity

Author

Chris Power, Gail Davies, Ilaria Gandin, Panagiotis Deloukas, Jennifer E. Huffman, Pascal Timshel, Albert V. Smith, A. Kong, Paul Lichtenstein, Joseph K. Pickrell, Philipp Koellinger, P. L. De Jager, Reedik Mägi, G. B. Chen, Neil Pendleton, B. V. Halldórsson, George Dedoussis, Antti-Pekka Sarin, Natalia Pervjakova, Veikko Salomaa, Simona Vaccargiu, Ozren Polasek, K. H. Jöckel, Elisabeth Steinhagen-Thiessen, Y. Milaneschi, Jessica D. Faul, Patricia A. Boyle, Patrik K. E. Magnusson, Igor Rudan, Christopher P. Nelson, Vilmundur Gudnason, John Attia, Jürgen Wellmann, Kristi Läll, Konstantin Strauch, Stuart J. Ritchie, Markus Perola, Nicola Pirastu, Klaus Bønnelykke, Robert Karlsson, R. de Vlaming, Liisa Keltigangas-Jarvinen, Thomas Meitinger, Riccardo E. Marioni, Anu Loukola, Barbera Franke, Reinhold Schmidt, Maël Lebreton, Sven Oskarsson, E. Mihailov, Harm-Jan Westra, David R. Weir, Aldi T. Kraja, Niek Verweij, Peter M. Visscher, Hans-Jörgen Grabe, Johannes H. Brandsma, Mark Adams, R. J. Scott, G. Thorleifsson, Tõnu Esko, Mika Kähönen, Saskia P. Hagenaars, Patrick Turley, Johannes Waage, Peter Lichtner, Dragana Vuckovic, Antonietta Robino, Henry Völzke, Lydia Quaye, C. de Leeuw, Marika Kaakinen, Wei Zhao, Abdel Abdellaoui, Reka Nagy, Pedro Marques-Vidal, Johan G. Eriksson, Alan F. Wright, Andres Metspalu, Lavinia Paternoster, Momoko Horikoshi, Jan A. Staessen, Tarunveer S. Ahluwalia, Tian Liu, Martin Kroh, Aldo Rustichini, Giorgia Girotto, Cristina Venturini, Lili Milani, Jennifer A. Smith, Ginevra Biino, Tessel E. Galesloot, Michael A. Horan, Gerardus A. Meddens, James F. Wilson, Francesco Cucca, Peter Vollenweider, Erika Salvi, P. J. van der Most, Jari Lahti, Campbell A, David Laibson, Andrew Bakshi, Wolfgang Hoffmann, Tomi Mäki-Opas, Andreas J. Forstner, C M van Duijn, Nicholas G. Martin, Jonathan Marten, Ute Bültmann, Olli T. Raitakari, David A. Bennett, A.G. Uitterlinden, J. E. De Neve, Ingrid B. Borecki, WD Hill, Bo Jacobsson, Antti Latvala, Katri Räikkönen, Michael B. Miller, Jonathan P. Beauchamp, S. J. van der Lee, Ilja Demuth, Stavroula Kanoni, Veronique Vitart, Elina Hyppönen, N. Eklund, Francesco P. Cappuccio, Robert F. Krueger, Maria Pina Concas, Jaime Derringer, F. J.A. Van Rooij, Helena Schmidt, Patrick J. F. Groenen, Valur Emilsson, Rico Rueedi, Aysu Okbay, Georg Homuth, Edith Hofer, W. E. R. Ollier, Hannah Campbell, Paolo Gasparini, Mark Alan Fontana, Magnus Johannesson, Seppo Koskinen, Christopher F. Chabris, Jouke-Jan Hottenga, Christine Meisinger, Kari Stefansson, Jun Ding, Tia Sorensen, Brenda W.J.H. Penninx, Michelle N. Meyer, James J. Lee, Diego Vozzi, Gonneke Willemsen, K. Petrovic, Sarah E. Medland, Mary F. Feitosa, Henning Tiemeier, L. J. Launer, William G. Iacono, Massimo Mangino, Tune H. Pers, S. E. Baumeister, Christopher Oldmeadow, Grant W. Montgomery, Marjo-Riitta Järvelin, Jaakko Kaprio, Catharine R. Gale, S.F.W. Meddens, Kevin Thom, Klaus Berger, Pablo V. Gejman, Lude Franke, Gyda Bjornsdottir, Daniel J. Benjamin, Steven F. Lehrer, Krista Fischer, Alan R. Sanders, S. Ulivi, Katharina E. Schraut, Tim D. Spector, Amy Hofman, Matt McGue, Terho Lehtimäki, D. C. Liewald, Hans Bisgaard, L. Eisele, Astanand Jugessur, George Davey Smith, T.B. Harris, A.R. Thurik, Cornelius A. Rietveld, David Schlessinger, Z. Kutalik, David J. Porteous, Lynne J. Hocking, N J Timpson, A. Palotie, Lambertus A. Kiemeney, Ian J. Deary, Sharon L.R. Kardia, Peter K. Joshi, Nilesh J. Samani, Michael A. Province, Börge Schmidt, Richa Gupta, Carmen Amador, Erin B. Ware, Joyce Y. Tung, Ioanna-Panagiota Kalafati, Lars Bertram, Caroline Hayward, P. van der Harst, Penelope A. Lind, Kadri Kaasik, N.A. Furlotte, Sarah E. Harris, B. St Pourcain, Susan M. Ring, Zhihong Zhu, Alexander Teumer, Behrooz Z. Alizadeh, Judith M. Vonk, Blair H. Smith, A Payton, Wouter J. Peyrot, Jacob Gratten, Douglas F. Levinson, C Gieger, Leanne M. Hall, Andrew Heath, Mario Pirastu, Peter Eibich, Nancy L. Pedersen, Ronny Myhre, Antonio Terracciano, David M. Evans, Raymond A. Poot, Uwe Völker, Dorret I. Boomsma, Clemens Baumbach, Unnur Thorsteinsdottir, Ivana Kolcic, Jia-Shu Yang, Dalton Conley, A. A. Vinkhuyzen, Danielle Posthuma, Karl-Oskar Lindgren, Olga Rostapshova, Jonas Bacelis, Daniele Cusi, Yong Qian, Bjarni Gunnarsson, George McMahon, Elizabeth G. Holliday, Pamela A. F. Madden, David A. Hinds, David Cesarini, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Applied Economics, Epidemiology, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Aletta Jacobs School of Public Health, Public Health Research (PHR), Stem Cell Aging Leukemia and Lymphoma (SALL), Cardiovascular Centre (CVC), Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, EMGO - Mental health, Complex Trait Genetics, Biological Psychology, Marioni, RE, Ritchie, SJ, Joshi, PK, Hagenaars, SP, Hypponen, E, Benjamin, DJ, Social Science Genetic Association Consortium, Marioni, Re, Ritchie, Sj, Joshi, Pk, Hagenaars, Sp, Okbay, A, Fischer, K, Adams, Mj, Hill, Wd, Davies, G, Nagy, R, Amador, C, Läll, K, Metspalu, A, Liewald, Dc, Campbell, A, Wilson, Jf, Hayward, C, Esko, T, Porteous, Dj, Gale, Cr, Deary, Ij, Beauchamp, Jp, Fontana, Ma, Lee, Jj, Pers, Th, Rietveld, Ca, Turley, P, Chen, Gb, Emilsson, V, Meddens, Sf, Oskarsson, S, Pickrell, Jk, Thom, K, Timshel, P, de Vlaming, R, Abdellaoui, A, Ahluwalia, T, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, Jh, Concas, MARIA PINA, Derringer, J, Furlotte, Na, Galesloot, Te, Girotto, Giorgia, Gupta, R, Hall, Lm, Harris, Se, Hofer, E, Horikoshi, M, Huffman, Je, Kaasik, K, Kalafati, Ip, Karlsson, R, Kong, A, Lahti, J, van der Lee, Sj, de Leeuw, C, Lind, Pa, Lindgren, Ko, Liu, T, Mangino, M, Marten, J, Mihailov, E, Miller, Mb, van der Most, Pj, Oldmeadow, C, Payton, A, Pervjakova, N, Peyrot, Wj, Qian, Y, Raitakari, O, Rueedi, R, Salvi, E, Schmidt, B, Schraut, Ke, Shi, J, Smith, Av, Poot, Ra, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N, Vuckovic, Dragana, Wellmann, J, Westra, Hj, Yang, J, Zhao, W, Zhu, Z, Alizadeh, Bz, Amin, N, Bakshi, A, Baumeister, Se, Biino, G, Bønnelykke, K, Boyle, Pa, Campbell, H, Cappuccio, Fp, De Neve, Je, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, Dm, Faul, Jd, Feitosa, Mf, Forstner, Aj, Gandin, Ilaria, Gunnarsson, B, Halldórsson, Bv, Harris, Tb, Heath, Ac, Hocking, Lj, Holliday, Eg, Homuth, G, Horan, Ma, Hottenga, Jj, de Jager, Pl, Jugessur, A, Kaakinen, Ma, Kähönen, M, Kanoni, S, Keltigangas Järvinen, L, Kiemeney, La, Kolcic, I, Koskinen, S, Kraja, At, Kroh, M, Kutalik, Z, Latvala, A, Launer, Lj, Lebreton, Mp, Levinson, Df, Lichtenstein, P, Lichtner, P, Loukola, A, Madden, Pa, Mägi, R, Mäki Opas, T, Marques Vidal, P, Meddens, Ga, Mcmahon, G, Meisinger, C, Meitinger, T, Milaneschi, Y, Milani, L, Montgomery, Gw, Myhre, R, Nelson, Cp, Nyholt, Dr, Ollier, We, Palotie, A, Paternoster, L, Pedersen, Nl, Petrovic, Ke, Räikkönen, K, Ring, Sm, Robino, Antonietta, Rostapshova, O, Rudan, I, Rustichini, A, Salomaa, V, Sanders, Ar, Sarin, Ap, Schmidt, H, Scott, Rj, Smith, Bh, Smith, Ja, Staessen, Ja, Steinhagen Thiessen, E, Strauch, K, Terracciano, A, Tobin, Md, Ulivi, Sheila, Vaccargiu, S, Quaye, L, van Rooij, Fj, Venturini, C, Vinkhuyzen, Aa, Völker, U, Völzke, H, Vonk, Jm, Vozzi, Diego, Waage, J, Ware, Eb, Willemsen, G, Attia, Jr, Bennett, Da, Berger, K, Bertram, L, Bisgaard, H, Boomsma, Di, Borecki, Ib, Bultmann, U, Chabris, Cf, Cucca, F, Cusi, D, Dedoussis, Gv, van Duijn, Cm, Eriksson, Jg, Franke, B, Franke, L, Gasparini, Paolo, Gejman, Pv, Gieger, C, Grabe, Hj, Gratten, J, Groenen, Pj, Gudnason, V, van der Harst, P, Hinds, Da, Hoffmann, W, Iacono, Wg, Jacobsson, B, Järvelin, Mr, Jöckel, Kh, Kaprio, J, Kardia, Sl, Lehtimäki, T, Lehrer, Sf, Magnusson, Pk, Martin, Ng, Mcgue, M, Pendleton, N, Penninx, Bw, Perola, M, Pirastu, Nicola, Pirastu, M, Polasek, O, Posthuma, D, Power, C, Province, Ma, Samani, Nj, Schlessinger, D, Schmidt, R, Sørensen, Ti, Spector, Td, Stefansson, K, Thorsteinsdottir, U, Thurik, Ar, Timpson, Nj, Tiemeier, H, Tung, Jy, Uitterlinden, Ag, Vitart, V, Vollenweider, P, Weir, Dr, Wright, Af, Conley, Dc, Krueger, Rf, Smith, Gd, Hofman, A, Laibson, Di, Medland, Se, Meyer, Mn, Johannesson, M, Visscher, Pm, Koellinger, Pd, Cesarini, D, and Benjamin, Dj

Subjects
Netherlands Twin Register (NTR), 0301 basic medicine, Male, Parents, education: longevity: prediction: polygenic score [genetics], Multifactorial Inheritance, polygenic, Lebenserwartung, Cohort Studies, 0302 clinical medicine, Databases, Genetic, Medicine, genetics, polygenic score, longevity, education, gene, Soziales und Gesundheit, media_common, Aged, 80 and over, education, Multidisciplinary, Longevity, Middle Aged, Biobank, humanities, 3. Good health, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Cohort, Educational Status, Female, Cohort study, Estonia, education, longevity, polygenic, Offspring, media_common.quotation_subject, Kultursektor, Prognose, Lernen, Lower risk, Education, 03 medical and health sciences, longevity, SDG 3 - Good Health and Well-being, Commentaries, Polygenic score, Journal Article, Genetics, Humans, Non-Profit-Sektor, Genetic Association Studies, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, ta1184, Genetic Variation, prediction, Educational attainment, United Kingdom, Gesundheitsstatistik, 030104 developmental biology, Genetic epidemiology, Scotland, Gesundheitszustand, Genetische Forschung, business, Prediction, Bildung, 030217 neurology & neurosurgery, Demography
Abstract

Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total n deaths = 79,702) and ∼2.4% lower risk for fathers (total n deaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity. Marioni RE, Ritchie SJ, Joshi PK, Hagenaars SP, Okbay A, Fischer K, Adams MJ, Hill WD, Davies G, Social Science Genetic Association Consortium, Nagy R, Amador C, Läll K, Metspalu A, Liewald DC, Campbell A, Wilson JF, Hayward C, Esko T, Porteous DJ, Proceedings of the National Academy of Sciences of the United States of America, 2016, vol. 113, no. 47, pp. 13366-13371, 2016 Refereed/Peer-reviewed

Published
2016

9. Genome-wide associations for birth weight and correlations with adult disease

Author

Anubha Mahajan, George McMahon, Charlotta Pisinger, Timothy M. Frayling, Elisabeth M. van Leeuwen, Felix R. Day, Virpi Lindi, Allan Vaag, Debbie A Lawlor, Natalie R. van Zuydam, Peter Kovacs, David Torrents, Bjarke Feenstra, Peter Vollenweider, David P. Strachan, Krina T. Zondervan, John R. B. Perry, Jorma Viikari, Pedro Marques-Vidal, Kalliope Panoutsopoulou, Ruifang Li-Gao, Juan Fernández-Tajes, Carolina Medina-Gomez, Nicole M. Warrington, Josep M. Mercader, Antje Körner, David M. Evans, Albert Hofman, Hans Bisgaard, Amanda J. Bennett, Eleanor Davies, Linda S. Adair, Oluf Pedersen, Mustafa Atalay, Sylvain Sebert, Ying Wu, Haja N. Kadarmideen, Ronald C.W. Ma, Lawrence J. Beilin, David M. Hougaard, Diana L. Cousminer, Louise A. Diver, Jing Hua Zhao, Nilufer Rahmioglu, Peter K. Joshi, Neil R. Robertson, Johannes Waage, Hugoline G. de Haan, Jens-Christian Holm, Dale R. Nyholt, Torben Hansen, Sara M. Willems, Sílvia Bonàs-Guarch, Carol A. Wang, Rico Rueedi, Lavinia Paternoster, James F. Wilson, Cilius Esmann Fonvig, Leo-Pekka Lyytikäinen, Hanieh Yaghootkar, Momoko Horikoshi, Gonneke Willemsen, Dennis O. Mook-Kanamori, Lisbeth Carstensen, Mariona Bustamante, Emil V. R. Appel, Christian Theil Have, Rebecca M. Reynolds, Niels Grarup, Seang-Mei Saw, Yik Ying Teo, Brian R. Walker, Anke Tönjes, Christopher J. Groves, Andrew P. Morris, Katja Pahkala, Marjolein N. Kooijman, Kyle J. Gaulton, Eskil Kreiner, Michael Stumvoll, Eleftheria Zeggini, Vincent W. V. Jaddoe, Zoltán Kutalik, Scott M. MacKenzie, George Davey Smith, Christine Power, Denise M. Scholtens, Joachim Heinrich, Samuel E. Jones, William L. Lowe, Eco J. C. de Geus, Jonathan P. Bradfield, Andrew T. Hattersley, Janine F. Felix, Wing Hung Tam, Frits R. Rosendaal, Wieland Kiess, Claudia H. T. Tam, Inga Prokopenko, Terho Lehtimäki, Frank D. Mentch, Marjo-Riitta Järvelin, Struan F.A. Grant, Santhi K. Ganesh, Fernando Rivadeneira, Thorkild I. A. Sørensen, André G. Uitterlinden, Marie Standl, Jian'an Luan, Gibran Hemani, Marcus A. Tuke, Andrew R. Wood, Robert A. Scott, Cæcilie Trier, Tarunveer S. Ahluwalia, Michael Nodzenski, Jouke-Jan Hottenga, Ken K. Ong, Po-Ru Loh, Nicholas J. Timpson, George Dedoussis, Friman Sánchez, Mark I. McCarthy, Frank Geller, Harri Niinikoski, Martine Vrijheid, Hakon Hakonarson, John P. Newnham, Xu Wang, Elina Hyppönen, Johan G. Eriksson, Craig E. Pennell, Niina Pitkänen, Rachel M. Freathy, Elisabeth Widen, Judith B. Borja, Karen L. Mohlke, Mads Melbye, Carla M. T. Tiesler, Susan M. Ring, Jessica Tyrrell, Elisabeth Thiering, Timo A. Lakka, Eileen Tai-Hui Boh, Olli T. Raitakari, Nicholas J. Wareham, Mario Murcia, Natalia Vilor-Tejedor, Katherine S. Ruth, Dorret I. Boomsma, Harry Campbell, Vasiliki Lagou, Robin N Beaumont, Klaus Bønnelykke, Claudia Langenberg, Catharina E. M. van Beijsterveldt, Mika Kähönen, Mads V. Hollegaard, Frank J.A. van Rooij, Katharina E. Schraut, Ioanna Ntalla, Raimo Joro, Cornelia M. van Duijn, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Day, Felix [0000-0003-3789-7651], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Wareham, Nicholas [0000-0003-1422-2993], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Erasmus MC other, Medical Microbiology & Infectious Diseases, Epidemiology, Medical Oncology, Child and Adolescent Psychiatry / Psychology, Public Health, Internal Medicine, Pediatrics, Horikoshi, Momoko, Beaumont, Robin N, Day, Felix R, Warrington, Nicole, Hyppönen, Elina, and Freathy, Rachel M

Subjects
Male, 0301 basic medicine, Netherlands Twin Register (NTR), Aging, Datasets as Topic, Physiology, Blood Pressure, Genome-wide association study, Coronary Artery Disease, Type 2 diabetes, Bioinformatics, CHARGE Consortium Hematology Working Group, Cohort Studies, 0302 clinical medicine, Birth Weight, Insulin, Glucose homeostasis, 030212 general & internal medicine, education.field_of_study, Multidisciplinary, Anthropometry, 3. Good health, Phenotype, Female, Glycogen, Signal Transduction, Adult, hypertension, Genotype, General Science & Technology, Birth weight, intrauterine growth, Population, Quantitative trait locus, Biology, Article, quantitative trait, Genomic Imprinting, 03 medical and health sciences, Fetus, SDG 3 - Good Health and Well-being, Early Growth Genetics (EGG) Consortium, MD Multidisciplinary, Genetic variation, medicine, Humans, metabolic disorders, Genetic Predisposition to Disease, education, genome, Genetic association, Genetic Variation, birth weight, ta3121, Chromatin Assembly and Disassembly, medicine.disease, ta3123, Glucose, 030104 developmental biology, Diabetes Mellitus, Type 2, Genetic Loci, genome-wide association studies, adult disease, Genome-Wide Association Study
Abstract

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P&thinsp

Published
2016

10. Using Genetic Variation to Explore the Causal Effect of Maternal Pregnancy Adiposity on Future Offspring Adiposity: A Mendelian Randomisation Study

Author

Rebecca C, Richmond, Nicholas J, Timpson, Janine F, Felix, Tom, Palmer, Romy, Gaillard, George, McMahon, George, Davey Smith, Vincent W, Jaddoe, and Debbie A, Lawlor

Subjects
Male, Adolescent, Physiology, Maternal Health, Research and Analysis Methods, Biochemistry, Body Mass Index, Fats, Absorptiometry, Photon, Mathematical and Statistical Techniques, Pregnancy, Medicine and Health Sciences, Genetics, Genome-Wide Association Studies, Humans, Longitudinal Studies, Obesity, Statistical Methods, Child, Alleles, Adiposity, Body Weight, Genetic Variation, Obstetrics and Gynecology, Biology and Life Sciences, Computational Biology, Human Genetics, Genomics, Mendelian Randomization Analysis, Genome Analysis, Lipids, England, Physiological Parameters, Genetic Loci, Multivariate Analysis, Physical Sciences, Regression Analysis, Women's Health, Female, Mathematics, Statistics (Mathematics), Research Article, Meta-Analysis
Abstract

Background It has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to early adulthood. Methods and Findings We used maternal genetic variants as instrumental variables (IVs) to test the causal effect of maternal BMI in pregnancy on offspring fatness (BMI and dual-energy X-ray absorptiometry [DXA] determined fat mass index [FMI]) in a MR approach. This was investigated, with repeat measurements, from ages 7 to 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2,521 to 3,720 for different ages). We then sought to replicate findings with results for BMI at age 6 in Generation R (n = 2,337 for replication sample; n = 6,057 for total pooled sample). In confounder-adjusted multivariable regression in ALSPAC, a 1 standard deviation (SD, equivalent of 3.7 kg/m2) increase in maternal BMI was associated with a 0.25 SD (95% CI 0.21–0.29) increase in offspring BMI at age 7, with similar results at later ages and when FMI was used as the outcome. A weighted genetic risk score was generated from 32 genetic variants robustly associated with BMI (minimum F-statistic = 45 in ALSPAC). The MR results using this genetic risk score as an IV in ALSPAC were close to the null at all ages (e.g., 0.04 SD (95% CI -0.21–0.30) at age 7 and 0.03 SD (95% CI -0.26–0.32) at age 18 per SD increase in maternal BMI), which was similar when a 97 variant generic risk score was used in ALSPAC. When findings from age 7 in ALSPAC were meta-analysed with those from age 6 in Generation R, the pooled confounder-adjusted multivariable regression association was 0.22 SD (95% CI 0.19–0.25) per SD increase in maternal BMI and the pooled MR effect (pooling the 97 variant score results from ALSPAC with the 32 variant score results from Generation R) was 0.05 SD (95%CI -0.11–0.21) per SD increase in maternal BMI (p-value for difference between the two results = 0.05). A number of sensitivity analyses exploring violation of the MR results supported our main findings. However, power was limited for some of the sensitivity tests and further studies with relevant data on maternal, offspring, and paternal genotype are required to obtain more precise (and unbiased) causal estimates. Conclusions Our findings provide little evidence to support a strong causal intrauterine effect of incrementally greater maternal BMI resulting in greater offspring adiposity., Using a Mendelian randomization approach, Rebecca Richmond and colleagues find limited evidence for a causal effect of maternal pregnancy adiposity on future offspring adiposity during childhood and adolescence., Author Summary Why Was This Study Done? Being overweight or obese in pregnancy causes babies to be born larger. Whether these babies go into childhood and adolescence more overweight as a result of their mothers being overweight in pregnancy has not been fully established. We wanted to investigate whether genetically elevated body mass index (BMI) of mothers in pregnancy was causally associated with higher levels of fatness in their offspring in childhood and adolescence, over and above the association expected given genetic transmission of BMI-associated variants. What Did the Researchers Do and Find? We used information on 6,057 mother–child pairs from two prospective birth cohort studies, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Generation R study to assess this. Our findings provide little evidence to support the long-term impact of maternal BMI in pregnancy on the child’s risk of fatness in childhood and adolescence. Rather, most of the association between a mother’s BMI in pregnancy and her child’s fatness is explained by genetic transmission of BMI-associated variants. What Do These Findings Mean? These findings suggest that public health interventions directed at all family members and at different stages of the life course are likely to be important and are potentially more likely to halt the obesity epidemic than a focus on maternal overweight and obesity status in pregnancy. Although we found no large effects of being overweight or obese in pregnancy on offspring’s risk of fatness in later life, further studies with relevant data are required to determine whether there might be smaller effects that our study was unable to detect.

Published
2016

11. Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

Author

Diane J. Berry, Bjarke Feenstra, Verena Sengpiel, Bo Jacobsson, Frank Geller, Ronny Myhre, Andrew P. Morris, Rachel M. Freathy, Timothy M. Frayling, Ville Huikari, Shikta Das, Bridget A. Knight, Eskil Kreiner-Møller, Penelope A. Lind, Lavinia Paternoster, Nicholas G. Martin, Marie-France Hivert, Jodie N. Painter, Janine F. Felix, Mads Melbye, Eco J. C. de Geus, Sylvain Sebert, Gonneke Willemsen, Susan M. Ring, Thorkild I. A. Sørensen, Janani Rangarajan, Debbie A Lawlor, Alana Cavadino, N. Maneka G. De Silva, Jessica Tyrrell, Luigi Bouchard, Mark I. McCarthy, Momoko Horikoshi, Denise M. Scholtens, Ellen A. Nohr, Jani Heikkinen, Sarah E. Medland, Vincent W. V. Jaddoe, Rebecca C Richmond, Hakon Hakonarson, Jouke-Jan Hottenga, Michael Nodzenski, Jonathan P. Bradfield, Loren L. Armstrong, M. Geoffrey Hayes, David M. Evans, Marjo-Riitta Järvelin, Catherine Allard, Struan F.A. Grant, George Davey Smith, Christine Power, Albert Hofman, George McMahon, Andrew T. Hattersley, Hans Bisgaard, Sarah Metrustry, Andrew R. Wood, Tom Palmer, Berthold Hocher, William L. Lowe, Christoph Reichetzeder, Elina Hyppönen, Jeff Murray, Tim D. Spector, Erasmus MC other, Epidemiology, Pediatrics, Tyrrell, Jessica, Richmond, Rebecca C, Palmer, Tom M, Feenstra, Bjarke, Hypponen, Elina, Freathy, Rachel M, Early Growth Genetics (EGG) Consortium, Biological Psychology, and EMGO+ - Lifestyle, Overweight and Diabetes

Subjects
Blood Glucose, Physiology, BLOOD-PRESSURE, Blood Pressure, VITAMIN-D STATUS, Type 2 diabetes, Overweight, Body Mass Index, 0302 clinical medicine, Pregnancy, Birth Weight, Medicine, Mass index, 030212 general & internal medicine, 2. Zero hunger, INSULIN-RESISTANCE, education.field_of_study, Research Support, Non-U.S. Gov't, Obstetrics and Gynecology, GESTATIONAL DIABETES-MELLITUS, 11 Medical And Health Sciences, Fasting, General Medicine, 3. Good health, PREGNANCY OUTCOME HAPO, MENDELIAN RANDOMIZATION, Female, medicine.symptom, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, Genotype, Offspring, Birth weight, European Continental Ancestry Group, Population, 030209 endocrinology & metabolism, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Medicine, General & Internal, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Early Growth Genetics (EGG) Consortium, General & Internal Medicine, Internal medicine, Mendelian randomization, Journal Article, Humans, Obesity, GENOME-WIDE ASSOCIATION, education, Triglycerides, Science & Technology, business.industry, Infant, Newborn, Mendelian Randomization Analysis, medicine.disease, BODY-MASS INDEX, Endocrinology, Diabetes Mellitus, Type 2, COHORT PROFILE, FETAL-GROWTH, business, Body mass index
Abstract

ImportanceNeonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.ObjectiveTo test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.Design, Setting, and ParticipantsMendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30 487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.ExposuresGenetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.Main Outcome and MeasureOffspring birth weight from 18 studies.ResultsAmong the 30 487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10−14) and −4 g (95% CI, −6 to −2g) per SBP-raising allele (P = 1×10−5), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, −394 to −21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.Conclusions and RelevanceIn this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Published
2016

12. Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Author

Ozren Polasek, Bo Jacobsson, Eleonora Porcu, Vinicius Tragante, Joel Eriksson, Jie Yao, Mika Kähönen, Mark Alan Fontana, Stefania Cappellani, J. Viikari, Rick Jansen, Crysovalanto Mamasoula, Linda Broer, Tamara B. Harris, Ellen A. Nohr, Genevieve Lachance, Johan G. Eriksson, Nicholas Eriksson, Rico Rueedi, Francesco Cucca, Jaakko Kaprio, Nicholas J. Timpson, George Dedoussis, Matt McGue, Per Magnus, Klaus Berger, Olli T. Raitakari, Cornelia M. van Duijn, Brenda W.J.H. Penninx, Jing Hua Zhao, Peter Eibich, Sheila Ulivi, Hugoline G. de Haan, Ronny Myhre, Ruth McQuillan, Florian Kronenberg, Markus Perola, Klaus Bønnelykke, Robert Karlsson, Martina La Bianca, Paul Mitchell, Ian J. Deary, Melinda Mills, Teresa Nutile, Patrick J. F. Groenen, Stacey A. Missmer, Nicholas G. Martin, Panos Deloukas, Mario Pirastu, Lindsay K. Matteson, Robert Luben, Veikko Salomaa, Renée de Mutsert, Chris Power, Nir Barzilai, Annette Kifley, Hamdi Mbarek, Denis A. Evans, Erica P. Gunderson, Tim D. Spector, Anke Tönjes, Michela Traglia, Claire Monnereau, Karin Halina Greiser, Sharon L.R. Kardia, John M. Starr, Peter K. Joshi, Sandra Lai, Doris Stöckl, James J. Lee, Heather J. Cordell, Andrew Bakshi, Nicholas J. Wareham, David C. Liewald, P Koponen, Paul M. Ridker, Joyce Y. Tung, Ilaria Gandin, Kauko Heikkilä, Johannes Haerting, Gonneke Willemsen, Janet W. Rich-Edwards, Andrew C. Heath, Astanand Jugessur, John L. Hopper, Stefan Kiechl, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Dan Mellström, Simon R. Cox, Yasaman Saba, Magnus Johannesson, Ginevra Biino, David Schlessinger, Kirsi Auro, Dennis O. Mook-Kanamori, Christa Meisinger, Igor Rudan, Audrey J. Gaskins, Lars Bertram, Roy Thurik, Laura M. Yerges-Armstrong, Caterina Barbieri, Katri Räikkönen, Lawrence F. Bielak, Aviv Bergman, Philipp Koellinger, Ronald de Vlaming, Tian Liu, Johannes W. A. Smit, Peter Kovacs, Vincent W. V. Jaddoe, Jennifer A. Smith, Sven Bergmann, Inga Prokopenko, Xiuqing Guo, Marina Ciullo, Krina T. Zondervan, Marcel den Hoed, Daniel J. Benjamin, Kathryn Roll, Alan F. Wright, Helena Schmidt, William G. Iacono, Jie Jin Wang, Harold Snieder, Juho Wedenoja, Tarunveer S. Ahluwalia, David R. Weir, Ken K. Ong, Daniela Toniolo, Ruifang Li-Gao, Evelin Mihailov, Edith Hofer, Leslie J. Raffel, Daniel I. Chasman, Alexander Kluttig, Bernard Keavney, Eco J. C. de Geus, Kathleen A. Ryan, Kristin L. Ayers, Lude Franke, S. Fleur W. Meddens, Alison Pattie, Jornt J. Mandemakers, Eva Albrecht, David Cesarini, Beverley Balkau, Grant W. Montgomery, Michael Stumvoll, Ahmad Vaez, Michael B. Miller, Najaf Amin, Gyda Bjornsdottir, Cecile Lecoeur, Enes Makalic, Marc Jan Bonder, Terho Lehtimäki, Albert Hofman, Loic Yengo, Lynda M. Rose, Lisette Stolk, Juergen Wellmann, Gail Davies, Eero Kajantie, Nicole Schupf, Hans Bisgaard, Unnur Thorsteinsdottir, Konstantin Strauch, Ivana Kolcic, Lili Milani, Chunyan He, Claes Ohlsson, Yongmei Liu, Gil Atzmon, Janine F. Felix, Christian Gieger, Mike A. Nalls, Riitta Luoto, Nicola Barban, Philippe Froguel, Daniel F. Schmidt, Dorret I. Boomsma, Harry Campbell, Xia Shen, Vasiliki Lagou, Danny Ben-Avraham, Veronique Vitart, Ioanna P. Kalafati, Kari Stefansson, Daria V. Zhernakova, Constance Turman, Julie E. Buring, Johannes Waage, James F. Wilson, Maria Pina Concas, Zoltán Kutalik, Peter Willeit, Jørn Olsen, Dan Rujescu, Caroline Hayward, Penelope A. Lind, George McMahon, Elizabeth G. Holliday, Ilja M. Nolte, Fahimeh Falahi, Minh Bui, Gudmar Thorleifsson, Patrick F. McArdle, Cinzia Sala, Alana Cavadino, Rossella Sorice, Wei Zhao, Andres Metspalu, Sander W. van der Laan, Stavroula Kanoni, Elina Hyppönen, Morris A. Swertz, Simona Vaccargiu, Felix C. Tropf, Michael Lucht, Susan M. Ring, Elizabeth A. Streeten, Reinhold Schmidt, Augustine Kong, Johann Willeit, Patricia A. Peyser, Jessica D. Faul, Patrik K. E. Magnusson, Tõnu Esko, Antonietta Robino, Lavinia Paternoster, Peter J. van der Most, Kumar B. Rajan, George Davey-Smith, Dragana Vuckovic, Hans J. Grabe, Jari Lahti, Giorgia Girotto, Jorge E. Chavarro, Robert F. Krueger, Hongyan Huang, Georg Homuth, Paolo Gasparini, Sarah E. Medland, Gert G. Wagner, Peter Kraft, André G. Uitterlinden, Cornelius A. Rietveld, Howard Andrews, Cecilia M. Lindgren, Peter Vollenweider, Perry, John [0000-0001-6483-3771], Zhao, Jing Hua [0000-0003-4930-3582], Luben, Robert [0000-0002-5088-6343], Ong, Kenneth [0000-0003-4689-7530], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, BARBAN N, Rick Jansen, Ronald de Vlaming, Ahmad Vaez, Jornt J Mandemaker, Felix C Tropf, Xia Shen, James F Wilson, Daniel I Chasman, Ilja M Nolte, Vinicius Tragante, Sander W van der Laan, John R B Perry, Augustine Kong, BIOS Consortium, Tarunveer S Ahluwalia, Eva Albrecht, Laura Yerges-Armstrong, Gil Atzmon, Kirsi Auro, Kristin Ayer, Andrew Bakshi, Danny Ben-Avraham, Klaus Berger, Aviv Bergman, Lars Bertram, Lawrence F Bielak, Gyda Bjornsdottir, Marc Jan Bonder, Linda Broer, Minh Bui, Caterina Barbieri, Alana Cavadino, Jorge E Chavarro, Constance Turman, Maria Pina Conca, Heather J Cordell, Gail Davie, Peter Eibich, Nicholas Eriksson, Tõnu Esko, Joel Eriksson, Fahimeh Falahi, Janine F Felix, Mark Alan Fontana, Lude Franke, Ilaria Gandin, Audrey J Gaskin, Christian Gieger, Erica P Gunderson, Xiuqing Guo, Caroline Hayward, Chunyan He, Edith Hofer, Hongyan Huang, Peter K Joshi, Stavroula Kanoni, Robert Karlsson, Stefan Kiechl, Annette Kifley, Alexander Kluttig, Peter Kraft, Vasiliki Lagou, Cecile Lecoeur, Jari Lahti, Ruifang Li-Gao, Penelope A Lind, Tian Liu, Enes Makalic, Crysovalanto Mamasoula, Lindsay Matteson, Hamdi Mbarek, Patrick F McArdle, George McMahon, S Fleur W Medden, Evelin Mihailov, Mike Miller, Stacey A Missmer, Claire Monnereau, Peter J van der Most, Ronny Myhre, Mike A Nall, Teresa Nutile, Ioanna Panagiota Kalafati, Eleonora Porcu, Inga Prokopenko, Kumar B Rajan, Janet Rich-Edward, Cornelius A Rietveld, Antonietta Robino, Lynda M Rose, Rico Rueedi, Kathleen A Ryan, Yasaman Saba, Daniel Schmidt, Jennifer A Smith, Lisette Stolk, Elizabeth Streeten, Anke Tönje, Gudmar Thorleifsson, Sheila Ulivi, Juho Wedenoja, Juergen Wellmann, Peter Willeit, Jie Yao, Loic Yengo, Jing Hua Zhao, Wei Zhao, Daria V Zhernakova, Najaf Amin, Howard Andrew, Beverley Balkau, Nir Barzilai, Sven Bergmann, Ginevra Biino, Hans Bisgaard, Klaus Bønnelykke, Dorret I Boomsma, Julie E Buring, Harry Campbell, Stefania Cappellani, Marina Ciullo, Simon R Cox, Francesco Cucca, Daniela Toniolo, George Davey-Smith, Ian J Deary, George Dedoussi, Panos Delouka, Cornelia M van Duijn, Eco J C de Geu, Johan G Eriksson, Denis A Evan, Jessica D Faul, Cinzia Felicita Sala, Philippe Froguel, Paolo Gasparini, Giorgia Girotto, Hans-Jörgen Grabe, Karin Halina Greiser, Patrick J F Groenen, Hugoline G de Haan, Johannes Haerting, Tamara B Harri, Andrew C Heath, Kauko Heikkilä, Albert Hofman, Georg Homuth, Elizabeth G Holliday, John Hopper, Elina Hyppönen, Bo Jacobsson, Vincent W V Jaddoe, Magnus Johannesson, Astanand Jugessur, Mika Kähönen, Eero Kajantie, Sharon L R Kardia, Bernard Keavney, Ivana Kolcic, Päivikki Koponen, Peter Kovac, Florian Kronenberg, Zoltan Kutalik, Martina La Bianca, Genevieve Lachance, William G Iacono, Sandra Lai, Terho Lehtimäki, David C Liewald, LifeLines Cohort Study, Cecilia M Lindgren, Yongmei Liu, Robert Luben, Michael Lucht, Riitta Luoto, Per Magnu, Patrik K E Magnusson, Nicholas G Martin, Matt McGue, Ruth McQuillan, Sarah E Medland, Christa Meisinger, Dan Mellström, Andres Metspalu, Michela Traglia, Lili Milani, Paul Mitchell, Grant W Montgomery, Dennis Mook-Kanamori, Renée de Mutsert, Ellen A Nohr, Claes Ohlsson, Jørn Olsen, Ken K Ong, Lavinia Paternoster, Alison Pattie, Brenda W J H Penninx, Markus Perola, Patricia A Peyser, Mario Pirastu, Ozren Polasek, Chris Power, Jaakko Kaprio, Leslie J Raffel, Katri Räikkönen, Olli Raitakari, Paul M Ridker, Susan M Ring, Kathryn Roll, Igor Rudan, Daniela Ruggiero, Dan Rujescu, Veikko Salomaa, David Schlessinger, Helena Schmidt, Reinhold Schmidt, Nicole Schupf, Johannes Smit, Rossella Sorice, Tim D Spector, John M Starr, Doris Stöckl, Konstantin Strauch, Michael Stumvoll, Morris A Swertz, Unnur Thorsteinsdottir, A Roy Thurik, Nicholas J Timpson, Joyce Y Tung, André G Uitterlinden, Simona Vaccargiu, Jorma Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Dragana Vuckovic, Johannes Waage, Gert G Wagner, Jie Jin Wang, Nicholas J Wareham, David R Weir, Gonneke Willemsen, Johann Willeit, Alan F Wright, Krina T Zondervan, Kari Stefansson, Robert F Krueger, James J Lee, Daniel J Benjamin, David Cesarini, Philipp D Koellinger, Marcel den Hoed, Harold Snieder & Melinda C Mills, Barban, N, Jansen, R, de Vlaming, R, Vaez, A, Mandemakers, Jj, Tropf, Fc, Shen, X, Wilson, Jf, Chasman, Di, Nolte, Im, Tragante, V, van der Laan, Sw, Perry, Jr, Kong, A, Ahluwalia, T, Albrecht, E, Yerges Armstrong, L, Atzmon, G, Auro, K, Ayers, K, Bakshi, A, Ben Avraham, D, Berger, K, Bergman, A, Bertram, L, Bielak, Lf, Bjornsdottir, G, Bonder, Mj, Broer, L, Bui, M, Barbieri, CATERINA MARIA, Cavadino, A, Chavarro, Je, Turman, C, Concas, MARIA PINA, Cordell, Hj, Davies, G, Eibich, P, Eriksson, N, Esko, T, Eriksson, J, Falahi, F, Felix, Jf, Fontana, Ma, Franke, L, Gandin, Ilaria, Gaskins, Aj, Gieger, C, Gunderson, Ep, Guo, X, Hayward, C, He, C, Hofer, E, Huang, H, Joshi, Pk, Kanoni, S, Karlsson, R, Kiechl, S, Kifley, A, Kluttig, A, Kraft, P, Lagou, V, Lecoeur, C, Lahti, J, Li Gao, R, Lind, Pa, Liu, T, Makalic, E, Mamasoula, C, Matteson, L, Mbarek, H, Mcardle, Pf, Mcmahon, G, Meddens, Sf, Mihailov, E, Miller, M, Missmer, Sa, Monnereau, C, van der Most, Pj, Myhre, R, Nalls, Ma, Nutile, T, Kalafati, Ip, Porcu, E, Prokopenko, I, Rajan, Kb, Rich Edwards, J, Rietveld, Ca, Robino, Antonietta, Rose, Lm, Rueedi, R, Ryan, Ka, Saba, Y, Schmidt, D, Smith, Ja, Stolk, L, Streeten, E, Tönjes, A, Thorleifsson, G, Ulivi, Sheila, Wedenoja, J, Wellmann, J, Willeit, P, Yao, J, Yengo, L, Zhao, Jh, Zhao, W, Zhernakova, Dv, Amin, N, Andrews, H, Balkau, B, Barzilai, N, Bergmann, S, Biino, G, Bisgaard, H, Bønnelykke, K, Boomsma, Di, Buring, Je, Campbell, H, Cappellani, Stefania, Ciullo, M, Cox, Sr, Cucca, F, Toniolo, D, Davey Smith, G, Deary, Ij, Dedoussis, G, Deloukas, P, van Duijn, Cm, de Geus, Ej, Eriksson, Jg, Evans, Da, Faul, Jd, Sala, Cf, Froguel, P, Gasparini, Paolo, Girotto, Giorgia, Grabe, Hj, Greiser, Kh, Groenen, Pj, de Haan, Hg, Haerting, J, Harris, Tb, Heath, Ac, Heikkilä, K, Hofman, A, Homuth, G, Holliday, Eg, Hopper, J, Hyppönen, E, Jacobsson, B, Jaddoe, Vw, Johannesson, M, Jugessur, A, Kähönen, M, Kajantie, E, Kardia, Sl, Keavney, B, Kolcic, I, Koponen, P, Kovacs, P, Kronenberg, F, Kutalik, Z, LA BIANCA, Martina, Lachance, G, Iacono, Wg, Lai, S, Lehtimäki, T, Liewald, Dc, Lindgren, Cm, Liu, Y, Luben, R, Lucht, M, Luoto, R, Magnus, P, Magnusson, Pk, Martin, Ng, Mcgue, M, Mcquillan, R, Medland, Se, Meisinger, C, Mellström, D, Metspalu, A, Traglia, Michela, Milani, L, Mitchell, P, Montgomery, Gw, Mook Kanamori, D, de Mutsert, R, Nohr, Ea, Ohlsson, C, Olsen, J, Ong, Kk, Paternoster, L, Pattie, A, Penninx, Bw, Perola, M, Peyser, Pa, Pirastu, M, Polasek, O, Power, C, Kaprio, J, Raffel, Lj, Räikkönen, K, Raitakari, O, Ridker, Pm, Ring, Sm, Roll, K, Rudan, I, Ruggiero, D, Rujescu, D, Salomaa, V, Schlessinger, D, Schmidt, H, Schmidt, R, Schupf, N, Smit, J, Sorice, R, Spector, Td, Starr, Jm, Stöckl, D, Strauch, K, Stumvoll, M, Swertz, Ma, Thorsteinsdottir, U, Thurik, Ar, Timpson, Nj, Tung, Jy, Uitterlinden, Ag, Vaccargiu, S, Viikari, J, Vitart, V, Völzke, H, Vollenweider, P, Vuckovic, Dragana, Waage, J, Wagner, Gg, Wang, Jj, Wareham, Nj, Weir, Dr, Willemsen, G, Willeit, J, Wright, Af, Zondervan, Kt, Stefansson, K, Krueger, Rf, Lee, Jj, Benjamin, Dj, Cesarini, D, Koellinger, Pd, den Hoed, M, Snieder, H, Mills, Mc, Sociology/ICS, Life Course Epidemiology (LCE), Isotope Research, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Barban, Nicola, Jansen, Rick, De Vlaming, Ronald, Vaez, Ahmad, Hyppönen, Elina, Mills, Melinda C, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, EMGO - Mental health, Applied Economics, Public Health, Internal Medicine, Erasmus MC other, Epidemiology, Econometrics, Pediatrics, EMGO+ - Lifestyle, Overweight and Diabetes, Complex Trait Genetics, and Biological Psychology

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), PROTEIN, WASS, Genome-wide association study, Reproductive Behavior, MOUSE, Genome-wide association studies, GWAS, reproductive behavior, fertility, 0302 clinical medicine, G1 PHASE, Pregnancy, Genetics & Heredity, Genetics, HUMAN-DISEASES, Reproduction, Human Reproduction, 11 Medical And Health Sciences, ASSOCIATION, Genome-Wide, POLYCYSTIC-OVARY-SYNDROME, Sociologie van Consumptie en Huishoudens, Parity, Phenotype, Behavioural genetics, Medical genetics, Female, BIOS Consortium, FOS: Medical biotechnology, Life Sciences & Biomedicine, Maternal Age, Infertility, medicine.medical_specialty, GENE PRIORITIZATION, Quantitative Trait Loci, Sociology of Consumption and Households, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, AGE, QUALITY-CONTROL, medicine, Journal Article, Life Science, SNP, Humans, gene, reproductive, behaviour, Science & Technology, ta1184, 06 Biological Sciences, medicine.disease, Genetic architecture, human reproductive behavior, 030104 developmental biology, Fertility, Human genome, Birth Order, 030217 neurology & neurosurgery, LifeLines Cohort Study, Developmental Biology, genome-wide analysis, Genome-Wide Association Study
Abstract

Barban N, Jansen R, de Vlaming R, Vaez A, Mandemakers JJ, Tropf FC, Shen X, Wilson JF, Chasman DI, Nolte IM, Tragante V, van der Laan SW, Perry JR, Kong A; BIOS Consortium, Ahluwalia TS, Albrecht E, Yerges-Armstrong L, Atzmon G, Auro K, Ayers K, Bakshi A, Ben-Avraham D, Berger K, Bergman A, Bertram L, Bielak LF, Bjornsdottir G, Bonder MJ, Broer L, Bui M, Barbieri C, Cavadino A, Chavarro JE, Turman C, Concas MP, Cordell HJ, Davies G, Eibich P, Eriksson N, Esko T, Eriksson J, Falahi F, Felix JF, Fontana MA, Franke L, Gandin I, Gaskins AJ, Gieger C, Gunderson EP, Guo X, Hayward C, He C, Hofer E, Huang H, Joshi PK, Kanoni S, Karlsson R, Kiechl S, Kifley A, Kluttig A, Kraft P, Lagou V, Lecoeur C, Lahti J, Li-Gao R, Lind PA, Liu T, Makalic E, Mamasoula C, Matteson L, Mbarek H, McArdle PF, McMahon G, Meddens SF, Mihailov E, Miller M, Missmer SA, Monnereau C, van der Most PJ, Myhre R, Nalls MA, Nutile T, Kalafati IP, Porcu E, Prokopenko I, Rajan KB, Rich-Edwards J, Rietveld CA, Robino A, Rose LM, Rueedi R, Ryan KA, Saba Y, Schmidt D, Smith JA, Stolk L, Streeten E, Tönjes A, Thorleifsson G, Ulivi S, Wedenoja J, Wellmann J, Willeit P, Yao J, Yengo L, Zhao JH, Zhao W, Zhernakova DV, Amin N, Andrews H, Balkau B, Barzilai N, Bergmann S, Biino G, Bisgaard H, Bønnelykke K, Boomsma DI, Buring JE, Campbell H, Cappellani S, Ciullo M, Cox SR, Cucca F, Toniolo D, Davey-Smith G, Deary IJ, Dedoussis G, Deloukas P, van Duijn CM, de Geus EJ, Eriksson JG, Evans DA, Faul JD, Sala CF, Froguel P, Gasparini P, Girotto G, Grabe HJ, Greiser KH, Groenen PJ, de Haan HG, Haerting J, Harris TB, Heath AC, Heikkilä K, Hofman A, Homuth G, Holliday EG, Hopper J, Hyppönen E, Jacobsson B, Jaddoe VW, Johannesson M, Jugessur A, Kähönen M, Kajantie E, Kardia SL, Keavney B, Kolcic I, Koponen P, Kovacs P, Kronenberg F, Kutalik Z, La Bianca M, Lachance G, Iacono WG, Lai S, Lehtimäki T, Liewald DC; LifeLines Cohort Study, Lindgren CM, Liu Y, Luben R, Lucht M, Luoto R, Magnus P, Magnusson PK, Martin NG, McGue M, McQuillan R, Medland SE, Meisinger C, Mellström D, Metspalu A, Traglia M, Milani L, Mitchell P, Montgomery GW, Mook-Kanamori D, de Mutsert R, Nohr EA, Ohlsson C, Olsen J, Ong KK, Paternoster L, Pattie A, Penninx BW, Perola M, Peyser PA, Pirastu M, Polasek O, Power C, Kaprio J, Raffel LJ, Räikkönen K, Raitakari O, Ridker PM, Ring SM, Roll K, Rudan I, Ruggiero D, Rujescu D, Salomaa V, Schlessinger D, Schmidt H, Schmidt R, Schupf N, Smit J, Sorice R, Spector TD, Starr JM, Stöckl D, Strauch K, Stumvoll M, Swertz MA, Thorsteinsdottir U, Thurik AR, Timpson NJ, Tung JY, Uitterlinden AG, Vaccargiu S, Viikari J, Vitart V, Völzke H, Vollenweider P, Vuckovic D, Waage J, Wagner GG, Wang JJ, Wareham NJ, Weir DR, Willemsen G, Willeit J, Wright AF, Zondervan KT, Stefansson K, Krueger RF, Lee JJ, Benjamin DJ, Cesarini D, Koellinger PD, den Hoed M, Snieder H, Mills MC.

Published
2016

13. Genome-wide Association Study of Three-Dimensional Facial Morphology Identifies a Variant in PAX3 Associated with Nasion Position

Author

Nicholas J. Timpson, Stephen Richmond, Beate St Pourcain, Lavinia Paternoster, David M. Evans, Wendy L. McArdle, John P. Kemp, Arshed M. Toma, George McMahon, George Davey Smith, Susan M. Ring, and Alexei I. Zhurov

Subjects
Male, Longitudinal study, Adolescent, Genotype, Population, Genome-wide association study, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Facial Bones, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Imaging, Three-Dimensional, Pregnancy, Report, medicine, Genetics, Humans, Paired Box Transcription Factors, Nasal Bone, Waardenburg Syndrome, Genetics(clinical), Longitudinal Studies, Allele, Craniofacial, 10. No inequality, education, PAX3 Transcription Factor, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, education.field_of_study, Waardenburg syndrome, 030206 dentistry, medicine.disease, medicine.anatomical_structure, Phenotype, Nasion, Female, Genome-Wide Association Study
Abstract

Craniofacial morphology is highly heritable, but little is known about which genetic variants influence normal facial variation in the general population. We aimed to identify genetic variants associated with normal facial variation in a population-based cohort of 15-year-olds from the Avon Longitudinal Study of Parents and Children. 3D high-resolution images were obtained with two laser scanners, these were merged and aligned, and 22 landmarks were identified and their x, y, and z coordinates used to generate 54 3D distances reflecting facial features. 14 principal components (PCs) were also generated from the landmark locations. We carried out genome-wide association analyses of these distances and PCs in 2,185 adolescents and attempted to replicate any significant associations in a further 1,622 participants. In the discovery analysis no associations were observed with the PCs, but we identified four associations with the distances, and one of these, the association between rs7559271 in PAX3 and the nasion to midendocanthion distance (n-men), was replicated (p = 4 × 10(-7)). In a combined analysis, each G allele of rs7559271 was associated with an increase in n-men distance of 0.39 mm (p = 4 × 10(-16)), explaining 1.3% of the variance. Independent associations were observed in both the z (nasion prominence) and y (nasion height) dimensions (p = 9 × 10(-9) and p = 9 × 10(-10), respectively), suggesting that the locus primarily influences growth in the yz plane. Rare variants in PAX3 are known to cause Waardenburg syndrome, which involves deafness, pigmentary abnormalities, and facial characteristics including a broad nasal bridge. Our findings show that common variants within this gene also influence normal craniofacial development.

Published
2012
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14. Associations between smoking and caffeine consumption in two European cohorts

Author

Jorien L, Treur, Amy E, Taylor, Jennifer J, Ware, George, McMahon, Jouke-Jan, Hottenga, Bart M L, Baselmans, Gonneke, Willemsen, Dorret I, Boomsma, Marcus R, Munafò, and Jacqueline M, Vink

Subjects
Adult, Male, Research Report, Tea, Smoking, coffee, NTR, Carbonated Beverages, Research Reports, Middle Aged, ALSPAC, United Kingdom, Cohort Studies, Europe, Young Adult, Caffeine, Surveys and Questionnaires, Tobacco Smoking, Energy Drinks, Humans, Female, Netherlands
Abstract

Aims To estimate associations between smoking initiation, smoking persistence and smoking heaviness and caffeine consumption in two population‐based samples from the Netherlands and the United Kingdom. Design Observational study employing data on self‐reported smoking behaviour and caffeine consumption. Setting Adults from the general population in the Netherlands and the United Kingdom. Participants Participants from the Netherlands Twin Register [NTR: n = 21 939, mean age 40.8, standard deviation (SD) = 16.9, 62.6% female] and the Avon Longitudinal Study of Parents and Children (ALSPAC: n = 9086, mean age 33.2, SD = 4.7, 100% female). Measurements Smoking initiation (ever versus never smoking), smoking persistence (current versus former smoking), smoking heaviness (number of cigarettes smoked) and caffeine consumption in mg per day through coffee, tea, cola and energy drinks. Findings After correction for age, gender (NTR), education and social class (ALSPAC), smoking initiation was associated with consuming on average 52.8 [95% confidence interval (CI) = 45.6–60.0; NTR] and 59.5 (95% CI = 51.8–67.2; ALSPAC) mg more caffeine per day. Smoking persistence was also associated with consuming more caffeine [+57.9 (95% CI = 45.2–70.5) and +83.2 (95% CI = 70.2–96.3) mg, respectively]. Each additional cigarette smoked per day was associated with 3.7 (95% CI = 1.9–5.5; NTR) and 8.4 (95% CI = 6.9–10.0; ALSPAC) mg higher daily caffeine consumption in current smokers. Smoking was associated positively with coffee consumption and less strongly with cola and energy drinks. For tea, associations were positive in ALSPAC and negative in NTR. Conclusions There appears to be a positive association between smoking and caffeine consumption in the Netherlands and the United Kingdom.

Published
2015

15. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

Author

Virpi Lindi, Clare S. Murray, Liming Liang, Wieland Kiess, Philippe Froguel, Tarunveer S. Ahluwalia, Hakon Hakonarson, Dorret I. Boomsma, Pitkänen Niina Pitkänen, Romy Gaillard, Mandy Geserick, John A. Curtin, Shana E. McCormack, Niinikoski Harri, Jens-Christian Holm, Vicente Gilsanz, Ville Huikari, Maties Torrent, Nicholas J. Timpson, George Dedoussis, Angela Simpson, Struan F.A. Grant, Klaus Bønnelykke, Anubha Mahajan, George McMahon, Raimo Joro, Christel M. Middeldorp, Johan G. Eriksson, Vilor-Tejedor Natalia Vilor-Tejedor, Gerard H. Koppelman, Frank Geller, Amélie Bonnefond, Hanna Maaria Lakka, Jinyan Huang, Craig E. Pennell, Johannes Waage, Jane Wardle, Torben Hansen, Olli T. Raitakari, John A. Shepherd, Lisbeth Carstensen, Andrea Kelly, Katja Pahkala, Jordi Sunyer, Claire M. A. Haworth, Per Magnus, Juan R. González, Babette S. Zemel, Mads Melbye, Steve Franks, Carla M. T. Tiesler, Roland Pfäffle, Momoko Horikoshi, Susan M. Ring, Adnan Custovic, Claudia Flexeder, Claire Monnereau, Heidi J. Kalkwarf, Janine F. Felix, Julie A. Marsh, Thorkild I. A. Sørensen, André G. Uitterlinden, Mustafa Atalay, Jouke-Jan Hottenga, Mark I. McCarthy, Joel N. Hirschhorn, Niels Grarup, Lude Franke, Diana L. Cousminer, Timo A. Lakka, Robert Plomin, Ronny Myhre, Albert Hofman, Baoshan Ma, Eskil Kreiner-Møller, Jesús Vioque, Vincent W. V. Jaddoe, Hans Bisgaard, Bjarke Feenstra, Sylvain Sebert, Evie Stergiakouli, Eleftheria Zeggini, Joachim Heinrich, Bo Jacobsson, Tune H. Pers, Dirkje S. Postma, Elina Hyppönen, Loic Yengo, Haja N. Kadarmideen, Alana Cavadino, Jonathan P. Bradfield, Elisabeth Thiering, Ralf J. P. van der Valk, George Davey Smith, Alexandra I. F. Blakemore, Christine Power, Marjo-Riitta Järvelin, Wei Ang, Ioanna Ntalla, Sharon E. Oberfield, Fernando Rivadeneira, Rebecca K. Vinding, Alexandra M. Lewin, Mika Kähönen, Verena Sengpiel, Maria M. Groen-Blokhuis, Anna-Liisa Hartikainen, Antje Körner, Oluf Pedersen, Joyce B. J. van Meurs, Alessandra Chesi, Widén Elisabeth Widén, Terho Lehtimäki, Thomas S. Price, Frank D. Mentch, Joan M. Lappe, Leo-Pekka Lyytikäinen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), Early Growth Genetics (EGG) Consortium, Bone Mineral Density in Childhood Study (BMDCS), Early Genetics and Lifecourse Epidemiology (EAGLE) consortium, Felix, Janine F, Bradfield, Jonathan P, Monnereau, Claire, van der Valk, Ralf JP, Hypponen, Elina, Jaddoe, Vincent WV, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Erasmus MC other, Epidemiology, Pediatrics, Child and Adolescent Psychiatry / Psychology, Internal Medicine, and Public Health

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Male, ADAM23, Genome-wide association study, VARIANTS, ENVIRONMENTAL-FACTORS, Body Mass Index, Child, Genetics (clinical), 2. Zero hunger, Genetics, education.field_of_study, Association Studies Articles, General Medicine, INSIGHTS, Child, Preschool, Female, childhood obesity, EXPRESSION, Adult, Risk, Adolescent, Population, body mass index, Single-nucleotide polymorphism, Biology, ta3111, Polymorphism, Single Nucleotide, Childhood obesity, White People, 03 medical and health sciences, Young Adult, children, SDG 3 - Good Health and Well-being, medicine, Humans, Obesity, Allele, education, Molecular Biology, METAANALYSIS, Genetic association, FAT DISTRIBUTION, ta3121, medicine.disease, ta3123, GENE, 030104 developmental biology, Genetic Loci, WEIGHT, Body mass index, Genome-Wide Association Study
Abstract

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. Refereed/Peer-reviewed

Published
2015

16. The association between lower educational attainment and depression owing to shared genetic effects?: Results in ~25,000 subjects

Author

Patricia A. Peyser, Jessica D. Faul, Patrik K. E. Magnusson, Nicholas D. Hastie, Beate St Pourcain, Marcus Ising, Gérard Waeber, Behrooz Z. Alizadeh, Judith M. Vonk, Lawrence F. Bielak, Sang Hong Lee, Wouter J. Peyrot, Thomas Illig, M. M. Weissman, Nicholas J. Timpson, George Dedoussis, Nicholas G. Martin, Tomi E. Mäkinen, Jorma Viikari, Lili Milani, Harold Snieder, Laura J. Bierut, A. C. Heath, Reinhold E. Schmidt, Mariza de Andrade, Vilmundur Gudnason, K. Petrovic, Robert M. Kirkpatrick, Marcela González Gross, William G. Iacono, Michelle N. Meyer, Henry Völzke, Marisa Loitfelder, Maria Dimitriou, Lude Franke, Robert F. Krueger, E. J. C. G. van den Oord, Sven Cichon, Michael Conlon O'Donovan, Ian W. Craig, Shawn N. Murphy, Danielle Posthuma, Brenda W.J.H. Penninx, Aarno Palotie, Roy Thurik, Panos Deloukas, Matt McGue, M. Preisig, Patricia A. Boyle, Osorio Meirelles, Ben A. Oostra, Klaus Berger, G. M. Montgomery, Sharon L.R. Kardia, Peter K. Joshi, K. Stefansson, Paul Lichtenstein, Andrew Heath, Andrea Schulz, Dena G. Hernandez, Debbie A Lawlor, S. P. Hamilton, James B. Potash, Z. Kutalik, Elisabeth Widen, Emil L. Sigurdsson, Rudolf S N Fehrmann, Matthias Nauck, Mikael Landén, Kurt Lohman, S.D. Gordon, Lefkos T. Middleton, Caroline Hayward, Anjali K. Henders, Philipp Koellinger, Jeffrey A. Boatman, G van Grootheest, M. Daly, Jian Yang, Peter Vollenweider, Penelope A. Lind, Stacy Steinberg, Frank J. A. van Rooij, Florian Holsboer, Hkon K. Gjessing, Erkki Vartiainen, Magnus Johannesson, Jingmei Li, David Laibson, Henrik Grönberg, Tõnu Esko, Ivana Kolcic, Niina Eklund, Kelly S. Benke, Henning Tiemeier, Isaac S. Kohane, Nicolas W. Martin, Ronny Myhre, Frans G. Zitman, Arpana Agrawal, James F. Wilson, Michael R. Barnes, Lei Yu, Thorgeir E. Thorgeirsson, Franois Bastardot, Katri Räikkönen, William Lawson, Willem A. Nolen, M. Rietschel, René Breuer, Bertram Müller-Myhsok, James A. Knowles, Grant W. Montgomery, Eva Reinmaa, Rudolf Uher, Andreas Mielck, Luigi Ferrucci, S. E. Medland, Yuri Milaneschi, Philip L. De Jager, Manfred Uhr, A. E. Farmer, Cornelia M. van Duijn, Samuli Ripatti, Marja-Liisa Nuotio, Manuel Mattheisen, Sebastian E. Baumeister, David R. Van Wagoner, Martin Preisig, Fernando Rivadeneira, Peter Lichtner, Christopher Oldmeadow, Hreinn Stefansson, Ian B. Hickie, Darina Czamara, Elizabeth G. Holliday, Astanand Jugessur, Carla A. Ibrahim-Verbaas, Jaime Derringer, Vivian S. Gainer, P. Muglia, Daniel J. Benjamin, Patrick K.E. Magnusson, Patience J. Gallagher, Jennifer A. Smith, Lynn Cherkas, Pamela A. F. Madden, David A. Bennett, Zoltán Kutalik, George Davey-Smith, Gudny Eiriksdottir, Jens Treutlein, N. Craddock, Juliette Harris, Antti Latvala, Roy H. Perlis, Markus M. Noethen, Jan-Emmanuel De Neve, Stanley I. Shyn, J.H. Smit, Dalton Conley, Adriaan Hofman, Jari Lahti, Patrick J. F. Groenen, Jüri Allik, Albert V. Smith, Ozren Polasek, Susan M. Ring, Thomas Bettecken, Michele L. Pergadia, Patrick J. McGrath, Katherine E. Tansey, Stephan Ripke, Hogni Oskarsson, Peng Lin, Douglas F. Levinson, Matthijs J. H. M. van der Loos, Melissa E. Garcia, Jonathan P. Beauchamp, Rodney J. Scott, Zhihong Zhu, Michel Guipponi, Lyle J. Palmer, Alexander Teumer, William Coryell, Stefan Kloiber, Gonneke Willemsen, John Frank, Victor M. Castro, Andrew M. McIntosh, John M. Starr, Antonio Terracciano, Mika Kähönen, Marco Masala, Markus Perola, André G. Uitterlinden, Sutapa Mukherjee, Alexander Viktorin, Lenore J. Launer, Elisabeth B. Binder, William A. Scheftner, Christel M. Middeldorp, D. H. R. Blackwood, I. Jones, Thais S. Rizzi, A. Teumer, Cornelius A. Rietveld, Aldo Rustichini, Guy Lewis, Susan L. Slager, David M. Evans, Dorret I. Boomsma, Harry Campbell, Susanne Churchill, Johan G. Eriksson, Alan F. Wright, Dan V. Iosifescu, W. Maier, Francesco Cucca, Federica Tozzi, David R. Weir, Eva Albrecht, L. Milani, Jennifer R. Harris, Min A. Jhun, Marjo-Riitta Järvelin, Martin F. Elderson, Ute Bültmann, Olli T. Raitakari, Konstantin Shakhbazov, Krista Fischer, Thomas G. Schulze, T. Jung-Ying, P. Lichtenstein, Terho Lethimäki, Jeffrey B. Weilburg, Rolf Holle, Bo Jacobsson, Pedro Marques Vidal, Jordan W. Smoller, Stavroula Kanoni, Kati Kristiansson, Sergey Goryachev, Michael Steffens, Peter M. Visscher, Toshiko Tanaka, Donald J. MacIntyre, Witte J.G. Hoogendijk, David Schlessinger, Ian J. Deary, Harm-Jan Westra, Erik Ingelsson, E.J.C. de Geus, Franziska Degenhardt, Lydia Quaye, John Barnard, David C. Liewald, John P. Rice, Christopher F. Chabris, P. McGuffin, Tamara B. Harris, C. M. Lewis, Gail Davies, Enda M. Byrne, H.-Erich Wichmann, Sara Hägg, David Cesarini, Najaf Amin, Juha Karjalainen, Dale R. Nyholt, Christian Gieger, Per Hall, Ania Korszun, Neale Bm, Wei Zhao, Abdel Abdellaoui, Andres Metspalu, Christina Holzapfel, Jae Hoon Sul, Christiaan de Leeuw, Antti-Pekka Sarin, Ida Surakka, Veikko Salomaa, Mina K. Chung, N. L. Pedersen, Gerome Breen, P. A. F. Madden, Martin A. Kohli, J Kaprio, John Attia, Jing Shi, Gibran Hemani, Rauli Svento, Veronique Vitart, Susanne Lucae, L. A. Jones, Jouke-Jan Hottenga, Daniel S. Evans, Hans-Jörgen Grabe, Yongmei Liu, Danyu Lin, Albert Hofman, George McMahon, Naomi R. Wray, Stefan Herms, Stefania Bandinelli, W. Hoffmann, P.F. Sullivan, Susanne Hoefels, Michael B. Miller, Alan W. McLean, Igor Rudan, Jürgen Wellmann, Anu Realo, Maurizio Fava, Matthew Kowgier, Marika Kaakinen, Helena Schmidt, Faculteit Medische Wetenschappen/UMCG, Peyrot, WJ, Lee, SH, Milaneschi, Y, Abdellaoui, A, Penninx, BWJH, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, Social Science Genetic Association Consortium, Psychiatry, NCA - Neurobiology of mental health, EMGO - Mental health, Applied Economics, Biological Psychology, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium (Corporate Collaborator), Social Science Genetic Association Consortium Corporate Collaborator, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium Corporate Collaborator, Lewis, C.M., Hamilton, S.P., Weissman, M.M., Breen, G., Blackwood, D.H., Cichon, S., Heath, A.C., Holsboer, F., Madden, P.A., McGuffin, P., Muglia, P., Pergadia, M.L., Lin, D., Müller-Myhsok, B., Steinberg, S., Grabe, H.J., Lichtenstein, P., Magnusson, P., Perlis, R.H., Preisig, M., Smoller, J.W., Stefansson, K., Uher, R., Kutalik, Z., Tansey, K.E., Teumer, A., Viktorin, A., Barnes, M.R., Bettecken, T., Binder, E.B., Breuer, R., Castro, V.M., Churchill, S.E., Coryell, W.H., Craddock, N., Craig, I.W., Czamara, D., Degenhardt, F., Farmer, A.E., Fava, M., Frank, J., Gainer, V.S., Gallagher, P.J., Gordon, S.D., Goryachev, S., Gross, M., Guipponi, M., Henders, A.K., Herms, S., Hickie, I.B., Hoefels, S., Hoogendijk, W., Iosifescu, D.V., Ising, M., Jones, I., Jones, L., Jung-Ying, T., Knowles, J.A., Kohane, I.S., Kohli, M.A., Korszun, A., Landen, M., Lawson, W.B., Lewis, G., Macintyre, D., Maier, W., Mattheisen, M., McGrath, P.J., McIntosh, A., McLean, A., Middeldorp, C.M., Middleton, L., Montgomery, G.M., Murphy, S.N., Nauck, M., Nolen, W.A., Nyholt, D.R., O'Donovan, M., Oskarsson, H., Pedersen, N., Scheftner, W.A., Schulz, A., Schulze, T.G., Shyn, S.I., Sigurdsson, E., Slager, S.L., Smit, J.H., Stefansson, H., Steffens, M., Thorgeirsson, T., Tozzi, F., Treutlein, J., Uhr, M., van den Oord, E.J., Van Grootheest, G., Völzke, H., Weilburg, J.B., Willemsen, G., Zitman, F.G., Neale, B., Daly, M., Sullivan, P.F., Agrawal, A., Albrecht, E., Alizadeh, B.Z., Allik, J., Amin, N., Attia, J.R., Bandinelli, S., Barnard, J., Bastardot, F., Baumeister, S.E., Beauchamp, J., Benjamin, D.J., Benke, K.S., Bennett, D.A., Berger, K., Bielak, L.F., Bierut, L.J., Boatman, J.A., Boyle, P.A., Bültmann, U., Campbell, H., Cesarini, D., Chabris, C.F., Cherkas, L., Chung, M.K., Conley, D., Cucca, F., Davey-Smith, G., Davies, G., de Andrade, M., De Jager, P.L., de Leeuw, C., De Neve, J.E., Deary, I.J., Dedoussis, G.V., Deloukas, P., Derringer, J., Dimitriou, M., Eiriksdottir, G., Eklund, N., Elderson, M.F., Eriksson, J.G., Evans, D.S., Evans, D.M., Faul, J.D., Fehrmann, R., Ferrucci, L., Fischer, K., Franke, L., Garcia, M.E., Gieger, C., Gjessing, H.K., Groenen, P.J., Grönberg, H., Gudnason, V., Hägg, S., Hall, P., Harris, J.R., Harris, J.M., Harris, T.B., Hastie, N.D., Hayward, C., Hernandez, D.G., Hoffmann, W., Hofman, A., Holle, R., Holliday, E.G., Holzapfel, C., Iacono, W.G., Ibrahim-Verbaas, C.A., Illig, T., Ingelsson, E., Jacobsson, B., Järvelin, M.R., Jhun, M.A., Johannesson, M., Joshi, P.K., Jugessur, A., Kaakinen, M., Kähönen, M., Kanoni, S., Kaprio, J., Kardia, S.L., Karjalainen, J., Kirkpatrick, R.M., Koellinger, P.D., Kolcic, I., Kowgier, M., Kristiansson, K., Krueger, R.F., Lahti, J., Laibson, D., Latvala, A., Launer, L.J., Lawlor, D.A., Lethimäki, T., Li, J., Lichtner, P.K., Liewald, D.C., Lin, P., Lind, P.A., Liu, Y., Lohman, K., Loitfelder, M., Magnusson, P.K., Mäkinen, T.E., Vidal, P.M., Martin, N.W., Masala, M., McGue, M., McMahon, G., Meirelles, O., Meyer, M.N., Mielck, A., Milani, L., Miller, M.B., Montgomery, G.W., Mukherjee, S., Myhre, R., Nuotio, M.L., Oldmeadow, C.J., Oostra, B.A., Palmer, L.J., Palotie, A., Perola, M., Petrovic, K.E., Peyser, P.A., Polašek, O., Posthuma, D., Quaye, L., Räikkönen, K., Raitakari, O.T., Realo, A., Reinmaa, E., Rice, J.P., Ring, S.M., Ripatti, S., Rivadeneira, F., Rizzi, T.S., Rudan, I., Rustichini, A., Salomaa, V., Sarin, A.P., Schlessinger, D., Schmidt, H., Schmidt, R., Scott, R.J., Shakhbazov, K., Smith, A.V., Smith, J.A., Snieder, H., Pourcain, B.S., Starr, J.M., Sul, J.H., Surakka, I., Svento, R., Tanaka, T., Terracciano, A., Thurik, A.R., Tiemeier, H., Timpson, N.J., Uitterlinden, A.G., van der Loos, M.J., van Duijn, C.M., van Rooij, F.J., Van Wagoner, D.R., Vartiainen, E., Viikari, J., Visscher, P.M., Vitart, V., Vollenweider, P.K., Vonk, J.M., Waeber, G., Weir, D.R., Wellmann, J., Westra, H.J., Wichmann, H.E., Widen, E., Wilson, J.F., Wright, A.F., Yang, J., Yu, L., and Zhao, W.

Subjects
Netherlands Twin Register (NTR), Male, Genome-wide association study, Logistic regression, Cohort Studies, Odds Ratio, pleiotropic genetic effects, Netherlands, Psychiatry, education.field_of_study, Likelihood Functions, Single Nucleotide, Middle Aged, Psychiatry and Mental health, educational attainment, depression, Major depressive disorder, Educational Status, Regression Analysis, Female, Psychology, Adult, Estonia, medicine.medical_specialty, Biochemistry & Molecular Biology, Aged, Depressive Disorder, Major/epidemiology, Depressive Disorder, Major/genetics, Depressive Disorder, Major/psychology, Estonia/epidemiology, Gene-Environment Interaction, Genetic Association Studies, Genotype, Humans, Netherlands/epidemiology, Polymorphism, Single Nucleotide/genetics, Psychiatric Status Rating Scales, Concordance, Population, SNP, Single-nucleotide polymorphism, Genetic correlation, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Article, Cellular and Molecular Neuroscience, mental disorders, medicine, Polymorphism, education, Molecular Biology, Depressive Disorder, Depressive Disorder, Major, major depressive disorder, ta1184, Neurosciences, Major, Odds ratio, medicine.disease, ta3124, Neurosciences & Neurology, polymorphisms, Demography
Abstract

An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14 949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15 138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884 105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on similar to 120 000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status. Refereed/Peer-reviewed

Published
2015

17. Assumption-free estimation of the genetic contribution to refractive error across childhood

Author

Jeremy A, Guggenheim, Beate, St Pourcain, George, McMahon, Nicholas J, Timpson, David M, Evans, and Cathy, Williams

Subjects
Male, Adolescent, Refractive Errors, Polymorphism, Single Nucleotide, Cohort Studies, Leisure Activities, Quantitative Trait, Heritable, England, Reading, Myopia, Humans, Female, Genetic Predisposition to Disease, Child, Genome-Wide Association Study, Research Article
Abstract

Purpose Studies in relatives have generally yielded high heritability estimates for refractive error: twins 75–90%, families 15–70%. However, because related individuals often share a common environment, these estimates are inflated (via misallocation of unique/common environment variance). We calculated a lower-bound heritability estimate for refractive error free from such bias. Methods Between the ages 7 and 15 years, participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) underwent non-cycloplegic autorefraction at regular research clinics. At each age, an estimate of the variance in refractive error explained by single nucleotide polymorphism (SNP) genetic variants was calculated using genome-wide complex trait analysis (GCTA) using high-density genome-wide SNP genotype information (minimum N at each age=3,404). Results The variance in refractive error explained by the SNPs (“SNP heritability”) was stable over childhood: Across age 7–15 years, SNP heritability averaged 0.28 (SE=0.08, p

Published
2015

18. Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

Author

Paul Mitchell, Arne Schillert, Tanja Zeller, Beate St Pourcain, Yi Lu, Christopher J Hammond, Nicholas G. Martin, René Höhn, Veluchamy A Barathi, Terri L. Young, Johannes R. Vingerling, Mario Pirastu, Veronique Vitart, André G. Uitterlinden, Virginie J. M. Verhoeven, Federico Murgia, Xin Zhou, Pirro G. Hysi, Christian Gieger, Jeremy A. Guggenheim, Robert Wojciechowski, Paul G. Sanfilippo, Alireza Mirshahi, Caroline Hayward, Terho Lehtimäki, Phillippa M. Cumberland, Caroline C W Klaver, Konrad Oexle, Tin Aung, Alan F. Wright, Eranga N. Vithana, Paul N. Baird, Qiao Fan, Ching-Yu Cheng, Andrew D. Paterson, Joan E. Bailey-Wilson, Thomas Meitinger, Mohammad Kamran Ikram, Janina S. Ried, Youchan Shin, Albert Hofman, David A. Mackey, Lennart C. Karssen, James F. Wilson, George McMahon, Najaf Amin, Ben A. Oostra, Brian W Fleck, Tien Yin Wong, Olavi Pärssinen, Cathy Williams, Kari-Matti Mäkelä, Kumari Neelam, Rosalynn Siantar, Yik Ying Teo, Alex W. Hewitt, Hoi Suen Wong, Olli T. Raitakari, Seyhan Yazar, Barbara E.K. Klein, Janice Lam, Shea Ping Yip, Ekaterina Yonova-Doing, Chiea Chuen Khor, Maurice Yap, David M. Evans, Harry Campbell, Goran Benčić, Jost B. Jonas, Yingfeng Zheng, Cristina Venturini, Claire L. Simpson, S. Mohsen Hosseini, Dwight Stambolian, E. Shyong Tai, Fernando Rivadeneira, Juho Wedenoja, John P. Kemp, Stuart MacGregor, Qing Li, Cornelia M. van Duijn, Ozren Polasek, Mika Kähönen, Ya Xing Wang, Kate Northstone, Jugnoo S Rahi, Seang-Mei Saw, Karl J. Lackner, Nicholas J. Timpson, Ophthalmology, Erasmus MC other, Epidemiology, Internal Medicine, Clinical Genetics, Department of Public Health, and Silmäklinikka

Subjects
Male, Refractive error, BLUE MOUNTAINS EYE, CORNEAL ASTIGMATISM, Spherical equivalent, Genome-wide association study, astigmatism, gene, SNP, DISEASE, Cohort Studies, 0302 clinical medicine, Statistics, Genetics(clinical), Neural Cell Adhesion Molecules, POPULATION, Genetics (clinical), Original Investigation, Genetics, 0303 health sciences, education.field_of_study, Age Factors, High Mobility Group Proteins, Middle Aged, 3142 Public health care science, environmental and occupational health, 3. Good health, Female, OPEN-ANGLE GLAUCOMA, Adult, Genetic Markers, EXPERIMENTALLY-INDUCED MYOPIA, Keratoconus, SUSCEPTIBILITY LOCI, Cell Adhesion Molecules, Neuronal, education, Population, Nerve Tissue Proteins, Astigmatism, Biology, White People, 03 medical and health sciences, AGE, Asian People, MAJOR LOCUS, medicine, Humans, 3125 Otorhinolaryngology, ophthalmology, 030304 developmental biology, Genetic association, Calcium-Binding Proteins, Heritability, medicine.disease, NONCODING RNAS, 030221 ophthalmology & optometry, Genome-Wide Association Study
Abstract

To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged

Published
2015

19. Genome-wide association study of blood lead shows multiple associations near ALAD

Author

Colin D Steer, Nicholas J. Timpson, Nicholas G. Martin, Caroline M Taylor, Nicole M. Warrington, George McMahon, Grant W. Montgomery, Andrew C. Heath, Gibran Hemani, Debbie A Lawlor, David M. Evans, Gu Zhu, John Whitfield, John P. Kemp, Pamela A. F. Madden, Jean Golding, Veronica Dy, George Davey Smith, and Beate St Pourcain

Subjects
Adult, Male, Genotype, Population, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Cohort Studies, Young Adult, ABO blood group system, Genetic variation, Genetics, Humans, Allele, education, Molecular Biology, Genetics (clinical), Genetic association, education.field_of_study, Association Studies Articles, Australia, Porphobilinogen Synthase, General Medicine, Environmental exposure, United Kingdom, Lead, Female, Genome-Wide Association Study
Abstract

Exposure to high levels of environmental lead, or biomarker evidence of high body lead content, is associated with anaemia, developmental and neurological deficits in children, and increased mortality in adults. Adverse effects of lead still occur despite substantial reduction in environmental exposure. There is genetic variation between individuals in blood lead concentration but the polymorphisms contributing to this have not been defined. We measured blood or erythrocyte lead content, and carried out genome-wide association analysis, on population-based cohorts of adult volunteers from Australia and UK (N = 5433). Samples from Australia were collected in two studies, in 1993-1996 and 2002-2005 and from UK in 1991-1992. One locus, at ALAD on chromosome 9, showed consistent association with blood lead across countries and evidence for multiple independent allelic effects. The most significant single nucleotide polymorphism (SNP), rs1805313 (P = 3.91 × 10(-14) for lead concentration in a meta-analysis of all data), is known to have effects on ALAD expression in blood cells but other SNPs affecting ALAD expression did not affect blood lead. Variants at 12 other loci, including ABO, showed suggestive associations (5 × 10(-6) > P > 5 × 10(-8)). Identification of genetic polymorphisms affecting blood lead reinforces the view that genetic factors, as well as environmental ones, are important in determining blood lead levels. The ways in which ALAD variation affects lead uptake or distribution are still to be determined.

Published
2015

20. Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder

Author

Kaya K. Jacobsen, Caroline M. Nievergelt, Tetyana Zayats, Tiffany A. Greenwood, Verneri Anttila, Hagop S. Akiskal, Jan Haavik, Ole Bernt Fasmer, John R. Kelsoe, Stefan Johansson, Ketil J. Oedegaard, Rebecca McKinney, Paul D. Shilling, Erin N. Smith, Nicholas J. Schork, Cinnamon S. Bloss, John I. Nurnberger, Howard J. Edenberg, Tatiana Foroud, Daniel L. Koller, Elliot S. Gershon, Judith A. Badner, Chunyu Liu, William A. Scheftner, William B. Lawson, Evaristus A. Nwulia, Maria Hipolito, James Potash, William Coryell, John Rice, William Byerley, Francis J. McMahon, Wade H. Berrettini, Peter P. Zandi, Pamela B. Mahon, Melvin G. McInnis, Sebastian Zöllner, Peng Zhang, David W. Craig, Szabolics Szelinger, Thomas B. Barrett, Thomas G. Schulze, Juho Wedenoja, Mari A. Kaunisto, Kauko Heikkilä, Jaakko Kaprio, Maija Wessman, Mikko Kallela, Markus Färkkilä, Ville Artto, Arpo Aromaa, Johan G. Eriksson, Bendik S. Winsvold, John-Anker Zwart, Padhraig Gormley, Aarno Palotie, Tobias Kurth, Lynda M. Rose, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Francesco Bettella, Stacy Steinberg, Hreinn Stefansson, Kari Stefansson, George McMahon, George Davey-Smith, Rainer Malik, Tobias Freilinger, Heinz Erich Wichmann, Martin Dichgans, Bertram Muller-Myhsok, Thomas Meitinger, Boukje de Vries, Gisela Terwindt, Anine H. Stam, Rune R. Frants, Nadine Pelzer, Claudia M. Weller, Ronald Zielman, Michel D. Ferrari, Arn M.J.M. van den Maagdenberg, Sarah E. Medland, Grant W. Montgomery, Nicholas G. Martin, Dale R. Nyholt, Unda Todt, Guntram Borck, Christian Kubisch, Lydia Quaye, Frances M.K. Williams, Lynn Cherkas, Markku Koiranen, Anna-Liisa Hartikainen, Anneli Pouta, Marjo-Riitta Jarvelin, M. Arfan Ikram, Joyce van den Ende, Andre G. Uitterlinden, Albert Hofman, Najaf Amin, Cornelia van Duijn, Terho Lehtimäki, Lannie Ligthart, Jouke-Jan Hottenga, Jacqueline M. Vink, Brenda W. Penninx, Dorret I. Boomsma, Markus Schürks, Finnbogi Jakobsson, Jean Schoenen, Andrew C. Heath, Pamela A.F. Madden, Hartmut Göbel, Axel Heinze, Katja Heinze-Kuhn, Stefan Schreiber, Mark J. Daly, Michael Alexander, Olli Raitakari, David P. Strachan, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Biological Psychology, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, Institute for Molecular Medicine Finland, Research Programs Unit, Sampsa Hautaniemi / Principal Investigator, Genome-Scale Biology (GSB) Research Program, Department of Public Health, Aarno Palotie / Principal Investigator, Hjelt Institute (-2014), Jaakko Kaprio / Principal Investigator, Department of Neurosciences, Neurologian yksikkö, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Diabetes and Obesity Research Program, Genomics of Neurological and Neuropsychiatric Disorders, and Genetic Epidemiology

Subjects
Netherlands Twin Register (NTR), Male, Bipolar Disorder, Genome-wide association study, Comorbidity, 3124 Neurology and psychiatry, GENETIC ASSOCIATION, GLUTAMATE, Medicine, POPULATION, Genetics, education.field_of_study, Medisinske fag: 700::Klinisk medisinske fag: 750::Psykiatri, barnepsykiatri: 757 [VDP], SDG 10 - Reduced Inequalities, PREVALENCE, NBEA, Clinical Psychology, Psychiatry and Mental health, Female, RECEPTOR TRAFFICKING, Adult, SUSCEPTIBILITY LOCI, Bipolar disorder, Migraine Disorders, Population, Single-nucleotide polymorphism, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Midical sciences: 700::Clinical medical sciences: 750::Psychiatry, child psychiatry: 757 [VDP], Article, Medisinske Fag: 700 [VDP], mental disorders, LINKAGE, SNP, Humans, Genetic Predisposition to Disease, AUTISM, education, METAANALYSIS, Migraine, Genetic association, business.industry, 3112 Neurosciences, medicine.disease, Neurobeachin, sense organs, business, Carrier Proteins, Genome-Wide Association Study
Abstract

Background Migraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine. Methods We performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS). Results We identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene ( P =2.97×10 −8 , OR: 1.82, 95% CI: 1.47–2.25), although this was not replicated in a smaller sample of 289 migraine cases. Limitations Our study is based on self-reported migraine. Conclusions NBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium ( n =118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder.

Published
2015

21. Does Vitamin D Mediate the Protective Effects of Time Outdoors On Myopia? Findings From a Prospective Birth Cohort

Author

Laura D Howe, Kate Northstone, Jeremy A. Guggenheim, George McMahon, Kate Tilling, Cathy Williams, Beate St Pourcain, and Debbie A Lawlor

Subjects
Male, medicine.medical_specialty, Longitudinal study, Pediatrics, Adolescent, Population, Cellular and Molecular Neuroscience, Leisure Activities, Ophthalmology, medicine, Vitamin D and neurology, Myopia, Humans, Longitudinal Studies, Prospective Studies, Vitamin D, education, Prospective cohort study, Child, Exercise, education.field_of_study, business.industry, Incidence (epidemiology), Incidence, Hazard ratio, Articles, Survival Analysis, Sensory Systems, Confidence interval, England, Female, business, Cohort study
Abstract

Purpose. More time outdoors is associated with a lesser risk of myopia, but the underlying mechanism is unclear. We tested the hypothesis that 25-hydroxyvitamin D (vitamin D) mediates the protective effects of time outdoors against myopia. Methods. We analyzed data for children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort: noncycloplegic autorefraction at age 7 to 15 years; maternal report of time outdoors at age 8 years and serum vitamin D2 and D3 at age 10 years. A survival analysis hazard ratio (HR) for incident myopia was calculated for children spending a high- versus low-time outdoors, before and after controlling for vitamin D level (N = 3677). Results. Total vitamin D and D3, but not D2, levels were higher in children who spent more time outdoors (mean [95% confidence interval (CI)] vitamin D in nmol/L: Total, 60.0 [59.4–60.6] vs. 56.9 [55.0–58.8], P = 0.001; D3, 55.4 [54.9–56.0] vs. 53.0 [51.3–54.9], P = 0.014; D2, 5.7 [5.5–5.8] vs. 5.4 [5.1–5.8], P = 0.23). In models including both time outdoors and sunlight-exposure–related vitamin D, there was no independent association between vitamin D and incident myopia (Total, HR = 0.83 [0.66–1.04], P = 0.11; D3, HR = 0.89 [0.72–1.10], P = 0.30), while time outdoors retained the same strong negative association with incident myopia as in unadjusted models (HR = 0.69 [0.55–0.86], P = 0.001). Conclusions. Total vitamin D and D3 were biomarkers for time spent outdoors, however there was no evidence they were independently associated with future myopia.

Published
2014

22. Genomic influences on alcohol problems in a population-based sample of young adults

Author

Alexis C, Edwards, Fazil, Aliev, Aaron R, Wolen, Jessica E, Salvatore, Charles O, Gardner, George, McMahon, David M, Evans, John, Macleod, Matthew, Hickman, Danielle M, Dick, and Kenneth S, Kendler

Subjects
Glucose Transporter Type 2, Male, Adolescent, Genotype, Calcium-Binding Proteins, Intracellular Signaling Peptides and Proteins, RNA-Binding Proteins, Genomics, Polymorphism, Single Nucleotide, United Kingdom, Article, Epigenesis, Genetic, Cohort Studies, Alcoholism, Phenotype, Peptide Initiation Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Alcohol-Related Disorders, Genome-Wide Association Study, Molecular Chaperones
Abstract

Alcohol problems (AP) contribute substantially to the global disease burden. Twin and family studies suggest that AP are genetically influenced, although few studies have identified variants or genes that are robustly associated with risk. This study identifies genetic and genomic influences on AP during young adulthood, which is often when drinking habits are established.We conducted a genome-wide association study of AP. We further conducted gene-based tests, gene ontology analyses and functional genomic enrichment analyses to assess genomic factors beyond single variants that are relevant to AP.The Avon Longitudinal Study of Parents and Children, a large population-based study of a UK birth cohort.Genetic and phenotypical data were available for 4304 participants.The AP phenotype was a factor score derived from items from the Alcohol Use Disorders Identification Test, symptoms of DSM-IV alcohol dependence, and three additional problem-related items.One variant met genome-wide significance criteria. Four out of 22,880 genes subjected to gene-based analyses survived a stringent significance threshold (q0.05); none of these have been implicated previously in alcohol-related phenotypes. Several biologically plausible gene ontologies were statistically over-represented among implicated single nucleotide polymorphisms (SNPs). SNPs on the Illumina 550 K SNP chip accounted for ~5% of the phenotypical variance in AP.Genetic and genomic factors appear to play a role in alcohol problems in young adults. Genes involved in nervous system-related processes, such as signal transduction and neurogenesis, potentially contribute to liability to alcohol problems, as do genes expressed in non-brain tissues.

Published
2014

23. Genetic variation associated with differential educational attainment in adults has anticipated associations with school performance in children

Author

Mary E, Ward, George, McMahon, Beate, St Pourcain, David M, Evans, Cornelius A, Rietveld, Daniel J, Benjamin, Philipp D, Koellinger, David, Cesarini, George, Davey Smith, and Nicholas J, Timpson

Subjects
Adult, Male, Adolescent, Epidemiology, Intelligence, Polymorphism, Single Nucleotide, Genetics, Medicine and Health Sciences, Humans, Learning, Public and Occupational Health, Longitudinal Studies, Child, Genetic Association Studies, Lifecourse Epidemiology, Intelligence Tests, Biology and Life Sciences, Human Genetics, Socioeconomic Aspects of Health, Health Care, Child, Preschool, Genetic Epidemiology, Educational Status, Female, Mathematics, Genome-Wide Association Study, Research Article
Abstract

Genome-wide association study results have yielded evidence for the association of common genetic variants with crude measures of completed educational attainment in adults. Whilst informative, these results do not inform as to the mechanism of these effects or their presence at earlier ages and where educational performance is more routinely and more precisely assessed. Single nucleotide polymorphisms exhibiting genome-wide significant associations with adult educational attainment were combined to derive an unweighted allele score in 5,979 and 6,145 young participants from the Avon Longitudinal Study of Parents and Children with key stage 3 national curriculum test results (SATS results) available at age 13 to 14 years in English and mathematics respectively. Standardised (z-scored) results for English and mathematics showed an expected relationship with sex, with girls exhibiting an advantage over boys in English (0.433 SD (95%CI 0.395, 0.470), p10(-10)) with more similar results (though in the opposite direction) in mathematics (0.042 SD (95%CI 0.004, 0.080), p = 0.030). Each additional adult educational attainment increasing allele was associated with 0.041 SD (95%CI 0.020, 0.063), p = 1.79×10(-04) and 0.028 SD (95%CI 0.007, 0.050), p = 0.01 increases in standardised SATS score for English and mathematics respectively. Educational attainment is a complex multifactorial behavioural trait which has not had heritable contributions to it fully characterised. We were able to apply the results from a large study of adult educational attainment to a study of child exam performance marking events in the process of learning rather than realised adult end product. Our results support evidence for common, small genetic contributions to educational attainment, but also emphasise the likely lifecourse nature of this genetic effect. Results here also, by an alternative route, suggest that existing methods for child examination are able to recognise early life variation likely to be related to ultimate educational attainment.

Published
2014

24. Phenotype refinement strengthens the association of AHR and CYP1A1 genotype with caffeine consumption

Author

George McMahon, Amy E Taylor, Marcus R. Munafò, and George Davey Smith

Subjects
Adult, Longitudinal study, Genotype, Epidemiology, Drinking Behavior, lcsh:Medicine, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pregnancy, Polymorphism (computer science), Caffeine, Surveys and Questionnaires, Epidemiological Statistics, Mendelian randomization, Basic Helix-Loop-Helix Transcription Factors, Cytochrome P-450 CYP1A1, Medicine and Health Sciences, Humans, Longitudinal Studies, 030212 general & internal medicine, Allele, lcsh:Science, Life Style, 030304 developmental biology, Genetics, Consumption (economics), 0303 health sciences, Multidisciplinary, Confounding, lcsh:R, Genetic Variation, Phenotype, Receptors, Aryl Hydrocarbon, chemistry, Genetic Epidemiology, Epidemiological Methods and Statistics, Female, lcsh:Q, Self Report, Research Article, Demography
Abstract

Two genetic loci, one in the cytochrome P450 1A1 (CYP1A1) and 1A2 (CYP1A2) gene region (rs2472297) and one near the aryl-hydrocarbon receptor (AHR) gene (rs6968865), have been associated with habitual caffeine consumption. We sought to establish whether a more refined and comprehensive assessment of caffeine consumption would provide stronger evidence of association, and whether a combined allelic score comprising these two variants would further strengthen the association. We used data from between 4,460 and 7,520 women in the Avon Longitudinal Study of Parents and Children, a longitudinal birth cohort based in the United Kingdom. Self-report data on coffee, tea and cola consumption (including consumption of decaffeinated drinks) were available at multiple time points. Both genotypes were individually associated with total caffeine consumption, and with coffee and tea consumption. There was no association with cola consumption, possibly due to low levels of consumption in this sample. There was also no association with measures of decaffeinated drink consumption, indicating that the observed association is most likely mediated via caffeine. The association was strengthened when a combined allelic score was used, accounting for up to 1.28% of phenotypic variance. This was not associated with potential confounders of observational association. A combined allelic score accounts for sufficient phenotypic variance in caffeine consumption that this may be useful in Mendelian randomization studies. Future studies may therefore be able to use this combined allelic score to explore causal effects of habitual caffeine consumption on health outcomes.

Published
2014

25. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

Author

Magnus Johannesson, André G. Uitterlinden, Cornelius A. Rietveld, Nicholas J. Timpson, Sarah E. Medland, Tõnu Esko, Beben Benyamin, Ian J. Deary, Sven J. van der Lee, Christiaan de Leeuw, Nicholas G. Martin, Matt McGue, Cornelia M. van Duijn, David C. Liewald, Patrick Turley, Nancy L. Pedersen, Paul Lichtenstein, Jaime Derringer, Frank C. Verhulst, James J. Lee, Carla A. Ibrahim-Verbaas, Dalton Conley, Philipp Koellinger, John M. Starr, Tune H. Pers, Christopher F. Chabris, David Cesarini, David Laibson, Edward L. Glaeser, Najaf Amin, Olga Rostapshova, Maciej Trzaskowski, Juha Karjalainen, Mary E. Ward, Caroline Hayward, Valur Emilsson, Patrik K. E. Magnusson, Henning Tiemeier, Daniel J. Benjamin, Robert Plomin, David J. Porteous, George Davey Smith, Michael B. Miller, Margaret J. Wright, Fernando Rivadeneira, Vincent W. V. Jaddoe, Anna A. E. Vinkhuyzen, William G. Iacono, Lude Franke, Peter M. Visscher, Rudolf S N Fehrmann, Gail Davies, Andrew D. Johnson, Steven Pinker, Riccardo E. Marioni, Blair H. Smith, George McMahon, Danielle Posthuma, Narelle K. Hansell, Human genetics, NCA - Brain mechanisms in health and disease, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Functional Genomics, Complex Trait Genetics, Tinbergen Institute, Amsterdam Neuroscience - Complex Trait Genetics, Rietveld, Cornelius A, Esko, Tõnu, Davies, Gail, Pers, Tune H, Benyamin, Beben, Koellinger, Philipp D, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Entrepreneurship & Innovation (ABS, FEB), Epidemiology, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, and Internal Medicine

Subjects
Male, Multifactorial Inheritance, Cell Adhesion Molecules, Neuronal, LOCI, Social Sciences, Single-nucleotide polymorphism, Genome-wide association study, INTELLIGENCE, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Synaptic Transmission, Corrections, Cognition, Memory, medicine, ACADEMIC-ACHIEVEMENT, Dementia, GWAS, Humans, Learning, Effects of sleep deprivation on cognitive performance, GENOME-WIDE ASSOCIATION, Neural Cell Adhesion Molecules, Genetics, Multidisciplinary, Neuronal Plasticity, proxy-phenotype method, Memoria, COMPONENTS, Calcium-Binding Proteins, medicine.disease, Multiple comparisons problem, Octamer Transcription Factors, Female, SDG 4 - Quality Education
Abstract

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxyphenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. Refereed/Peer-reviewed

Published
2014

26. Birth order and myopia

Author

Seyhan Yazar, Igor Kaiserman, David A. Mackey, Richard A. Stone, Terri L. Young, George McMahon, Yossi Mandel, Jeremy A. Guggenheim, Seang-Mei Saw, Hannah Forward, Xiao-Yu Lin, Kate Northstone, and Cathy Williams

Subjects
Male, Longitudinal study, Refractive error, Adolescent, Epidemiology, Article, Young Adult, Risk Factors, Myopia, Odds Ratio, Prevalence, Medicine, Humans, Young adult, Israel, Child, Singapore, business.industry, Australia, Odds ratio, medicine.disease, Confidence interval, United Kingdom, Ophthalmology, Birth order, Increased risk, Optometry, Female, Birth Order, business, Demography, Cohort study, Follow-Up Studies
Abstract

Purpose: An association between birth order and reduced unaided vision (a surrogate for myopia) has been observed previously. We examined the association between birth order and myopia directly in four subject groups. Methods: Subject groups were participants in (1) the Avon Longitudinal Study of Parents and Children (ALSPAC; UK; age 15 years; N = 4401), (2) the Singapore Cohort Study of Risk Factors for Myopia (SCORM; Singapore; age 13 years; N = 1959), (3) the Raine Eye Health Study (REHS; Australia; age 20 years; N = 1344), and (4) Israeli Defense Force Pre-recruitment Candidates (IDFC; Israel; age 16–22 years; N = 888,277). The main outcome was odds ratios (OR) for myopia in first-born versus non-first-born individuals after adjusting for potential risk factors. Results: The prevalence of myopia was numerically higher in first-born versus non-first-born individuals in all study groups, but the strength of evidence varied widely. Adjusted ORs (95% confidence intervals, CIs) were: ALSPAC, 1.31 (1.05–1.64); SCORM, 1.25 (0.89–1.77); REHS, 1.18 (0.90–1.55); and IDFC, 1.04 (1.03–1.06). In the large IDFC sample, the effect size was greater (a) for the first-born versus fourth- or higher-born comparison than for the first-born versus second/third-born comparison (p

Published
2013

27. Coordinated genetic scaling of the human eye: shared determination of axial eye length and corneal curvature

Author

Kate Northstone, Nicholas J. Timpson, Ching-Yu Cheng, Susan M. Ring, Qiao Fan, Xin Zhou, George McMahon, John P. Kemp, Jeremy A. Guggenheim, Seang-Mei Saw, Cathy Williams, Tien Yin Wong, David M. Evans, Beate St Pourcain, Tin Aung, and Chiea Chuen Khor

Subjects
Adult, Male, medicine.medical_specialty, Refractive error, Adolescent, Body height, White People, Cornea, Asian People, Ophthalmology, medicine, Humans, Longitudinal Studies, Scaling, Mathematics, Aged, Aged, 80 and over, Corneal curvature, Mathematical analysis, Genetic variants, Axial length, Articles, Middle Aged, medicine.disease, Refractive Errors, Body Height, Axial Length, Eye, medicine.anatomical_structure, Cross-Sectional Studies, Human eye, Female, RE
Abstract

To examine the extent to which the two major determinants of refractive error, corneal curvature and axial length, are scaled relative to one another by shared genetic variants, along with their relationship to the genetic scaling of height.Corneal curvature, axial length, and height were measured in unrelated 14- to 17-year-old white European participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 1915) and in unrelated 40- to 80-year-old participants of the Singapore Chinese Eye Study (SCES; n = 1642). Univariate and bivariate heritability analyses were performed with methods that avoid confounding by common family environment, using information solely from genome-wide high-density genotypes.IN ALSPAC SUBJECTS, AXIAL LENGTH, CORNEAL CURVATURE, AND HEIGHT HAD SIMILAR LOWER-BOUND HERITABILITY ESTIMATES: axial length, h(2) = 0.46 (SE = 0.16, P = 0.002); corneal curvature, h(2) = 0.42 (SE = 0.16, P = 0.004); height, h(2) = 0.48 (SE = 0.17, P = 0.002). The corresponding estimates in the SCES were 0.79 (SE = 0.18, P0.001), 0.35 (SE = 0.20, P = 0.036), and 0.31 (SE = 0.20, P = 0.061), respectively. The genetic correlation between corneal curvature and axial length was 0.69 (SE = 0.17, P = 0.019) for ALSPAC participants and 0.64 (SE = 0.22, P = 0.003) for SCES participants. In the subset of 1478 emmetropic ALSPAC individuals, the genetic correlation was 0.85 (SE = 0.12, P = 0.008).These results imply that coordinated scaling of ocular component dimensions is largely achieved by hundreds to thousands of common genetic variants, each with a small pleiotropic effect. Furthermore, genome-wide association studies (GWAS) for either axial length or corneal curvature are likely to identify variants controlling overall eye size when using discovery cohorts dominated by emmetropes, but trait-specific variants in discovery cohorts dominated by ametropes.

Published
2013

28. Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

Author

Ching-Yu Cheng, Maria Schache, M. Kamran Ikram, Terri L. Young, Jeremy A. Guggenheim, Veronique Vitart, Stuart MacGregor, Virginie J.M. Verhoeven, Veluchamy A. Barathi, Jiemin Liao, Pirro G. Hysi, Joan E. Bailey-Wilson, Beate St. Pourcain, John P. Kemp, George McMahon, Nicholas J. Timpson, David M. Evans, Grant W. Montgomery, Aniket Mishra, Ya Xing Wang, Jie Jin Wang, Elena Rochtchina, Ozren Polasek, Alan F. Wright, Najaf Amin, Elisabeth M. van Leeuwen, James F. Wilson, Craig E. Pennell, Cornelia M. van Duijn, Paulus T.V.M. de Jong, Johannes R. Vingerling, Xin Zhou, Peng Chen, Ruoying Li, Wan-Ting Tay, Yingfeng Zheng, Merwyn Chew, Kathryn P. Burdon, Jamie E. Craig, Sudha K. Iyengar, Robert P. Igo, Jonathan H. Lass, Emily Y. Chew, Toomas Haller, Evelin Mihailov, Andres Metspalu, Juho Wedenoja, Claire L. Simpson, Robert Wojciechowski, René Höhn, Alireza Mirshahi, Tanja Zeller, Norbert Pfeiffer, Karl J. Lackner, Thomas Bettecken, Thomas Meitinger, Konrad Oexle, Mario Pirastu, Laura Portas, Abhishek Nag, Katie M. Williams, Ekaterina Yonova-Doing, Ronald Klein, Barbara E. Klein, S. Mohsen Hosseini, Andrew D. Paterson, Kari-Matti Makela, Terho Lehtimaki, Mika Kahonen, Olli Raitakari, Nagahisa Yoshimura, Fumihiko Matsuda, Li Jia Chen, Chi Pui Pang, Shea Ping Yip, Maurice K.H. Yap, Akira Meguro, Nobuhisa Mizuki, Hidetoshi Inoko, Paul J. Foster, Jing Hua Zhao, Eranga Vithana, E-Shyong Tai, Qiao Fan, Liang Xu, Harry Campbell, Brian Fleck, Igor Rudan, Tin Aung, Albert Hofman, André G. Uitterlinden, Goran Bencic, Chiea-Chuen Khor, Hannah Forward, Olavi Pärssinen, Paul Mitchell, Fernando Rivadeneira, Alex W. Hewitt, Cathy Williams, Ben A. Oostra, Yik-Ying Teo, Christopher J. Hammond, Dwight Stambolian, David A. Mackey, Caroline C.W. Klaver, Tien-Yin Wong, Seang-Mei Saw, Paul N. Baird, William Reinhart, Michael W. Belin, Robert L. Schultze, Todd Morason, Alan Sugar, Shahzad Mian, Hunson Kaz Soong, Kathryn Colby, Ula Jurkunas, Richard Yee, Mark Vital, Eduardo Alfonso, Carol Karp, Yunhee Lee, Sonia Yoo, Kristin Hammersmith, Elisabeth Cohen, Peter Laibson, Christopher Rapuano, Brandon Ayres, Christopher Croasdale, James Caudill, Sanjay Patel, Keith Baratz, William Bourne, Leo Maguire, Joel Sugar, Elmer Tu, Ali Djalilian, Vinod Mootha, James McCulley, Wayne Bowman, H. Dwight Cavanaugh, Steven Verity, David Verdier, Ann Renucci, Matt Oliva, Walter Rotkis, David R. Hardten, Ahmad Fahmy, Marlene Brown, Sherman Reeves, Elizabeth A. Davis, Richard Lindstrom, Scott Hauswirth, Stephen Hamilton, W. Barry Lee, Francis Price, Marianne Price, Kathleen Kelly, Faye Peters, Michael Shaughnessy, Thomas Steinemann, B.J. Dupps, David M. Meisler, Mark Mifflin, Randal Olson, Anthony Aldave, Gary Holland, Bartly J. Mondino, George Rosenwasser, Mark Gorovoy, Steven P. Dunn, David G. Heidemann, Mark Terry, Neda Shamie, Steven I. Rosenfeld, Brandon Suedekum, David Hwang, Donald Stone, James Chodosh, Paul G. Galentine, David Bardenstein, Katrina Goddard, Hemin Chin, Mark Mannis, Rohit Varma, Ingrid Borecki, Ophthalmology, Epidemiology, Internal Medicine, Clinical Genetics, Obstetrics & Gynecology, and Netherlands Institute for Neuroscience (NIN)

Subjects
Adult, Male, Refractive error, Adolescent, Gene Expression, Locus (genetics), Genome-wide association study, Biology, Ocular Axial Length, Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, 0302 clinical medicine, Asian People, SDG 3 - Good Health and Well-being, medicine, Genetics, Humans, GWAS, Genetic Predisposition to Disease, Genetics(clinical), RSPO1, Eye Proteins, Gene, Genetics (clinical), 030304 developmental biology, Genetic association, Aged, 0303 health sciences, ta1184, Heritability, Middle Aged, ta3121, medicine.disease, Refractive Errors, Axial Length, Eye, Genetic Loci, 030221 ophthalmology & optometry, Eye disorder, Female, Genome-Wide Association Study, Signal Transduction
Abstract

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Published
2013

29. Genome-wide association study identifies loci affecting blood copper, selenium and zinc

Author

John P. Kemp, George Davey Smith, Grant W. Montgomery, Andrew C. Heath, Veronica Dy, Beate St Pourcain, Debbie A Lawlor, Nicholas G. Martin, Pamela A. F. Madden, George McMahon, David M. Evans, Colin D Steer, John Whitfield, Gu Zhu, Jean Golding, and Nicholas J. Timpson

Subjects
Adult, Male, Erythrocytes, Genotype, chemistry.chemical_element, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Cohort Studies, Selenium, Pregnancy, Genetic variation, Genetics, Chromosomes, Human, Humans, Longitudinal Studies, Allele, Molecular Biology, Gene, Genetics (clinical), Association Studies Articles, Australia, Chromosome, Genetic Variation, General Medicine, United Kingdom, Zinc, chemistry, Genetic Loci, Female, Copper, Genome-Wide Association Study
Abstract

Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and > 2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P = 5.03 × 10(-10), and rs2769264, P = 2.63 × 10(-20)); for Se, a locus on chromosome 5 was significant in both cohorts (combined P = 9.40 × 10(-28) at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P = 6.40 × 10(-12); rs2120019, P = 1.55 × 10(-18); and rs4826508, P = 1.40 × 10(-12), respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).

Published
2013

30. GWAS of 126559 Individuals Identifies Genetic Variants Associated with Educational Attainment

Author

Maria Dimitriou, Klaus Berger, Jian Yang, Nicholas J. Timpson, George Dedoussis, Magnus Johannesson, Igor Rudan, Marisa Loitfelder, Kurt Lohman, Jürgen Wellmann, Osorio Meirelles, Johan G. Eriksson, Cornelia M. van Duijn, Francesco Cucca, Anu Realo, Gérard Waeber, David R. Van Wagoner, Samuli Ripatti, Alan F. Wright, George McMahon, Elizabeth G. Holliday, Lili Milani, Ute Bültmann, Olli T. Raitakari, Behrooz Z. Alizadeh, Reinhold Schmidt, Matthew Kowgier, André G. Uitterlinden, Sutapa Mukherjee, William G. Iacono, Judith M. Vonk, Lude Franke, John M. Starr, Antonio Terracciano, Rudolf Ferhmann, Pamela A. F. Madden, Marika Kaakinen, Helena Schmidt, Dorret I. Boomsma, Harry Campbell, Konstantin Shakhbazov, Lei Yu, Albert Hofman, Tõnu Esko, Cornelius A. Rietveld, Albert V. Smith, Arpana Agrawal, Wouter J. Peyrot, Stefania Bandinelli, David M. Evans, Nicolas W. Martin, Martin F. Elderson, Melissa E. Garcia, Danielle Posthuma, Ozren Polasek, Panos Deloukas, Pedro Marques Vidal, Sang Hong Lee, James F. Wilson, Robert F. Krueger, Paul Lichtenstein, Jan-Emmanuel De Neve, Fernando Rivadeneira, Laura J. Bierut, Sebastian E. Baumeister, Lawrence F. Bielak, Peter M. Visscher, Philipp Koellinger, Thais S. Rizzi, Rodney J. Scott, Mika Kähönen, Marco Masala, Debbie A Lawlor, Yongmei Liu, Ben A. Oostra, Jaime Derringer, Zoltán Kutalik, Carla A. Ibrahim-Verbaas, Toshiko Tanaka, Håkon K. Gjessing, Jae Hoon Sul, Marjo-Riitta Järvelin, Krista Fischer, Erik Ingelsson, David R. Weir, Kati Kristiansson, Thomas Illig, Jorma Viikari, George Davey-Smith, Antti-Pekka Sarin, Matt McGue, Ida Surakka, Andreas Mielck, Ivana Kolcic, Astanand Jugessur, Aldo Rustichini, Sarah E. Medland, Ronny Myhre, Veikko Salomaa, Mina K. Chung, H.-Erich Wichmann, Lynn Cherkas, Peter Lichtner, Michael B. Miller, Peter Vollenweider, Jüri Allik, Henning Tiemeier, Grant W. Montgomery, Eva Reinmaa, Dalton Conley, Adriaan Hofman, Patricia A. Peyser, David Schlessinger, Martin Preisig, Jessica D. Faul, Patrik K. E. Magnusson, David A. Bennett, Erkki Vartiainen, David Laibson, François Bastardot, Niina Eklund, Wolfgang Hoffmann, Terho Lehtimäki, Nicholas D. Hastie, John P. Rice, Rolf Holle, Antti Latvala, Guoný Eiríksdóttir, Luigi Ferrucci, Jennifer A. Smith, Christian Gieger, Veronique Vitart, Gail Davies, Sara Hägg, Juha Karjalainen, Matthijs J. H. M. van der Loos, Bo Jacobsson, Lydia Quaye, John Barnard, Beate St Pourcain, Jouke-Jan Hottenga, Daniel S. Evans, Jonathan P. Beauchamp, Tamara B. Harris, Ian J. Deary, Jari Lahti, Peng Lin, Markus Perola, Henry Völzke, Lenore J. Launer, David C. Liewald, Brenda W.J.H. Penninx, David Cesarini, Najaf Amin, Dale R. Nyholt, Roy Thurik, Aarno Palotie, Patrick J. F. Groenen, Elisabeth Widen, Caroline Hayward, Penelope A. Lind, Susan M. Ring, Lyle J. Palmer, Alexander Teumer, Kelly S. Benke, Christopher Oldmeadow, Katja Petrovic, Gonneke Willemsen, Andrew C. Heath, Harold Snieder, Jaakko Kaprio, Marja-Liisa Nuotio, Frank J. A. van Rooij, Robert M. Kirkpatrick, Nicholas G. Martin, Tomi E. Mäkinen, Michelle N. Meyer, Katri Räikkönen, Harm-Jan Westra, Daniel J. Benjamin, Jeffrey A. Boatman, Henrik Grönberg, Eva Albrecht, Sharon L.R. Kardia, Peter K. Joshi, Philip L. De Jager, Mariza de Andrade, Patricia A. Boyle, Jennifer R. Harris, Vilmundur Guonason, Christiaan de Leeuw, Juliette Harris, Dena G. Hernandez, Jingmei Li, Per Hall, Wei Zhao, Abdel Abdellaoui, Andres Metspalu, Christina Holzapfel, Stavroula Kanoni, Christopher F. Chabris, John Attia, Rauli Svento, Erasmus School of Economics, Epidemiology, Surgery, Neurology, Applied Economics, Research Methods and Techniques, Clinical Genetics, Internal Medicine, Child and Adolescent Psychiatry / Psychology, Econometrics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Biological Psychology, Functional Genomics, Management and Organisation, Tinbergen Institute, Amsterdam Neuroscience - Complex Trait Genetics, Rietveld, Cornelius A, Medland, Sarah E, Derringer, Jaime, Yang, Jian, Lee, Sang Hong, Koellinger, Philipp D, LifeLines Cohort Study, ABS Other Research (FEB), Reproductive Origins of Adult Health and Disease (ROAHD), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Public Health Research (PHR), Teaching and Teacher Education, Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes

Subjects
Netherlands Twin Register (NTR), Male, medicine.medical_specialty, Multifactorial Inheritance, Endophenotypes, social-science genetics, LOCI, SNP, Single-nucleotide polymorphism, Genome-wide association study, Biology, PREFERENCES, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Cognition, Polymorphism (computer science), medicine, GWAS, Humans, Allele, Polymorphism, education, gene, attainment, 030304 developmental biology, Genetics, 0303 health sciences, ENVIRONMENT, genome-wide association study, Multidisciplinary, Data Science, Replicate, Single Nucleotide, single-nucleotide polymorphism, linear polygenic score, ta3121, Educational attainment, Multidisciplinary Sciences, Educational Status, Female, Genetic Loci, Genome-Wide Association Study, educational attainment, Endophenotype, Medical genetics, 030217 neurology & neurosurgery
Abstract

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

Published
2013

31. A genome-wide association study for corneal curvature identifies the platelet-derived growth factor receptor α gene as a quantitative trait locus for eye size in white Europeans

Author

Jeremy A, Guggenheim, George, McMahon, John P, Kemp, Saeed, Akhtar, Beate, St Pourcain, Kate, Northstone, Susan M, Ring, David M, Evans, George Davey, Smith, Nicholas J, Timpson, and Cathy, Williams

Subjects
Male, Receptor, Platelet-Derived Growth Factor alpha, Adolescent, Quantitative Trait Loci, Astigmatism, Organ Size, Eye, Polymorphism, Single Nucleotide, eye diseases, Linkage Disequilibrium, White People, Cohort Studies, Cornea, Europe, Myopia, Humans, Female, sense organs, Genome-Wide Association Study, Research Article
Abstract

Purpose Corneal curvature is a key determinant of the refractive power of the eye. Variants in two genes, FKBP12-rapamycin complex-associated protein 1 (FRAP1) on chromosome 1p36.2 and platelet-derived growth factor receptor alpha (PDGFRA) on chromosome 4q12, have shown genome-wide significant association with normal variation in corneal curvature in a study of subjects of Asian origin. Variants at the PDGFRA locus have also shown genome-wide significant association with corneal astigmatism. Whether these variants influence other ocular parameters such as axial length has yet to be reported. We performed a genome-wide association study for corneal curvature in white European subjects from a population-based birth cohort, with the aim of replicating and extending the above findings. Methods White European children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were examined at age about 15.5 years (95% confidence interval=15.45 to 15.48 years). Radius of corneal curvature and axial eye length were measured with an IOLmaster. DNA samples were genotyped with Illumina HumanHap550 arrays and untyped variants imputed using MACH, with CEU individuals from HapMap release 22, Phase II NCBI B36, Single Nucleotide Polymorphism database 126 as the reference panel. Association between corneal curvature and single nucleotide polymorphism (SNP) genotype was tested, genome-wide, using mach2qtl, with sex as a covariate (n=2023; 46.6% male). Results The variant exhibiting the strongest evidence for association with corneal curvature (rs6554163; p=2.8×10−6) was located in the same linkage disequilibrium block as the previously discovered PDGFRA variants. Meta-analysis of the current and prior findings enhanced the evidence for association (rs17084051, p=4.5×10−14). rs6554163 genotype predicted 1.0% of variation in corneal curvature. In addition, these PDGFRA variants were associated with axial eye length, predicting 0.6% of the normal trait variation (p=5.3×10−4). Each copy of the minor allele of variants at the locus also increased the risk of corneal astigmatism in this white European cohort (odds ratio [OR]=1.24, 95% confidence interval=1.07–1.45; p=0.006). Conclusion As in Asians, variants at the PDGFRA locus influence corneal curvature (and corneal astigmatism). However, rather than affecting corneal curvature in isolation, this locus influences the size of the eye while maintaining its scaling.

Published
2012

32. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism

Author

Keith M. Godfrey, Aline Meirhaeghe, Jing Hua Zhao, Elina Hyppönen, Luis A. Moreno, Torben Hansen, James F. Wilson, Virpi Lindi, Eco J. C. de Geus, Ben A. Oostra, Karen A. Jameson, Liang Kee Goh, Philippe Froguel, Antje Körner, Ali Al-Odaib, H. Rob Taal, Dorret I. Boomsma, Craig E. Pennell, Terho Lehtimäki, Nicholas J. Timpson, George Dedoussis, Jorma Viikari, Haitao Zhang, Maiju Saarinen, Frédéric Gottrand, Daniel R. Witte, Vasiliki Lagou, Michael Stumvoll, Chris Power, Linda S. Adair, Anubha Mahajan, Karen L. Mohlke, Marcel den Hoed, Amanda J. Bennett, Dorota Monies, George McMahon, Zoltán Kutalik, Fowzan S. Alkuraya, Ewan R. Pearson, Marjan Kerkhof, Oluf Pedersen, Torben Jørgensen, Rachel M. Freathy, Albert Hofman, Elisabeth Widen, Bjarke Feenstra, Peter Vollenweider, Shikta Das, Frank Geller, Timo A. Lakka, Timothy M. Frayling, Seang-Mei Saw, Nadja Hawwa Vissing, Tuomas O. Kilpeläinen, Elisabeth Thiering, Jean Dallongeville, Hans Bisgaard, Eskil Kreiner-Møller, Sylvain Sebert, Mònica Guxens, Fernando Rivadeneira, Christina Kanaka-Gantenbein, Mads Melbye, Carla M. T. Tiesler, Susan M. Ring, Brian F. Meyer, Anke Tönjes, Nicholas J. Wareham, Ulla Sovio, Hazel Inskip, Nicole M. Warrington, Mirna Kirin, Claudia Flexeder, Marie Neergaard Harder, Berthold Hocher, Ehm A. Andersson, Andrew M. Prentice, Philippe Amouyel, Jouke-Jan Hottenga, Momoko Horikoshi, Jessica L. Buxton, Struan F.A. Grant, Ken K. Ong, Mariona Bustamante, Torsten Slowinski, Hakon Hakonarson, Marika Kaakinen, Jani Heikkinen, Gonneke Willemsen, Anneli Pouta, John P. Newnham, Allan Vaag, Christopher J. Groves, Thiemo Pfab, Debbie A Lawlor, Joachim Heinrich, Beverley M. Shields, Jianhua Zhao, Wieland Kiess, Olli Simell, Xavier Estivill, George Davey Smith, Andrew T. Hattersley, Colin Boreham, Bridget A. Knight, Ying Wu, Klaus Bønnelykke, Aaron Isaacs, Louise Pedersen, Kaixin Zhou, André G. Uitterlinden, Elisabeth M. van Leeuwen, John W. Holloway, Inga Prokopenko, Neil R. Robertson, Rany M. Salem, Alexandra I. F. Blakemore, Ruth J. F. Loos, Marjo-Riitta Järvelin, Sheila J. Barton, Beate St Pourcain, Jacqueline M. Vink, Norman Klopp, Anthony J. C. Fulford, David M. Evans, Gerard H. Koppelman, Hanieh Yaghootkar, Dennis O. Mook-Kanamori, David M. Hougaard, Christopher W. Kuzawa, Cyrus Cooper, Vincent W. V. Jaddoe, Diana L. Cousminer, Dirkje S. Postma, Matthew W. Gillman, Jonathan P. Bradfield, Pimphen Charoen, John P. Kemp, Ioanna Ntalla, Branwen J. Hennig, Cornelia M. van Duijn, Diane J. Berry, Mads V. Hollegaard, Johan G. Eriksson, Olli T. Raitakari, Mark I. McCarthy, Joel N. Hirschhorn, Harri Niinikoski, Faculty of Behavioural and Movement Sciences, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Medical Research Council (MRC), Erasmus MC other, Epidemiology, Medical Microbiology & Infectious Diseases, Clinical Genetics, Internal Medicine, Medical Oncology, Pediatrics, Groningen Research Institute of Pharmacy, Faculteit Medische Wetenschappen/UMCG, Groningen Research Institute for Asthma and COPD (GRIAC), Meta-Analyses of Glucose and Insulin related traits Consortium (MAGIC), Early Growth Genetics (EGG) Consortium, Horikoshi, Momoko, Yaghootkar, Hanieh, Mook-Kanamori, Dennis O, Sovio, Ulla, Hypponen, Elina Tuulikki, Freathy, Rachel M, Insulin-related traits Consortium (MAGIC), Meta-Analyses of, Glucose, Gastroenterology & Hepatology, Hematology, and Public Health

Subjects
Type 2/genetics, Netherlands Twin Register (NTR), Male, Genetic Linkage, Birth Weight/genetics, Physiology, Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, Type 2 diabetes, Head circumference, Genome-wide association studies, Fetal Development, GLUCOKINASE GENE, 0302 clinical medicine, Birth Weight, GENETICS & HEREDITY, Genetics & Heredity, 0303 health sciences, ADCY5, Body Height/genetics, COMMON VARIANTS, 11 Medical And Health Sciences, Single Nucleotide, Glucokinase gene, Metaanalysis, 3. Good health, HEAD CIRCUMFERENCE, Adult Birth Weight/*genetics Blood Pressure/genetics Body Height/*genetics Diabetes Mellitus, Type 2/genetics Female Fetal Development/*genetics *Genetic Linkage Genetic Predisposition to Disease Genome-Wide Association Study Humans Infant, Newborn Male Meta-Analysis as Topic Polymorphism, Single Nucleotide *Quantitative Trait Loci, Diabetes Mellitus, Type 2/genetics, Female, Life Sciences & Biomedicine, Blood-pressure, Adult, SUSCEPTIBILITY LOCI, Blood Pressure/genetics, Birth weight, Meta-Analyses of Glucose- and Insulin-related traits Consortium (MAGIC), Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, Genetic linkage, Early Growth Genetics (EGG) Consortium, Genetics, medicine, Diabetes Mellitus, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Polymorphism, Fetal Development/genetics, Genome-Wide Association Study, Infant, Newborn, CDKAL1, METAANALYSIS, 030304 developmental biology, Genetic association, Fasting glucose, Science & Technology, Infant, ta3121, 06 Biological Sciences, medicine.disease, Newborn, Body Height, INDIVIDUALS, Diabetes Mellitus, Type 2, Institut für Ernährungswissenschaft, TYPE-2 DIABETES RISK, FASTING GLUCOSE, Developmental Biology
Abstract

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism. Major funding for the research in this paper is provided by the Academy of Finland (project grants 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), 41071 (Skidi), 209072, 129255, 104781, 120315, 129269, 1114194, 206374, 251360, 139900/24300796, Center of Excellence in Complex Disease Genetics and SALVE) and Biocentrum Helsinki; Arthritis Research UK; the Augustinus Foundation; the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the Biomedical Research Council, Singapore (BMRC 06/1/21/19/466); BIF: Boehringer Ingelheim Fonds (travel grant to A.T.); the British Heart Foundation; the C.G. Sundell Foundation; the Canadian Institutes of Health Research (grant MOP-82893); Cancer Research UK; the Chief Scientist Office of the Scottish Government; the Children’s Hospital of Philadelphia (Institute Development Award); Conselleria de Sanitat Generalitat Valenciana; the Copenhagen Graduate School of Health Sciences; the Cotswold Foundation (Research Development Award); the Curtin University and Women and Infants Research Foundation; the Danish Health Insurance Societies (Health Fund); the Danish Medical Research Council; the Danish National Research Foundation; the Danish Pediatric Asthma Centre; the Danish Pharmacists’ Fund; the Danish Strategic Research Council; the Darlington Trust; the Department of Health and Social Services in Northern Ireland; Deutsche Forschungsgemeinschaft (DFG); Diabetes Hilfs- und Forschungsfonds Deutschland (DHFD; travel grant to M. Stumvoll); Diabetes UK (grants RD08/0003704 and RD08/0003692); the Dunhill Medical Trust; the Dutch Asthma Foundation (grants 3.4.01.26, 3.2.06.022, 3.4.09.081 and 3.2.10.085CO); the Dutch Ministry of the Environment (EFRE): Europäische Fonds für Regionale Entwicklung (LIFE Child Obesity); the Egmont Foundation; the Else Kröner-Fresenius Foundation; the Emil Aaltonen Foundation (T.L.); the ENGAGE project and grant agreement HEALTH-F4-2007-201413; the Erasmus Medical Center; Erasmus University, Rotterdam; the European Commission (EURO-BLCS, Beta-JUDO, Framework 5 award QLG1-CT-2000-01643, GABRIEL (Integrated Program LSH-2004-1.2.5-1 contract 018996), framework programme 6 EUROSPAN project (contract LSHG-CT-2006-018947), Sixth Research, Technological Development (RTD) Framework Programme (Contract FOOD-CT-2005-007034) and Seventh Framework Programme (FP7/2007-2013)); the European Research Council (ERC Advanced; 230374); the European Science Foundation (ESF; EU/QLRT-2001-01254); the Exeter NHS Research and Development; Faculty of Biology and Medicine of Lausanne; the Finnish Foundation of Cardiovascular Research; the Finnish Cultural Foundation; the Finnish Innovation Fund Sitra; the Finnish Ministry of Education and Culture; the Finnish Ministry of Social Affairs and Health; the Finnish Social Insurance Institution; the Foundation for Paediatric Research; Fundació La Marató de TV3; Fundación Roger Torné; Generalitat de Catalunya–Interminesterial Council for Research and Technological Innovation (CIRIT; 1999SGR) 00241; the German Diabetes Association (A.T.); the German Bundesministerium fuer Forschung und Technology (grants 01 AK 803 A-H and 01 IG 07015 G); the German Research Foundation for the Clinical Research Group Atherobesity KFO 152 (KO3512/1 to A.K.); GlaxoSmithKline; the Hagedorn Research Institute; Instituto de Salud Carlos III (CB06/02/0041, FIS PI041436, PI081151, PI041705 and PS09/00432 and FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314 and 09/02647); the Interdisciplinary Centre for Clinical Research at the University of Leipzig (B27 to A.T. and M. Stumvoll); the Integrated Research and Treatment Centre (IFB) Adiposity Diseases; the Jackstädt-Foundation; the Juho Vainio Foundation; the Juvenile Diabetes Research Foundation International (JDRF); Kuopio, Tampere and Turku University Hospital Medical Funds (grant 5031343 to T.A. Lakka and grant 9M048 to T.L.); The Lundbeck Foundation; the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care (LuCAMP); the March of Dimes Birth Defects Foundation (6-FY09-507); the MRC, UK (grants 74882, G0000934, G0601653, G0500539, G0600705, G0601261, G0600331, PrevMetSyn/SALVE PS0476 and MC-A760-5QX00); the Munich Center of Health Sciences (MC Health); the National Health and Medical Research Council of Australia (grants 403981 and 003209); the US National Human Genome Research Institute; the US National Institute of Allergy and Infectious Diseases; the US National Institute of Child Health and Human Development; the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); the US National Institutes of Health (grants U01DK062418, U01HG004423, U01HG004446, U01HG004438, R01DK075787, 1R01HD056465-01A, R01D0042157-01A, DK078150, TW05596, HL085144, HD054501, RR20649, ES10126, DK56350 and Biomedical Research Centers funding); the Netherlands Bioinformatics Centre (NBIC) BioAssist (RK/2008.024); a National Heart, Lung, and Blood Institute (NHLBI) grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01); the NIH Genetic Association Information Network (GAIN); the NIH/National Institute of Mental Health (NIMH) (5R01MH63706:02 and MH081802); the Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06); the Novo Nordisk Foundation Center for Basic Metabolic Research; the Center for Medical Systems Biology (CMSB; NWO Genomics); the Netherlands Organization for Scientific Research (NWO: Social Sciences (MaGW) and the Netherlands Organization for Health Research and Development (ZonMw) (Middelgroot-911-09-032, Spinozapremie 56-464-14192, 904-61-090, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 985-10-002, 40-0056-98-9032 and 912-03-031); the Paavo Nurmi Foundation; the Peninsula NIHR Clinical Research Facility; the Pharmacy Foundation of 1991; the PhD School of Molecular Metabolism University of Southern Denmark; the Raine Medical Research Foundation; the Royal Society; the Sigrid Juselius Foundation; South West NHS Research and Development; the Spanish Ministry of Science and Innovation (SAF2008-00357), Turku University Hospital; the Swiss National Science Foundation (33CSCO-122661); the Tampere Tuberculosis Foundation; the Telethon Institute for Child Health Research; the Turku University Foundation; the US Centers for Disease Control and Prevention; University Hospital Oulu, Biocenter, the University of Oulu (75617); the University of Bristol; the University of Potsdam; the University of Southampton; the University of Western Australia (UWA); the VU Institute for Health and Care Research (EMGO+) and the Neuroscience Campus Amsterdam (NCA); the Wellcome Trust (grants GR069224, WT088806, 068545/Z/02, 076467, 085301, 090532, 083270, 083948, 085541/Z/08/Z, WT089549 and WT083431MA); and the Yrjö Jahnsson Foundation.

Published
2012

33. Time outdoors and physical activity as predictors of incident myopia in childhood: a prospective cohort study

Author

Andy R Ness, George McMahon, Cathy Williams, Jeremy A. Guggenheim, Kate Northstone, Callum Mattocks, Beate St Pourcain, and Kevin Deere

Subjects
Male, medicine.medical_specialty, Longitudinal study, Time Factors, Adolescent, genetic structures, RJ101, Emmetropia, Kaplan-Meier Estimate, Leisure Activities, Risk Factors, Surveys and Questionnaires, medicine, Myopia, Humans, Prospective Studies, Prospective cohort study, Child, Exercise, Dioptre, Proportional hazards model, business.industry, Incidence, Hazard ratio, Articles, Confidence interval, eye diseases, England, Physical therapy, Regression Analysis, RE, Female, business, Cohort study, Demography
Abstract

PURPOSE: Time spent in "sports/outdoor activity" has shown a negative association with incident myopia during childhood. We investigated the association of incident myopia with time spent outdoors and physical activity separately. METHODS: Participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed by noncycloplegic autorefraction at ages 7, 10, 11, 12, and 15 years, and classified as myopic (≤-1 diopters) or as emmetropic/hyperopic (≥-0.25 diopters) at each visit (N = 4,837-7,747). Physical activity at age 11 years was measured objectively using an accelerometer, worn for 1 week. Time spent outdoors was assessed via a parental questionnaire administered when children were aged 8-9 years. Variables associated with incident myopia were examined using Cox regression. RESULTS: In analyses using all available data, both time spent outdoors and physical activity were associated with incident myopia, with time outdoors having the larger effect. The results were similar for analyses restricted to children classified as either nonmyopic or emmetropic/hyperopic at age 11 years. Thus, for children nonmyopic at age 11, the hazard ratio (95% confidence interval, CI) for incident myopia was 0.66 (0.47-0.93) for a high versus low amount of time spent outdoors, and 0.87 (0.76-0.99) per unit standard deviation above average increase in moderate/vigorous physical activity. CONCLUSION: Time spent outdoors was predictive of incident myopia independently of physical activity level. The greater association observed for time outdoors suggests that the previously reported link between "sports/outdoor activity" and incident myopia is due mainly to its capture of information relating to time outdoors rather than physical activity.

Published
2012

34. Season of birth, daylight hours at birth, and high myopia

Author

Yen-Po Chen, Cathy Williams, Tetyana Zayats, Ankush Prashar, Jeremy A. Guggenheim, and George McMahon

Subjects
Adult, Male, medicine.medical_specialty, genetic structures, Season of birth, Adolescent, Cross-sectional study, Birth weight, Photoperiod, Young Adult, Risk Factors, Ophthalmology, Myopia, Prevalence, Medicine, Humans, Daylight, Aged, Retrospective Studies, Aged, 80 and over, medicine.diagnostic_test, business.industry, Parturition, Dose-Response Relationship, Radiation, Odds ratio, Middle Aged, eye diseases, Confidence interval, United Kingdom, Cross-Sectional Studies, Eye examination, Population study, RE, Female, Seasons, business, Demography
Abstract

Purpose: Mandel et al recently reported that season of birth and daylight hours (photoperiod) at birth were associated with moderate and high levels of myopia in Israeli conscripts. We sought to investigate whether these associations were evident in subjects from the United Kingdom (UK). Design: Retrospective cross-sectional study. Participants: The study population comprised 74,459 subjects aged 18 to 100 years attending UK optometry practices for an eye examination. Methods: Data comprising non-cycloplegic spectacle prescription, sex, date of birth, and date of eye examination were collected from UK optometry practices. The average refractive error in fellow eyes was used to classify the degree of myopia in diopters (D) for each subject as follows: absent (??0.75 D), low (?0.75 to ?2.99 D), moderate (?3.00 to ?5.99 D), or high (??6.00 D). The average monthly hours of daylight for London, UK, were classified into 1 of 4 “photoperiod categories,” following Mandel et al. The odds ratio (OR) for each level of severity of myopia was calculated using multivariate logistic regression with age, sex, and either season of birth or photoperiod category as risk factors. Main Outcome Measures: The OR for season of birth and photoperiod category as potential risk factors for myopia. Results: Season of birth was significantly associated with the presence of high myopia: Subjects born in summer or autumn were more likely to be highly myopic compared with those born in winter (summer OR ? 1.17; 95% confidence interval [CI], 1.05–1.30; P ? 0.006; autumn OR ? 1.16; 95% CI, 1.04–1.30; P ? 0.007). However, season of birth was not a significant risk factor for low or moderate myopia. Photoperiod category was weakly associated with low myopia (OR ? 0.94; 95% CI, 0.89–0.99; P ? 0.019), but with a direction of effect opposite to that observed by Mandel et al. Conclusions: As in Israel, a disproportionate number of UK high myopes were born in summer or autumn rather than in winter. However, unlike the situation in Israel, this association does not seem to be related to daylight hours during the postnatal period, implicating alternative physiologic influences that vary with season, such as birth weight.

Published
2008

35. Body Stature Growth Trajectories during Childhood and the Development of Myopia

Author

Jeremy A. Guggenheim, Kate Northstone, Laura D Howe, Lavinia Paternoster, Cathy Williams, John P. Kemp, George McMahon, and Kate Tilling

Subjects
Male, Refractive error, Longitudinal study, Adolescent, genetic structures, Article, Prospective analysis, Optics, Weight growth, Myopia, Humans, Medicine, Prospective Studies, Child, Prospective cohort study, business.industry, Body Weight, Infant, Newborn, Infant, Regression analysis, Refractive Errors, medicine.disease, Body Height, Adult height, Ophthalmology, Child, Preschool, Regression Analysis, Female, business, Birth cohort, Demography
Abstract

Stature at a particular age can be considered the cumulative result of growth during a number of preceding growth trajectory periods. We investigated whether height and weight growth trajectories from birth to age 10 years were related to refractive error at ages 11 and 15 years, and eye size at age 15 years.Prospective analysis in a birth cohort.Children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) U.K. birth cohort (minimum N = 2676).Growth trajectories between birth and 10 years were modeled from a series of height and weight measurements (N = 6815). Refractive error was assessed by noncycloplegic autorefraction at ages 11 and 15 years (minimum N = 4737). Axial length (AXL) and radius of corneal curvature were measured with an IOLMaster (Carl Zeiss Meditec, Welwyn Garden City, U.K.) at age 15 years (minimum N = 2676). Growth trajectories and an allelic score for 180 genetic variants associated with adult height were tested for association with refractive error and eye size.Noncycloplegic autorefraction at ages 11 and 15 years, and AXL and corneal curvature at age 15 years.Height growth trajectory during the linear phase between 2.5 and 10 years was negatively associated with refractive error at 11 and 15 years (P0.001), but explained0.5% of intersubject variation. Height and weight growth trajectories, especially shortly after birth, were positively associated with AXL and corneal curvature (P0.001), predicting 1% to 5% of trait variation. Height growth after 2.5 years was not associated with corneal curvature, whereas the association with AXL continued up to 10 years. The height allelic score was associated with corneal curvature (P = 0.03) but not with refractive error or AXL.Up to the age of 10 years, shared growth mechanisms contribute to scaling of eye and body size but minimally to the development of myopia.The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Published
2013

36. Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero

Author

Nicole M, Warrington, Enisa, Shevroja, Gibran, Hemani, Pirro G, Hysi, Yunxuan, Jiang, Adam, Auton, Cindy G, Boer, Massimo, Mangino, Carol A, Wang, John P, Kemp, George, McMahon, Carolina, Medina-Gomez, Martha, Hickey, Katerina, Trajanoska, Dieter, Wolke, M Arfan, Ikram, Grant W, Montgomery, Janine F, Felix, Margaret J, Wright, David A, Mackey, Vincent W, Jaddoe, Nicholas G, Martin, Joyce Y, Tung, George, Davey Smith, Craig E, Pennell, Tim D, Spector, Joyce, van Meurs, Fernando, Rivadeneira, Sarah E, Medland, David M, Evans, Erasmus MC other, Internal Medicine, Epidemiology, and Pediatrics

Subjects
Adult, Male, Sex Characteristics, Genetic Variation, Fingers, Pregnancy, Androgens, Humans, Female, Testosterone, Association Studies Article, Biomarkers, Genome-Wide Association Study, Retrospective Studies
Abstract

The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a non-invasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sex-specific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N = 15 661, with replication N = 75 821), we identified 11 loci (9 novel) explaining 3.8% of the variance in mean 2D:4D ratio. We also found weak evidence for association (β = 0.06; P = 0.02) between 2D:4D ratio and sensitivity to testosterone [length of the CAG microsatellite repeat in the androgen receptor (AR) gene] in females only. Furthermore, genetic variants associated with (adult) testosterone levels and/or sex hormone-binding globulin were not associated with 2D:4D ratio in our sample. Although we were unable to find strong evidence from our genetic study to support the hypothesis that 2D:4D ratio is a direct biomarker of prenatal exposure to androgens in healthy individuals, our findings do not explicitly exclude this possibility, and pathways involving testosterone may become apparent as the size of the discovery sample increases further. Our findings provide new insight into the underlying biology shaping 2D:4D variation in the general population.

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37. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Author

Jing Hua Zhao, Vilmundur Gudnason, Robin Haring, Enda M. Byrne, Christian Gieger, Marek Zygmunt, Lude Franke, Peter Kraft, Eric Boerwinkle, Matthias W. Beckmann, Catharina A. Hartman, Thorkild I. A. Sørensen, Aida Karina Dieffenbach, André G. Uitterlinden, Grant W. Montgomery, Graham G. Giles, Felix R. Day, Anja Rudolph, Arto Mannermaa, Sven Bergmann, Nora Franceschini, Julian Peto, Ellen W. Demerath, Diana L. Cousminer, Wei Ang, Gudmar Thorleifsson, Patrick F. McArdle, Dieter Flesch-Janys, Albertine J. Oldehinkel, Irene L. Andrulis, Aarno Palotie, Nicholas J. Timpson, Paolo Peterlongo, Johan G. Eriksson, Bernardo Bonanni, Dorret I. Boomsma, J. Margriet Collée, Immaculata De Vivo, Bjarke Feenstra, Teresa Ferreira, Cornelia M. van Duijn, Nancy L. Pedersen, Deborah J. Thompson, Peter Vollenweider, Douglas F. Easton, Pascal Guénel, Anna Maria Storniolo, Erik Ingelsson, Gisli Masson, Annika Lindblom, Stefania Bandinelli, Elisabeth Widen, Doris Stöckl, Veikko Salomaa, Zoltán Kutalik, Nicholas J. Wareham, Joanne M. Murabito, Eleonora Porcu, Fergus J. Couch, Katri Pylkäs, Luigi Ferrucci, Wendy L. McArdle, Frank Geller, Andrea D. Coviello, Lynda M. Rose, Daniel L. Koller, Ute Hamann, Ulla Sovio, Daniel F. Gudbjartsson, Georgia Chenevix-Trench, Roger L. Milne, Unnur Thorsteinsdottir, Paul M. Ridker, Henry Völzke, John R. B. Perry, Stephen J. Chanock, Tanguy Corre, Mads Melbye, Ben A. Oostra, Albert V. Smith, Tõnu Esko, Melissa E. Garcia, Debbie A Lawlor, Meir J. Stampfer, Per Hall, Patrick Sulem, Massimo Mangino, Nicholas G. Martin, David J. Hunter, Laura Crisponi, Tatiana Foroud, Antonietta Robino, Michael J. Econs, Susan M. Ring, Natalia Tšernikova, Dirkje S. Postma, Lavinia Paternoster, Peter A. Fasching, Tamara B. Harris, Ellen A. Nohr, Javier Benitez, Ruth J. F. Loos, Robert Winqvist, Andres Metspalu, Jenny A. Visser, Heather A. Boyd, Jonathan Tyrer, Alexander Teumer, Tim D. Spector, Sandra Lai, Douglas P. Kiel, Kamila Czene, Hiltrud Brauch, George Davey Smith, Julia A. Knight, Erin K. Wagner, Suiqun Guo, Tune H. Pers, Patrik K. E. Magnusson, Kathryn L. Lunetta, Hoda Anton-Culver, Marjanka K. Schmidt, George McMahon, Ken K. Ong, Adamo Pio D'Adamo, Veli-Matti Kosma, Jinhui Chen, Paul D.P. Pharoah, Diether Lambrechts, Femke Atsma, Serena Sanna, Ilja M. Nolte, Eco de Geus, Daniel I. Chasman, Emmi Tikkanen, John L. Hopper, Anna Murray, Laura M. Yerges-Armstrong, Sanela Kjellqvist, Eva Albrecht, Hermann Brenner, Paolo Gasparini, Bruce H. R. Wolffenbuttel, Alison M. Dunning, John P. Rice, Craig E. Pennell, Mark I. McCarthy, Andrea Ganna, Henri Wallaschofski, Frank B. Hu, Gérard Waeber, Henrik Flyger, Evelin Mihailov, Peter Devilee, Lisette Stolk, Behrooz Z. Alizadeh, Jouke-Jan Hottenga, Najaf Amin, Patrick Neven, Reedik Mägi, Kyriaki Michailidou, Kari Stefansson, Munro Peacock, Julie E. Buring, Laura J. Bierut, Cathy E. Elks, Marjo-Riitta Järvelin, Montserrat Garcia-Closas, Anneli Pouta, David Schlessinger, Harold Snieder, Chunyan He, Joe Dennis, Heli Nevanlinna, Gonneke Willemsen, Andrew C. Heath, Elizabeth A. Streeten, Albert Hofman, Angela Cox, Maartje J. Hooning, Lili Milani, Margaret J. Wright, Fernando Rivadeneira, Gudny Eiriksdottir, Mellissa C. Southey, Qin Wang, Paolo Radice, Manjeet K. Bolla, Kay-Tee Khaw, Carl Blomqvist, Melanie Waldenberger, Sheila Ulivi, David Couper, Jenny Chang-Claude, David Karasik, Stig E. Bojesen, Andrew D. Johnson, David P. Strachan, Perry, John [0000-0001-6483-3771], Day, Felix [0000-0003-3789-7651], Thompson, Deborah [0000-0003-1465-5799], Zhao, Jing Hua [0000-0003-4930-3582], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Sovio, Ulla [0000-0002-0799-1105], Tyrer, Jonathan [0000-0003-3724-4757], Wang, Jean [0000-0002-9139-0627], Khaw, Kay-Tee [0000-0002-8802-2903], Wareham, Nicholas [0000-0003-1422-2993], Easton, Douglas [0000-0003-2444-3247], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Australian Ovarian Cancer Study, GENICA Network, kConFab, LifeLines Cohort Study, InterAct Consortium, Early Growth Genetics (EGG) Consortium, Cousminer, D.L., Stergiakouli, E., Berry, D.J., Ang, W., Groen-Blokhuis, M.M., Körner, A., Siitonen, N., Ntalla, I., Marinelli, M., Perry, J.R., Kettunen, J., Jansen, R., Surakka, I., Timpson, N.J., Ring, S., McMahon, G., Power, C., Wang, C., Kähönen, M., Viikari, J., Lehtimäki, T., Middeldorp, C.M., Hulshoff Pol, H.E., Neef, M., Weise, S., Pahkala, K., Niinikoski, H., Zeggini, E., Panoutsopoulou, K., Bustamante, M., Penninx, B.W., Murabito, J., Torrent, M., Dedoussis, G.V., Kiess, W., Boomsma, D.I., Pennell, C.E., Raitakari, O.T., Hyppönen, E., Davey Smith, G., Ripatti, S., McCarthy, M.I., Widén, E., Alizadeh, B.Z., de Boer, R.A., Boezen, H.M., Bruinenberg, M., Franke, L., van der Harst, P., Hillege, H.L., van der Klauw, M.M., Navis, G., Ormel, J., Postma, D., Rosmalen, J.G., Slaets, J.P., Snieder, H., Stolk, R.P., Wolffenbuttel, B.H., Wijmenga, C., Forouhi, N., Kerrison, N.D., Langenberg, C., Scott, R.A., Sharp, S.J., Sims, M., Barroso, I., Deloukas, P., Arriola, L., Balkau, B., Barricarte, A., Boeing, H., Franks, P.W., Gonzalez, C., Grioni, S., Kaaks, R., Key, T.J., Navarro, C., Nilsson, P.M., Overvad, K., Palli, D., Panico, S., Quirós, J., Rolandsson, O., Sacerdote, C., Sánchez, M.J., Slimani, N., Tjonneland, A., Tumino, R., van der A, D.L., van der Schouw, Y.T., Riboli, E., Wareham, N.J., Bowtell, D.D., Green, A., Chenevix-Trench, G., deFazio, A., Gertig, D., Webb, P.M., Brauch, H., Justenhoven, C., Hamann, U., Ko, Y.D., Baisch, C., Fischer, H.P., Pesch, B., Rabstein, S., Spickenheuer, A., Harth, V., Aghmesheh, M., Amor, D., Andrews, L., Antill, Y., Armitage, S., Arnold, L., Balleine, R., Bankier, A., Bastick, P., Beesley, J., Beilby, J., Bennett, I., Bennett, B., Berry, G., Blackburn, A., Bogwitz, M., Brennan, M., Brown, M., Buckley, M., Burgess, M., Burke, J., Butow, P., Byron, K., Callen, D., Campbell, I., Chauhan, D., Christian, A., Clarke, C., Colley, A., Cotton, D., Crook, A., Cui, J., Culling, B., Cummings, M., Dawson, S.J., Delatycki, M., Dickson, R., Dixon, J., Dobrovic, A., Dudding, T., Edkins, T., Edwards, S., Eisenbruch, M., Farshid, G., Fawcett, S., Fellows, A., Fenton, G., Field, M., Firgaira, F., Flanagan, J., Fleming, J., Fong, P., Forbes, J., Fox, S., French, J., Friedlander, M., Gaff, C., Gardner, M., Gattas, M., George, P., Giles, G., Gill, G., Goldblatt, J., Greening, S., Grist, S., Eric, H., Hardie, K., Harris, M., Hart, S., Hayward, N., Healey, S., Heiniger, L., Hopper, J., Humphrey, E., Hunt, C., James, P., Jenkins, M., Jones, A., Kefford, R., Kidd, A., Kiely, B., Kirk, J., Koehler, J., Kollias, J., Kovalenko, S., Lakhani, S., Leaming, A., Leary, J., Lim, J., Lindeman, G., Lipton, L., Lobb, L., Mann, G., Marsh, D., McLachlan, S.A., Meiser, B., Meldrum, C., Milne, R., Mitchell, G., Newman, B., O'Connell, S., O'Loughlin, I., Osborne, R., Pachter, N., Patterson, B., Peters, L., Phillips, K., Price, M., Purser, L., Reeve, J., Reeve, T., Richards, R., Rickard, E., Robinson, B., Rudzki, B., Saleh, M., Salisbury, E., Sambrook, J., Saunders, C., Saunus, J., Sayer, R., Scott, E., Scott, R., Scott, C., Seshadri, R., Sexton, A., Sharma, R., Shelling, A., Simpson, P., Southey, M., Spurdle, A., Suthers, G., Sykes, P., Taylor, D., Taylor, J., Thierry, B., Thompson, E., Thorne, H., Townshend, S., Trainer, A., Tran, L., Tucker, K., Tyler, J., Visvader, J., Walker, L., Walpole, I., Waring, P., Warner, B., Warren, G., Williams, R., Wilson, J., Winship, I., Wu, K., Young, M.A., Public Health, Internal Medicine, Epidemiology, Clinical Genetics, Medical Oncology, Child and Adolescent Psychiatry / Psychology, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Research Institute for Asthma and COPD (GRIAC), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Political Science, Perry, John R. B, Day, Felix, Elks, Cathy E, Sulem, Patrick, Thompson, Deborah J, Ferreira, Teresa, He, Chunyan, Chasman, Daniel I, Esko, Tõnu, Thorleifsson, Gudmar, Albrecht, Eva, Ang, Wei Q, Corre, Tanguy, Cousminer, Diana L, Feenstra, Bjarke, Franceschini, Nora, Ganna, Andrea, Johnson, Andrew D, Kjellqvist, Sanela, Lunetta, Kathryn L, Mcmahon, George, Nolte, Ilja M, Paternoster, Lavinia, Porcu, Eleonora, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Tšernikova, Natalia, Tikkanen, Emmi, Ulivi, Sheila, Wagner, Erin K, Amin, Najaf, Bierut, Laura J, Byrne, Enda M, Hottenga, Jouke Jan, Koller, Daniel L, Mangino, Massimo, Pers, Tune H, Yerges Armstrong, Laura M, Hua Zhao, Jing, Andrulis, Irene L, Anton Culver, Hoda, Atsma, Femke, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Buring, Julie E, Chang Claude, Jenny, Chanock, Stephen, Chen, Jinhui, Chenevix Trench, Georgia, Collée, J. Margriet, Couch, Fergus J, Couper, David, Coviello, Andrea D, Cox, Angela, Czene, Kamila, D'Adamo, Adamo Pio, Davey Smith, George, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dieffenbach, Aida K, Dunning, Alison M, Eiriksdottir, Gudny, Eriksson, Johan G, Fasching, Peter A, Ferrucci, Luigi, Flesch Janys, Dieter, Flyger, Henrik, Foroud, Tatiana, Franke, Lude, Garcia, Melissa E, García Closas, Montserrat, Geller, Frank, de Geus, Eco E. J, Giles, Graham G, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Guo, Suiqun, Hall, Per, Hamann, Ute, Haring, Robin, Hartman, Catharina A, Heath, Andrew C, Hofman, Albert, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Hunter, David J, Karasik, David, Kiel, Douglas P, Knight, Julia A, Kosma, Veli Matti, Kutalik, Zoltan, Lai, Sandra, Lambrechts, Diether, Lindblom, Annika, Mägi, Reedik, Magnusson, Patrik K, Mannermaa, Arto, Martin, Nicholas G, Masson, Gisli, Mcardle, Patrick F, Mcardle, Wendy L, Melbye, Mad, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L, Nevanlinna, Heli, Neven, Patrick, Nohr, Ellen A, Oldehinkel, Albertine J, Oostra, Ben A, Palotie, Aarno, Peacock, Munro, Pedersen, Nancy L, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul D. 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Subjects
Netherlands Twin Register (NTR), Male, Parents, CENTRAL PRECOCIOUS PUBERTY, Genome-wide association study, Disease, VARIANTS, DISEASE, Body Mass Index, 0302 clinical medicine, Adolescent, Age Factors, Alleles, Breast Neoplasms/genetics, Cardiovascular Diseases/genetics, Child, Diabetes Mellitus, Type 2/genetics, Europe/ethnology, Female, Genetic Loci/genetics, Genome-Wide Association Study, Genomic Imprinting/genetics, Humans, Hypothalamo-Hypophyseal System/physiology, Intercellular Signaling Peptides and Proteins/genetics, Membrane Proteins/genetics, Menarche/genetics, Obesity/genetics, Ovary/physiology, Polymorphism, Single Nucleotide/genetics, Potassium Channels, Tandem Pore Domain/genetics, Proteins/genetics, Quantitative Trait Loci/genetics, Receptors, GABA-B/metabolism, Receptors, Retinoic Acid/metabolism, Ribonucleoproteins/genetics, Intercellular Signaling Peptides and Protein, Age Factor, Tandem Pore Domain, GENE-EXPRESSION, 0303 health sciences, BREAST-CANCER RISK, 3. Good health, Ribonucleoproteins, Cardiovascular Diseases, Menarche, Intercellular Signaling Peptides and Proteins, Science & Technology - Other Topics, GENICA Network, Breast Neoplasm, Type 2, Human, Hypothalamo-Hypophyseal System, Quantitative Trait Loci, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, REVEALS, Diabetes Mellitus, Polymorphism, METAANALYSIS, Science & Technology, ta1184, Calcium-Binding Proteins, Proteins, HUMAN PREFRONTAL CORTEX, ta3121, ta3123, Diabetes Mellitus, Type 2, Genetic Loci, CELLS, 030217 neurology & neurosurgery, LifeLines Cohort Study, Potassium Channels, Receptors, Retinoic Acid, Retinoic Acid, Australian Ovarian Cancer Study, Polymorphism (computer science), Cardiovascular Disease, Receptors, WIDE ASSOCIATION, Membrane Protein, Allele, 2. Zero hunger, Genetics, Multidisciplinary, Single Nucleotide, Europe, Multidisciplinary Sciences, kConFab, Breast Neoplasms, Genomic Imprinting, Membrane Proteins, Obesity, Ovary, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain, Receptors, GABA-B, General Science & Technology, Ubiquitin-Protein Ligases, Quantitative trait locus, Biology, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Early Growth Genetics (EGG) Consortium, 030304 developmental biology, Protein, GABA-B, Ribonucleoprotein, InterAct Consortium, Genetic architecture, Parent, Genomic imprinting
Abstract

Contains fulltext : 136472.pdf (Publisher’s version ) (Closed access) Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

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