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4 results on '"Genomic Imprinting/genetics"'

1. Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus

Author

Andrea Gazzin, Diana Carli, Federica Maria Valente, Suzanna G.M. Frints, Marielle Alders, Alessandro Mussa, Flavia Cerrato, Basilia Acurzio, Monica Franzese, Claudia Angelini, Giovanni Battista Ferrero, Laura Pignata, Andrea Freschi, Katherine L. Hill-Harfe, Andrea Riccio, Saskia M. Maas, Charles A. Williams, Fulvio Gabbarini, Jet Bliek, Angela Sparago, Valente, Federica Maria, Sparago, Angela, Freschi, Andrea, Hill-Harfe, Katherine, Maas, Saskia M., Frints, Suzanna Gerarda Maria, Alders, Marielle, Pignata, Laura, Franzese, Monica, Angelini, Claudia, Carli, Diana, Mussa, Alessandro, Gazzin, Andrea, Gabbarini, Fulvio, Acurzio, Basilia, Ferrero, Giovanni Battista, Bliek, Jet, Williams, Charles A., Riccio, Andrea, Cerrato, Flavia, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, MUMC+: DA KG Bedrijfsbureau (9), Klinische Genetica, and RS: FHML non-thematic output

Subjects
Male, Non-Mendelian inheritance, Beckwith-Wiedemann Syndrome, Beckwith–Wiedemann syndrome, Chromosomes, Human, Pair 11/genetics, Mice, COPY NUMBER VARIATIONS, imprinting disorders, Copy-number variation, Pair 11, Imprinting (psychology), Child, Genetics (clinical), Genetics, 0303 health sciences, DNA methylation, Beckwith-Wiedemann Syndrome/epidemiology, 030305 genetics & heredity, PREVALENCE, Pedigree, Child, Preschool, KCNQ1 Potassium Channel, Female, Maternal Inheritance, Maternal Inheritance/genetics, Haploinsufficiency, DNA Methylation/genetics, Human, Adult, Adolescent, Locus (genetics), LONG-QT SYNDROME, Biology, Pair 11/genetics, Article, Chromosomes, MECHANISMS, Introns/genetics, Genomic Imprinting, Young Adult, 03 medical and health sciences, long QT syndrome, medicine, CONTROL REGION, Animals, Humans, genomic imprinting, Chromosomes, Human, Pair 11, DNA Methylation, Infant, Introns, Preschool, 030304 developmental biology, imprinting disorder, Genomic Imprinting/genetics, MUTATIONS, DELETION, medicine.disease, GENE, RNA, Genomic imprinting, KCNQ1 Potassium Channel/genetics
Abstract

Purpose: Beckwith-Wiedemann syndrome (BWS) is a developmental disorder caused by dysregulation of the imprinted gene cluster of chromosome 11p15.5 and often associated with loss of methylation (LOM) of the imprinting center 2 (IC2) located in KCNQ1 intron 10. To unravel the etiological mechanisms underlying these epimutations, we searched for genetic variants associated with IC2 LOM.Methods: We looked for cases showing the clinical features of both BWS and long QT syndrome (LQTS), which is often associated with KCNQ1 variants. Pathogenic variants were identified by genomic analysis and targeted sequencing. Functional experiments were performed to link these pathogenic variants to the imprinting defect.Results: We found three rare cases in which complete IC2 LOM is associated with maternal transmission of KCNQ1 variants, two of which were demonstrated to affect KCNQ1 transcription upstream of IC2. As a consequence of KCNQ1 haploinsufficiency, these variants also cause LQTS on both maternal and paternal transmission.Conclusion: These results are consistent with the hypothesis that, similar to what has been demonstrated in mouse, lack of transcription across IC2 results in failure of methylation establishment in the female germline and BWS later in development, and also suggest a new link between LQTS and BWS that is important for genetic counseling.

Published
2019
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2. Imprinting analysis in spermatozoa prepared for intracytoplasmic sperm injection (ICSI)

Author

Willy Lissens, Wolfgang Weidner, Martina Manning, Ingeborg Liebaers, Andre Van Steirteghem, Communication Sciences, Department of Embryology and Genetics, and Embriology and Human Genetics

Subjects
Adult, Male, endocrine system, Urology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Semen, Biology, Polymerase Chain Reaction, Infertility, Male/genetics, Intracytoplasmic sperm injection, law.invention, Male infertility, Andrology, Genomic Imprinting, law, medicine, Humans, Sperm Injections, Intracytoplasmic, Imprinting (psychology), Gene, Infertility, Male, Polymerase chain reaction, Chromosomes, Human, Pair 15, Genomic Imprinting/genetics, urogenital system, Methylation, DNA Methylation, Middle Aged, medicine.disease, Spermatozoa, Reproductive Medicine, Genomic imprinting
Abstract

Genetic imprinting is a mechanism of gene regulation by which only one of the parental copies of a gene is expressed. This process is mediated by the methylation of DNA. As spermatozoa represent exclusively the paternal contribution to a future individual, they are expected to carry the paternal imprint only. For intracytoplasmic sperm injection (ICSI), spermatozoa mostly have to be selected from samples with pathological semen parameters. Correct establishment of the paternal imprint in these spermatozoa has not yet beets demonstrated. In the present study, imprinting analysis was undertaken using DNA extracted from spermatozoa from men with normal semen analysis (group A: n = 30 patients) and from men with an abnormal sperm count (B: n = 30 patients with 5-20 million spermatozoa/mL and C: n = 30 patients with ≤5 million spermatozoa/mL) from the ICSI program. It was performed using firstly a conventional methylation-specific polymerase-chain-reaction (M-PCR) and secondly a more sensitive modified hemi-nested M-PCR technique. In addition, a single cell PCR was performed on a total of 88 single spermatozoa (collected from nine males) and on 25 leucocytes (control group). With the conventional M-PCR, exclusively paternal imprints were found in all groups. Using the more sensitive hemi-nested M-PCR, additional maternal imprints were found in 63% of the samples in A, 57% in B and 60% in C. In the single cell PCR, exclusively paternal imprints were detected. Because of the very small amount of DNA (3 pg), a complete amplification failure occurred in 43% of spermatozoa. The correct paternal and maternal imprints were found in 56% of the analysed leucocytes (complete amplification failure in the other 44%). In conclusion, ejaculated spermatozoa from males with medium or high-grade semen pathology proved to have the same imprinting status as those from males with normal semen parameters. As the additional maternal imprints were never found at the single cell level, they were classified as contamination by diploid cells such as leucocytes or immature germ cells in the processed and purified semen samples, which can be detected by a more sensitive PCR method in contrast to the conventional standard PCR.

Published
2001
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3. Maternal and paternal lineages in Albania and the genetic structure of Indo-European populations

Author

Estella S. Poloni, Rosa Casalotti, Michele Belledi, Laurent Excoffier, Ilia Mikerezi, J. Tagliavini, and Franco Conterio

Subjects
Genetic Markers, Mitochondrial DNA, Population, Biology, Y chromosome, DNA, Mitochondrial, Molecular Evolution, White People, Gene flow, Europe/epidemiology, Evolution, Molecular, Genomic Imprinting, Gene Frequency, Y Chromosome, Mitochondrial/genetics DNA, Genetics, Ethnicity, Humans, European Continental Ancestry Group/genetics, education, Allele frequency, Genetics (clinical), ddc:599.9, Language, education.field_of_study, Albania/epidemiology, Genomic Imprinting/genetics, digestive, oral, and skin physiology, Ethnic Groups/classification/genetics, Sequence Analysis, DNA, Europe, Genetics, Population, Genetic marker, Genetic structure, Albania, Y Chromosome/genetics, Genomic imprinting, DNA Sequence Analysis, geographic locations, Population Genetics
Abstract

Mitochondrial DNA HV1 sequences and Y chromosome haplotypes (DYS19 STR and YAP) were characterised in an Albanian sample and compared with those of several other Indo-European populations from the European continent. No significant difference was observed between Albanians and most other Europeans, despite the fact that Albanians are clearly different from all other Indo-Europeans linguistically. We observe a general lack of genetic structure among Indo-European populations for both maternal and paternal polymorphisms, as well as low levels of correlation between linguistics and genetics, even though slightly more significant for the Y chromosome than for mtDNA. Altogether, our results show that the linguistic structure of continental Indo-European populations is not reflected in the variability of the mitochondrial and Y chromosome markers. This discrepancy could be due to very recent differentiation of Indo-European populations in Europe and/or substantial amounts of gene flow among these populations.

Published
2000

4. 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. P, Postma, Dirkje S, Pouta, Anneli, Pylkäs, Katri, Radice, Paolo, Ring, Susan, Rivadeneira, Fernando, Robino, Antonietta, Rose, Lynda M, Rudolph, Anja, Salomaa, Veikko, Sanna, Serena, Schlessinger, David, Schmidt, Marjanka K, Southey, Mellissa C, Sovio, Ulla, Stampfer, Meir J, Stöckl, Dori, Storniolo, Anna M, Timpson, Nicholas J, Tyrer, Jonathan, Visser, Jenny A, Vollenweider, Peter, Völzke, Henry, Waeber, Gerard, Waldenberger, Melanie, Wallaschofski, Henri, Wang, Qin, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R, Wright, Margaret J, Boomsma, Dorret I, Econs, Michael J, Khaw, Kay Tee, Loos, Ruth J. F, Mccarthy, Mark I, Montgomery, Grant W, Rice, John P, Streeten, Elizabeth A, Thorsteinsdottir, Unnur, van Duijn, Cornelia M, Alizadeh, Behrooz Z, Bergmann, Sven, Boerwinkle, Eric, Boyd, Heather A, Crisponi, Laura, Gasparini, Paolo, Gieger, Christian, Harris, Tamara B, Ingelsson, Erik, Järvelin, Marjo Riitta, Kraft, Peter, Lawlor, Debbie, Metspalu, Andre, Pennell, Craig E, Ridker, Paul M, Snieder, Harold, Sørensen, Thorkild I. A, Spector, Tim D, Strachan, David P, Uitterlinden, André G, Wareham, Nicholas J, Widen, Elisabeth, Zygmunt, Marek, Murray, Anna, Easton, Douglas F, Stefansson, Kari, Murabito, Joanne M, Ong, Ken K., Panico, Salvatore, Perry, John R. B., Elks, Cathy E., Thompson, Deborah J., Chasman, Daniel I., Ang, Wei Q., Cousminer, Diana L., Johnson, Andrew D., Lunetta, Kathryn L., Nolte, Ilja M., Smith, Albert V., Wagner, Erin K., Bierut, Laura J., Byrne, Enda M., Koller, Daniel L., Pers, Tune H., Yerges Armstrong, Laura M., Zhao, Jing Hua, Andrulis, Irene L., Beckmann, Matthias W., Bojesen, Stig E., Bolla, Manjeet K., Buring, Julie E., Couch, Fergus J., Coviello, Andrea D., D'Adamo, ADAMO PIO, Smith, George Davey, Demerath, Ellen W., Dieffenbach, Aida K., Dunning, Alison M., Eriksson, Johan G., Fasching, Peter A., Garcia, Melissa E., De Geus, Eco E. J., Giles, Graham G., Gudbjartsson, Daniel F., Hartman, Catharina A., Heath, Andrew C., Hooning, Maartje J., Hopper, John L., Hu, Frank B., Hunter, David J., Kiel, Douglas P., Knight, Julia A., Magnusson, Patrik K., Martin, Nicholas G., Mcardle, Patrick F., Mcardle, Wendy L., Milne, Roger L., Nohr, Ellen A., Oldehinkel, Albertine J., Oostra, Ben A., Pedersen, Nancy L., Pharoah, Paul D. P., Postma, Dirkje S., Rose, Lynda M., Schmidt, Marjanka K., Southey, Mellissa C., Stampfer, Meir J., Storniolo, Anna M., Timpson, Nicholas J., Visser, Jenny A., Wolffenbuttel, Bruce H. R., Wright, Margaret J., Boomsma, Dorret I., Econs, Michael J., Loos, Ruth J. F., Mccarthy, Mark I., Montgomery, Grant W., Rice, John P., Streeten, Elizabeth A., Van Duijn, Cornelia M., Alizadeh, Behrooz Z., Boyd, Heather A., Harris, Tamara B., Pennell, Craig E., Ridker, Paul M., Sørensen, Thorkild I. A., Spector, Tim D., Strachan, David P., Uitterlinden, André G., Wareham, Nicholas J., Easton, Douglas F., and Murabito, Joanne M.

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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