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1. Genetic links between ovarian ageing, cancer risk and de novo mutation rates

Author

Stankovic, Stasa, Shekari, Saleh, Huang, Qin Qin, Gardner, Eugene J., Ivarsdottir, Erna V., Owens, Nick D. L., Mavaddat, Nasim, Azad, Ajuna, Hawkes, Gareth, Kentistou, Katherine A., Beaumont, Robin N., Day, Felix R., Zhao, Yajie, Jonsson, Hakon, Rafnar, Thorunn, Tragante, Vinicius, Sveinbjornsson, Gardar, Oddsson, Asmundur, Styrkarsdottir, Unnur, Gudmundsson, Julius, Stacey, Simon N., Gudbjartsson, Daniel F., Kennedy, Kitale, Wood, Andrew R., Weedon, Michael N., Ong, Ken K., Wright, Caroline F., Hoffmann, Eva R., Sulem, Patrick, Hurles, Matthew E., Ruth, Katherine S., Martin, Hilary C., Stefansson, Kari, Perry, John R. B., and Murray, Anna

Published
2024
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3. Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height

Author

Hawkes, Gareth, Beaumont, Robin N., Li, Zilin, Mandla, Ravi, Li, Xihao, Albert, Christine M., Arnett, Donna K., Ashley-Koch, Allison E., Ashrani, Aneel A., Barnes, Kathleen C., Boerwinkle, Eric, Brody, Jennifer A., Carson, April P., Chami, Nathalie, Chen, Yii-Der Ida, Chung, Mina K., Curran, Joanne E., Darbar, Dawood, Ellinor, Patrick T., Fornage, Myrian, Gordeuk, Victor R., Guo, Xiuqing, He, Jiang, Hwu, Chii-Min, Kalyani, Rita R., Kaplan, Robert, Kardia, Sharon L. R., Kooperberg, Charles, Loos, Ruth J. F., Lubitz, Steven A., Minster, Ryan L., Naseri, Take, Viali, Satupa’itea, Mitchell, Braxton D., Murabito, Joanne M., Palmer, Nicholette D., Psaty, Bruce M., Redline, Susan, Shoemaker, M. Benjamin, Silverman, Edwin K., Telen, Marilyn J., Weiss, Scott T., Yanek, Lisa R., Zhou, Hufeng, Liu, Ching-Ti, North, Kari E., Justice, Anne E., Locke, Jonathan M., Owens, Nick, Murray, Anna, Patel, Kashyap, Frayling, Timothy M., Wright, Caroline F., Wood, Andrew R., Lin, Xihong, Manning, Alisa, and Weedon, Michael N.

Published
2024
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6. Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

Author

Beaumont, Robin N., Flatley, Christopher, Vaudel, Marc, Wu, Xiaoping, Chen, Jing, Moen, Gunn-Helen, Skotte, Line, Helgeland, Øyvind, Solé-Navais, Pol, Banasik, Karina, Albiñana, Clara, Ronkainen, Justiina, Fadista, João, Stinson, Sara Elizabeth, Trajanoska, Katerina, Wang, Carol A., Westergaard, David, Srinivasan, Sundararajan, Sánchez-Soriano, Carlos, Bilbao, Jose Ramon, Allard, Catherine, Groleau, Marika, Kuulasmaa, Teemu, Leirer, Daniel J., White, Frédérique, Jacques, Pierre-Étienne, Cheng, Haoxiang, Hao, Ke, Andreassen, Ole A., Åsvold, Bjørn Olav, Atalay, Mustafa, Bhatta, Laxmi, Bouchard, Luigi, Brumpton, Ben Michael, Brunak, Søren, Bybjerg-Grauholm, Jonas, Ebbing, Cathrine, Elliott, Paul, Engelbrechtsen, Line, Erikstrup, Christian, Estarlich, Marisa, Franks, Stephen, Gaillard, Romy, Geller, Frank, Grove, Jakob, Hougaard, David M., Kajantie, Eero, Morgen, Camilla S., Nohr, Ellen A., Nyegaard, Mette, Palmer, Colin N. A., Pedersen, Ole Birger, Rivadeneira, Fernando, Sebert, Sylvain, Shields, Beverley M., Stoltenberg, Camilla, Surakka, Ida, Thørner, Lise Wegner, Ullum, Henrik, Vaarasmaki, Marja, Vilhjalmsson, Bjarni J., Willer, Cristen J., Lakka, Timo A., Gybel-Brask, Dorte, Bustamante, Mariona, Hansen, Torben, Pearson, Ewan R., Reynolds, Rebecca M., Ostrowski, Sisse R., Pennell, Craig E., Jaddoe, Vincent W. V., Felix, Janine F., Hattersley, Andrew T., Melbye, Mads, Lawlor, Deborah A., Hveem, Kristian, Werge, Thomas, Nielsen, Henriette Svarre, Magnus, Per, Evans, David M., Jacobsson, Bo, Järvelin, Marjo-Riitta, Zhang, Ge, Hivert, Marie-France, Johansson, Stefan, Freathy, Rachel M., Feenstra, Bjarke, and Njølstad, Pål R.

Published
2023
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7. The impact of Mendelian sleep and circadian genetic variants in a population setting

Author

Weedon, Michael N, Jones, Samuel E, Lane, Jacqueline M, Lee, Jiwon, Ollila, Hanna M, Dawes, Amy, Tyrrell, Jess, Beaumont, Robin N, Partonen, Timo, Merikanto, Ilona, Rich, Stephen S, Rotter, Jerome I, Frayling, Timothy M, Rutter, Martin K, Redline, Susan, Sofer, Tamar, Saxena, Richa, and Wood, Andrew R

Subjects
Biological Sciences, Genetics, Sleep Research, Clinical Research, Neurosciences, Human Genome, 2.1 Biological and endogenous factors, Circadian Rhythm, Humans, Phenotype, Receptors, G-Protein-Coupled, Sleep, Sleep Wake Disorders, Developmental Biology
Abstract

Rare variants in ten genes have been reported to cause Mendelian sleep conditions characterised by extreme sleep duration or timing. These include familial natural short sleep (ADRB1, DEC2/BHLHE41, GRM1 and NPSR1), advanced sleep phase (PER2, PER3, CRY2, CSNK1D and TIMELESS) and delayed sleep phase (CRY1). The association of variants in these genes with extreme sleep conditions were usually based on clinically ascertained families, and their effects when identified in the population are unknown. We aimed to determine the effects of these variants on sleep traits in large population-based cohorts. We performed genetic association analysis of variants previously reported to be causal for Mendelian sleep and circadian conditions. Analyses were performed using 191,929 individuals with data on sleep and whole-exome or genome-sequence data from 4 population-based studies: UK Biobank, FINRISK, Health-2000-2001, and the Multi-Ethnic Study of Atherosclerosis (MESA). We identified sleep disorders from self-report, hospital and primary care data. We estimated sleep duration and timing measures from self-report and accelerometery data. We identified carriers for 10 out of 12 previously reported pathogenic variants for 8 of the 10 genes. They ranged in frequency from 1 individual with the variant in CSNK1D to 1,574 individuals with a reported variant in the PER3 gene in the UK Biobank. No carriers for variants reported in NPSR1 or PER2 were identified. We found no association between variants analyzed and extreme sleep or circadian phenotypes. Using sleep timing as a proxy measure for sleep phase, only PER3 and CRY1 variants demonstrated association with earlier and later sleep timing, respectively; however, the magnitude of effect was smaller than previously reported (sleep midpoint ~7 mins earlier and ~5 mins later, respectively). We also performed burden tests of protein truncating (PTVs) or rare missense variants for the 10 genes. Only PTVs in PER2 and PER3 were associated with a relevant trait (for example, 64 individuals with a PTV in PER2 had an odds ratio of 4.4 for being "definitely a morning person", P = 4x10-8; and had a 57-minute earlier midpoint sleep, P = 5x10-7). Our results indicate that previously reported variants for Mendelian sleep and circadian conditions are often not highly penetrant when ascertained incidentally from the general population.

Published
2022

12. Genetic insights into biological mechanisms governing human ovarian ageing

Author

Ruth, Katherine S, Day, Felix R, Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E, Azad, Ajuna, Thompson, Deborah J, Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L, Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B, Sulem, Patrick, Walters, Robin G, Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N, Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W, Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul RHJ, Ahearn, Thomas U, Alizadeh, Behrooz Z, Naderi, Elnaz, Andrulis, Irene L, Arnold, Alice M, Aronson, Kristan J, Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M, Beaumont, Robin N, Becher, Heiko, Beckmann, Matthias W, Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Boomsma, Dorret I, Bowker, Nicholas, Brody, Jennifer A, Broer, Linda, Buring, Julie E, Campbell, Archie, Campbell, Harry, Castelao, Jose E, Catamo, Eulalia, Chanock, Stephen J, Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J, Cox, Angela, Crisponi, Laura, Cross, Simon S, Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco JCN, de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Dunning, Alison M, Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A, Faul, Jessica D, Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M, Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, and Heiss, Gerardo

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Contraception/Reproduction, Estrogen, Prevention, Aging, Infertility, Women's Health, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Good Health and Well Being, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Europe, Asia, Eastern, Female, Fertility, Fragile X Mental Retardation Protein, Genetic Predisposition to Disease, Genome-Wide Association Study, Healthy Aging, Humans, Longevity, Menopause, Menopause, Premature, Mice, Mice, Inbred C57BL, Middle Aged, Ovary, Primary Ovarian Insufficiency, Uterus, Biobank-based Integrative Omics Study (BIOS) Consortium, eQTLGen Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, kConFab Investigators, LifeLines Cohort Study, InterAct consortium, 23andMe Research Team, General Science & Technology
Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Published
2021

13. Genetic effects on the timing of parturition and links to fetal birth weight

Author

Solé-Navais, Pol, Flatley, Christopher, Steinthorsdottir, Valgerdur, Vaudel, Marc, Juodakis, Julius, Chen, Jing, Laisk, Triin, LaBella, Abigail L., Westergaard, David, Bacelis, Jonas, Brumpton, Ben, Skotte, Line, Borges, Maria C., Helgeland, Øyvind, Mahajan, Anubha, Wielscher, Matthias, Lin, Frederick, Briggs, Catherine, Wang, Carol A., Moen, Gunn-Helen, Beaumont, Robin N., Bradfield, Jonathan P., Abraham, Abin, Thorleifsson, Gudmar, Gabrielsen, Maiken E., Ostrowski, Sisse R., Modzelewska, Dominika, Nohr, Ellen A., Hypponen, Elina, Srivastava, Amit, Talbot, Octavious, Allard, Catherine, Williams, Scott M., Menon, Ramkumar, Shields, Beverley M., Sveinbjornsson, Gardar, Xu, Huan, Melbye, Mads, Lowe, Jr, William, Bouchard, Luigi, Oken, Emily, Pedersen, Ole B., Gudbjartsson, Daniel F., Erikstrup, Christian, Sørensen, Erik, Lie, Rolv T., Teramo, Kari, Hallman, Mikko, Juliusdottir, Thorhildur, Hakonarson, Hakon, Ullum, Henrik, Hattersley, Andrew T., Sletner, Line, Merialdi, Mario, Rifas-Shiman, Sheryl L., Steingrimsdottir, Thora, Scholtens, Denise, Power, Christine, West, Jane, Nyegaard, Mette, Capra, John A., Skogholt, Anne H., Magnus, Per, Andreassen, Ole A., Thorsteinsdottir, Unnur, Grant, Struan F. A., Qvigstad, Elisabeth, Pennell, Craig E., Hivert, Marie-France, Hayes, Geoffrey M., Jarvelin, Marjo-Riitta, McCarthy, Mark I., Lawlor, Deborah A., Nielsen, Henriette S., Mägi, Reedik, Rokas, Antonis, Hveem, Kristian, Stefansson, Kari, Feenstra, Bjarke, Njolstad, Pål, Muglia, Louis J., Freathy, Rachel M., Johansson, Stefan, Zhang, Ge, and Jacobsson, Bo

Published
2023
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14. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.

Author

Liu, Xueping, Helenius, Dorte, Skotte, Line, Beaumont, Robin N, Wielscher, Matthias, Geller, Frank, Juodakis, Julius, Mahajan, Anubha, Bradfield, Jonathan P, Lin, Frederick TJ, Vogelezang, Suzanne, Bustamante, Mariona, Ahluwalia, Tarunveer S, Pitkänen, Niina, Wang, Carol A, Bacelis, Jonas, Borges, Maria C, Zhang, Ge, Bedell, Bruce A, Rossi, Robert M, Skogstrand, Kristin, Peng, Shouneng, Thompson, Wesley K, Appadurai, Vivek, Lawlor, Debbie A, Kalliala, Ilkka, Power, Christine, McCarthy, Mark I, Boyd, Heather A, Marazita, Mary L, Hakonarson, Hakon, Hayes, M Geoffrey, Scholtens, Denise M, Rivadeneira, Fernando, Jaddoe, Vincent WV, Vinding, Rebecca K, Bisgaard, Hans, Knight, Bridget A, Pahkala, Katja, Raitakari, Olli, Helgeland, Øyvind, Johansson, Stefan, Njølstad, Pål R, Fadista, João, Schork, Andrew J, Nudel, Ron, Miller, Daniel E, Chen, Xiaoting, Weirauch, Matthew T, Mortensen, Preben Bo, Børglum, Anders D, Nordentoft, Merete, Mors, Ole, Hao, Ke, Ryckman, Kelli K, Hougaard, David M, Kottyan, Leah C, Pennell, Craig E, Lyytikainen, Leo-Pekka, Bønnelykke, Klaus, Vrijheid, Martine, Felix, Janine F, Lowe, William L, Grant, Struan FA, Hyppönen, Elina, Jacobsson, Bo, Jarvelin, Marjo-Riitta, Muglia, Louis J, Murray, Jeffrey C, Freathy, Rachel M, Werge, Thomas M, Melbye, Mads, Buil, Alfonso, and Feenstra, Bjarke

Subjects
Chromosomes, Human, Pair 2, Fetus, Humans, Premature Birth, Cytokines, Gestational Age, Pregnancy, Polymorphism, Single Nucleotide, Genome, Human, Infant, Newborn, Female, Genome-Wide Association Study, Chromosomes, Human, Pair 2, Polymorphism, Single Nucleotide, Genome, Infant, Newborn
Abstract

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

Published
2019

15. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author

Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Helgeland, Øyvind, Laurin, Charles, Bacelis, Jonas, Peng, Shouneng, Hao, Ke, Feenstra, Bjarke, Wood, Andrew R, Mahajan, Anubha, Tyrrell, Jessica, Robertson, Neil R, Rayner, N William, Qiao, Zhen, Moen, Gunn-Helen, Vaudel, Marc, Marsit, Carmen J, Chen, Jia, Nodzenski, Michael, Schnurr, Theresia M, Zafarmand, Mohammad H, Bradfield, Jonathan P, Grarup, Niels, Kooijman, Marjolein N, Li-Gao, Ruifang, Geller, Frank, Ahluwalia, Tarunveer S, Paternoster, Lavinia, Rueedi, Rico, Huikari, Ville, Hottenga, Jouke-Jan, Lyytikäinen, Leo-Pekka, Cavadino, Alana, Metrustry, Sarah, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Vilor-Tejedor, Natalia, Joshi, Peter K, Painter, Jodie N, Ntalla, Ioanna, Myhre, Ronny, Pitkänen, Niina, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Richmond, Rebecca C, Espinosa, Ana, Barton, Sheila J, Inskip, Hazel M, Holloway, John W, Santa-Marina, Loreto, Estivill, Xavier, Ang, Wei, Marsh, Julie A, Reichetzeder, Christoph, Marullo, Letizia, Hocher, Berthold, Lunetta, Kathryn L, Murabito, Joanne M, Relton, Caroline L, Kogevinas, Manolis, Chatzi, Leda, Allard, Catherine, Bouchard, Luigi, Hivert, Marie-France, Zhang, Ge, Muglia, Louis J, Heikkinen, Jani, Morgen, Camilla S, van Kampen, Antoine HC, van Schaik, Barbera DC, Mentch, Frank D, Langenberg, Claudia, Luan, Jian’an, Scott, Robert A, Zhao, Jing Hua, Hemani, Gibran, Ring, Susan M, Bennett, Amanda J, Gaulton, Kyle J, Fernandez-Tajes, Juan, van Zuydam, Natalie R, Medina-Gomez, Carolina, de Haan, Hugoline G, Rosendaal, Frits R, Kutalik, Zoltán, Marques-Vidal, Pedro, Das, Shikta, Willemsen, Gonneke, Mbarek, Hamdi, Müller-Nurasyid, Martina, Standl, Marie, Appel, Emil VR, Fonvig, Cilius E, and Trier, Caecilie

Subjects
Biological Sciences, Genetics, Cardiovascular, Perinatal Period - Conditions Originating in Perinatal Period, Nutrition, Prevention, Preterm, Low Birth Weight and Health of the Newborn, Pediatric, Obesity, Conditions Affecting the Embryonic and Fetal Periods, Infant Mortality, 2.1 Biological and endogenous factors, Aetiology, Reproductive health and childbirth, Good Health and Well Being, Adult, Birth Weight, Blood Pressure, Body Height, Diabetes Mellitus, Type 2, Female, Fetal Development, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Diseases, Humans, Infant, Newborn, Male, Maternal Inheritance, Maternal-Fetal Exchange, Metabolic Diseases, Models, Genetic, Polymorphism, Single Nucleotide, Pregnancy, Risk Factors, EGG Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Published
2019

18. Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies

Author

Harlow, Charli E., Gandawijaya, Josan, Bamford, Rosemary A., Martin, Emily-Rose, Wood, Andrew R., van der Most, Peter J., Tanaka, Toshiko, Leonard, Hampton L., Etheridge, Amy S., Innocenti, Federico, Beaumont, Robin N., Tyrrell, Jessica, Nalls, Mike A., Simonsick, Eleanor M., Garimella, Pranav S., Shiroma, Eric J., Verweij, Niek, van der Meer, Peter, Gansevoort, Ron T., Snieder, Harold, Gallins, Paul J., Jima, Dereje D., Wright, Fred, Zhou, Yi-hui, Ferrucci, Luigi, Bandinelli, Stefania, Hernandez, Dena G., van der Harst, Pim, Patel, Vickas V., Waterworth, Dawn M., Chu, Audrey Y., Oguro-Ando, Asami, and Frayling, Timothy M.

Published
2022
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20. Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling.

Author

Kentistou, Katherine A., Lim, Brandon E. M., Kaisinger, Lena R., Steinthorsdottir, Valgerdur, Sharp, Luke N., Patel, Kashyap A., Tragante, Vinicius, Hawkes, Gareth, Gardner, Eugene J., Olafsdottir, Thorhildur, Wood, Andrew R., Zhao, Yajie, Thorleifsson, Gudmar, Day, Felix R., Ozanne, Susan E., Hattersley, Andrew T., O'Rahilly, Stephen, Stefansson, Kari, Ong, Ken K., and Beaumont, Robin N.

Subjects
SOMATOMEDIN, MEDICAL sciences, LIFE sciences, CHILDBIRTH, FETAL tissues, BIRTH weight, FETUS
Abstract

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests. We identify 9 genes; 5 with fetal-only effects on birth weight, 1 with maternal-only effects, 3 with both, and observe directionally concordant associations in an independent sample. Four of the genes were previously implicated by GWAS of birth weight. IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (fetal-acting) are involved in adipose tissue regulation, and the latter two also show associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG (fetal-acting) in adipocyte differentiation and placental angiogenesis. NOS3 (fetal and maternal-acting), NRK (fetal), and ADAMTS8 (maternal-acting) have been implicated in placental function and hypertension. To conclude, our analysis of rare coding variants identifies regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, and further evidence for the role of insulin-like growth factors. An exome-wide association study for fetal and maternal rare deleterious variants affecting the normal variation in birth weight identifies nine genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling. [ABSTRACT FROM AUTHOR]

Published
2025
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22. Higher maternal adiposity reduces offspring birthweight if associated with a metabolically favourable profile

Author

Thompson, William D., Beaumont, Robin N., Kuang, Alan, Warrington, Nicole M., Ji, Yingjie, Tyrrell, Jessica, Wood, Andrew R., Scholtens, Denise M., Knight, Bridget A., Evans, David M., Lowe, Jr, William L., Santorelli, Gillian, Azad, Rafaq, Mason, Dan, Hattersley, Andrew T., Frayling, Timothy M., Yaghootkar, Hanieh, Borges, Maria Carolina, Lawlor, Deborah A., and Freathy, Rachel M.

Published
2021
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23. Author Correction: Genetic effects on the timing of parturition and links to fetal birth weight

Author

Solé-Navais, Pol, Flatley, Christopher, Steinthorsdottir, Valgerdur, Vaudel, Marc, Juodakis, Julius, Chen, Jing, Laisk, Triin, LaBella, Abigail L., Westergaard, David, Bacelis, Jonas, Brumpton, Ben, Skotte, Line, Borges, Maria C., Helgeland, Øyvind, Mahajan, Anubha, Wielscher, Matthias, Lin, Frederick, Briggs, Catherine, Wang, Carol A., Moen, Gunn-Helen, Beaumont, Robin N., Bradfield, Jonathan P., Abraham, Abin, Thorleifsson, Gudmar, Gabrielsen, Maiken E., Ostrowski, Sisse R., Modzelewska, Dominika, Nohr, Ellen A., Hypponen, Elina, Srivastava, Amit, Talbot, Octavious, Allard, Catherine, Williams, Scott M., Menon, Ramkumar, Shields, Beverley M., Sveinbjornsson, Gardar, Xu, Huan, Melbye, Mads, Lowe, Jr, William, Bouchard, Luigi, Oken, Emily, Pedersen, Ole B., Gudbjartsson, Daniel F., Erikstrup, Christian, Sørensen, Erik, Lie, Rolv T., Teramo, Kari, Hallman, Mikko, Juliusdottir, Thorhildur, Hakonarson, Hakon, Ullum, Henrik, Hattersley, Andrew T., Sletner, Line, Merialdi, Mario, Rifas-Shiman, Sheryl L., Steingrimsdottir, Thora, Scholtens, Denise, Power, Christine, West, Jane, Nyegaard, Mette, Capra, John A., Skogholt, Anne H., Magnus, Per, Andreassen, Ole A., Thorsteinsdottir, Unnur, Grant, Struan F. A., Qvigstad, Elisabeth, Pennell, Craig E., Hivert, Marie-France, Hayes, Geoffrey M., Jarvelin, Marjo-Riitta, McCarthy, Mark I., Lawlor, Deborah A., Nielsen, Henriette S., Mägi, Reedik, Rokas, Antonis, Hveem, Kristian, Stefansson, Kari, Feenstra, Bjarke, Njolstad, Pål, Muglia, Louis J., Freathy, Rachel M., Johansson, Stefan, Zhang, Ge, and Jacobsson, Bo

Published
2023
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26. Genome-wide associations for birth weight and correlations with adult disease

Author

Horikoshi, Momoko, Beaumont, Robin N, Day, Felix R, Warrington, Nicole M, Kooijman, Marjolein N, Fernandez-Tajes, Juan, Feenstra, Bjarke, van Zuydam, Natalie R, Gaulton, Kyle J, Grarup, Niels, Bradfield, Jonathan P, Strachan, David P, Li-Gao, Ruifang, Ahluwalia, Tarunveer S, Kreiner, Eskil, Rueedi, Rico, Lyytikäinen, Leo-Pekka, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Hottenga, Jouke-Jan, Vilor-Tejedor, Natalia, Joshi, Peter K, Boh, Eileen Tai Hui, Ntalla, Ioanna, Pitkänen, Niina, Mahajan, Anubha, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Nodzenski, Michael, Diver, Louise A, Zondervan, Krina T, Bustamante, Mariona, Marques-Vidal, Pedro, Mercader, Josep M, Bennett, Amanda J, Rahmioglu, Nilufer, Nyholt, Dale R, Ma, Ronald CW, Tam, Claudia HT, Tam, Wing Hung, Ganesh, Santhi K, van Rooij, Frank JA, Jones, Samuel E, Loh, Po-Ru, Ruth, Katherine S, Tuke, Marcus A, Tyrrell, Jessica, Wood, Andrew R, Yaghootkar, Hanieh, Scholtens, Denise M, Paternoster, Lavinia, Prokopenko, Inga, Kovacs, Peter, Atalay, Mustafa, Willems, Sara M, Panoutsopoulou, Kalliope, Wang, Xu, Carstensen, Lisbeth, Geller, Frank, Schraut, Katharina E, Murcia, Mario, van Beijsterveldt, Catharina EM, Willemsen, Gonneke, Appel, Emil VR, Fonvig, Cilius E, Trier, Caecilie, Tiesler, Carla MT, Standl, Marie, Kutalik, Zoltán, Bonàs-Guarch, Sílvia, Hougaard, David M, Sánchez, Friman, Torrents, David, Waage, Johannes, Hollegaard, Mads V, de Haan, Hugoline G, Rosendaal, Frits R, Medina-Gomez, Carolina, Ring, Susan M, Hemani, Gibran, McMahon, George, Robertson, Neil R, Groves, Christopher J, Langenberg, Claudia, Luan, Jian’an, Scott, Robert A, Zhao, Jing Hua, Mentch, Frank D, MacKenzie, Scott M, Reynolds, Rebecca M, Lowe, William L, Tönjes, Anke, Stumvoll, Michael, Lindi, Virpi, Lakka, Timo A, and van Duijn, Cornelia M

Subjects
Nutrition, Perinatal Period - Conditions Originating in Perinatal Period, Human Genome, Genetics, Clinical Research, Preterm, Low Birth Weight and Health of the Newborn, Obesity, Prevention, Pediatric, Infant Mortality, 2.1 Biological and endogenous factors, Aetiology, Adult, Aging, Anthropometry, Birth Weight, Blood Pressure, Chromatin Assembly and Disassembly, Cohort Studies, Coronary Artery Disease, Datasets as Topic, Diabetes Mellitus, Type 2, Female, Fetus, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genomic Imprinting, Genotype, Glucose, Glycogen, Humans, Insulin, Male, Phenotype, Signal Transduction, CHARGE Consortium Hematology Working Group, Early Growth Genetics (EGG) Consortium, General Science & Technology
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

Published
2016

30. Penetrance of Pathogenic Genetic Variants Associated With Premature Ovarian Insufficiency

Author

Shekari, Saleh, primary, Stankovic, Stasa, additional, Gardner, Eugene J., additional, Hawkes, Gareth, additional, Kentistou, Katherine A., additional, Beaumont, Robin N., additional, Mörseburg, Alexander, additional, Wood, Andrew R., additional, Prague, Julia K., additional, Mishra, Gita D., additional, Day, Felix R., additional, Baptista, Julia, additional, Wright, Caroline F., additional, Weedon, Michael N., additional, Hoffmann, Eva R., additional, Ruth, Katherine S., additional, Ong, Ken K., additional, Perry, John R. B., additional, and Murray, Anna, additional

Published
2024
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32. Dynamics of stratospheric sudden warming events : data analysis and modelling

Author

Beaumont, Robin Nicholas, Kwasniok, Frank, and Thuburn, John

Subjects
510, Stratospheric Sudden Warming, Polar Vortex
Abstract

The polar vortex is a large scale cyclone located in the middle atmosphere near to the planet’s geographic poles. These vortices form during the hemispheric winter and break down in the spring of the following year. They may also break down in mid winter, causing a sudden stratospheric warming event (SSW). The vortex is thought to be preconditioned leading up to these warming events, resulting in the breakdown of the vortex. Integral diagnostics are used to investigate the stripping of air from the vortex as part of this preconditioning. Contour diagnostics of mass and circulation are calculated using ERA-40 reanalysis data for the stratosphere. The edge of the vortex is easily identifiable in these diagnostics as a high gradient of Ertel’s potential vorticity (PV), and the warming events are also clearly visible. From these the amount of air removed from the vortex is determined from the balance equation of the mass integral. These terms show that there are significant amounts of air removed from the vortex, with several stripping events identifiable in them through the winter, especially in those during which a major sudden warming event occurred. These stripping events can be seen in corresponding PV maps, where tongues of PV can be seen to be stripped from the vortex and mixed into the surrounding surf zone of turbulent air. From the integral diagnostics a Lagrangian measure of the meridional circulation in the stratosphere is also calculated. In the final part of the thesis a shallow water model is used to investigate a quantitative link between forcing and the amount of stripping of the vortex. It is found that when the forcing is large enough there is significant stripping of mass from the vortex. This does not lead to SSWs in all cases, and the total amount of stripping is not found to be proportional to the maximum amplitude of the forcing.

Published
2014

33. Using human genetics to understand the disease impacts of testosterone in men and women

Author

Ruth, Katherine S, Day, Felix R, Tyrrell, Jessica, Thompson, Deborah J, Wood, Andrew R, Mahajan, Anubha, and Beaumont, Robin N

Subjects
Demographic aspects, Health aspects, Testosterone -- Health aspects, Genetic variation -- Health aspects -- Demographic aspects
Abstract

Author(s): Katherine S Ruth [sup.1] , Felix R Day [sup.2] , Jessica Tyrrell [sup.1] , Deborah J Thompson [sup.3] , Andrew R Wood [sup.1] , Anubha Mahajan [sup.4] , Robin [...], Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses. Genetic analysis of data from over 400,000 participants in the UK Biobank Study shows that circulating testosterone levels have sex-specific implications for cardiometabolic diseases and cancer outcomes.

Published
2020
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34. Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development

Author

Nielsen, Jonas B., Fritsche, Lars G., Zhou, Wei, Teslovich, Tanya M., Holmen, Oddgeir L., Gustafsson, Stefan, Gabrielsen, Maiken E., Schmidt, Ellen M., Beaumont, Robin, Wolford, Brooke N., Lin, Maoxuan, Brummett, Chad M., Preuss, Michael H., Refsgaard, Lena, Bottinger, Erwin P., Graham, Sarah E., Surakka, Ida, Chu, Yunhan, Skogholt, Anne Heidi, Dalen, Håvard, Boyle, Alan P., Oral, Hakan, Herron, Todd J., Kitzman, Jacob, Jalife, José, Svendsen, Jesper H., Olesen, Morten S., Njølstad, Inger, Løchen, Maja-Lisa, Baras, Aris, Gottesman, Omri, Marcketta, Anthony, O’Dushlaine, Colm, Ritchie, Marylyn D., Wilsgaard, Tom, Loos, Ruth J.F., Frayling, Timothy M., Boehnke, Michael, Ingelsson, Erik, Carey, David J., Dewey, Frederick E., Kang, Hyun M., Abecasis, Gonçalo R., Hveem, Kristian, and Willer, Cristen J.

Published
2018
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35. Effects of the maternal and fetal proteome on birth weight: a Mendelian randomization analysis

Author

McBride, Nancy, primary, Fernández-Sanlés, Alba, additional, Arab, Marwa Al, additional, Bond, Tom A., additional, Zheng, Jie, additional, Magnus, Maria C., additional, Corfield, Elizabeth C., additional, Clayton, Gemma L, additional, Hwang, Liang-Dar, additional, Beaumont, Robin N., additional, Evans, David M., additional, Freathy, Rachel M., additional, Gaunt, Tom R., additional, Lawlor, Deborah A, additional, and Borges, Maria Carolina, additional

Published
2023
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37. Direct and INdirect effects analysis of Genetic lOci (DINGO): A software package to increase the power of locus discovery in GWAS meta-analyses of perinatal phenotypes and traits influenced by indirect genetic effects

Author

Hwang, Liang-Dar, primary, Cuellar-Partida, Gabriel, additional, Yengo, Loic, additional, Zeng, Jian, additional, Beaumont, Robin N., additional, Freathy, Rachel M., additional, Moen, Gunn-Helen, additional, Warrington, Nicole M., additional, and Evans, David M., additional

Published
2023
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38. Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour

Author

Jones, Samuel E., van Hees, Vincent T., Mazzotti, Diego R., Marques-Vidal, Pedro, Sabia, Séverine, van der Spek, Ashley, Dashti, Hassan S., Engmann, Jorgen, Kocevska, Desana, Tyrrell, Jessica, Beaumont, Robin N., Hillsdon, Melvyn, Ruth, Katherine S., Tuke, Marcus A., Yaghootkar, Hanieh, Sharp, Seth A., Ji, Yingjie, Harrison, Jamie W., Freathy, Rachel M., Murray, Anna, Luik, Annemarie I., Amin, Najaf, Lane, Jacqueline M., Saxena, Richa, Rutter, Martin K., Tiemeier, Henning, Kutalik, Zoltán, Kumari, Meena, Frayling, Timothy M., Weedon, Michael N., Gehrman, Philip R., and Wood, Andrew R.

Published
2019
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39. Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates

Author

Dashti, Hassan S., Jones, Samuel E., Wood, Andrew R., Lane, Jacqueline M., van Hees, Vincent T., Wang, Heming, Rhodes, Jessica A., Song, Yanwei, Patel, Krunal, Anderson, Simon G., Beaumont, Robin N., Bechtold, David A., Bowden, Jack, Cade, Brian E., Garaulet, Marta, Kyle, Simon D., Little, Max A., Loudon, Andrew S., Luik, Annemarie I., Scheer, Frank A. J. L., Spiegelhalder, Kai, Tyrrell, Jessica, Gottlieb, Daniel J., Tiemeier, Henning, Ray, David W., Purcell, Shaun M., Frayling, Timothy M., Redline, Susan, Lawlor, Deborah A., Rutter, Martin K., Weedon, Michael N., and Saxena, Richa

Published
2019
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40. Genetic effects on the timing of parturition and links to fetal birth weight:[Inkl. Correction]

Author

Solé-Navais, Pol, Flatley, Christopher, Steinthorsdottir, Valgerdur, Vaudel, Marc, Juodakis, Julius, Chen, Jing, Laisk, Triin, LaBella, Abigail L., Westergaard, David, Bacelis, Jonas, Brumpton, Ben, Skotte, Line, Borges, Maria C., Helgeland, Øyvind, Mahajan, Anubha, Wielscher, Matthias, Lin, Frederick, Briggs, Catherine, Wang, Carol A., Moen, Gunn Helen, Beaumont, Robin N., Bradfield, Jonathan P., Abraham, Abin, Thorleifsson, Gudmar, Gabrielsen, Maiken E., Ostrowski, Sisse R., Modzelewska, Dominika, Nohr, Ellen A., Hypponen, Elina, Srivastava, Amit, Talbot, Octavious, Allard, Catherine, Williams, Scott M., Menon, Ramkumar, Shields, Beverley M., Sveinbjornsson, Gardar, Xu, Huan, Melbye, Mads, Lowe, William, Bouchard, Luigi, Oken, Emily, Pedersen, Ole B., Gudbjartsson, Daniel F., Erikstrup, Christian, Sørensen, Erik, McCarthy, Mark I., Lie, Rolv T., Ullum, Henrik, Nyegaard, Mette, Nielsen, Henriette S., Solé-Navais, Pol, Flatley, Christopher, Steinthorsdottir, Valgerdur, Vaudel, Marc, Juodakis, Julius, Chen, Jing, Laisk, Triin, LaBella, Abigail L., Westergaard, David, Bacelis, Jonas, Brumpton, Ben, Skotte, Line, Borges, Maria C., Helgeland, Øyvind, Mahajan, Anubha, Wielscher, Matthias, Lin, Frederick, Briggs, Catherine, Wang, Carol A., Moen, Gunn Helen, Beaumont, Robin N., Bradfield, Jonathan P., Abraham, Abin, Thorleifsson, Gudmar, Gabrielsen, Maiken E., Ostrowski, Sisse R., Modzelewska, Dominika, Nohr, Ellen A., Hypponen, Elina, Srivastava, Amit, Talbot, Octavious, Allard, Catherine, Williams, Scott M., Menon, Ramkumar, Shields, Beverley M., Sveinbjornsson, Gardar, Xu, Huan, Melbye, Mads, Lowe, William, Bouchard, Luigi, Oken, Emily, Pedersen, Ole B., Gudbjartsson, Daniel F., Erikstrup, Christian, Sørensen, Erik, McCarthy, Mark I., Lie, Rolv T., Ullum, Henrik, Nyegaard, Mette, and Nielsen, Henriette S.

Abstract

The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal–fetal relationship between gestational duration and birth weight.

Published
2023

41. Intrauterine Growth and Offspring Neurodevelopmental Traits: A Mendelian Randomization Analysis of the Norwegian Mother, Father and Child Cohort Study (MoBa).

Author

D'Urso, Shannon, Moen, Gunn-Helen, Hwang, Liang-Dar, Hannigan, Laurie J., Corfield, Elizabeth C., Ask, Helga, Johannson, Stefan, Njølstad, Pål Rasmus, Beaumont, Robin N., Freathy, Rachel M., Evans, David M., and Havdahl, Alexandra

Subjects
FETAL development, LOW birth weight, CHILD Behavior Checklist, NEURAL development, BEHAVIORAL assessment
Abstract

Key Points: Question: Is the association between lower birth weight and offspring neurodevelopmental difficulties causal? Findings: In this conventional epidemiological cohort study of 46 970 offspring, lower birth weight was associated with neurodevelopmental difficulties across various offspring ages. However, mendelian randomization causal analyses of 44 134 mother-child dyads did not find evidence for a causal association between intrauterine growth (with maternal genetic factors influencing fetal growth as a proxy) and offspring neurodevelopmental difficulties. Meaning: This study found that maternal factors influencing intrauterine growth do not appear to drive the observational association between lower birth weight and offspring neurodevelopmental difficulties. Importance: Conventional epidemiological analyses have suggested that lower birth weight is associated with later neurodevelopmental difficulties; however, it is unclear whether this association is causal. Objective: To investigate the relationship between intrauterine growth and offspring neurodevelopmental difficulties. Design, Setting, and Participants: MoBa is a population-based pregnancy cohort that recruited pregnant women from June 1999 to December 2008 included approximately 114 500 children, 95 200 mothers, and 75 200 fathers. Observational associations between birth weight and neurodevelopmental difficulties were assessed with a conventional epidemiological approach. Mendelian randomization analyses were performed to investigate the potential causal association between maternal allele scores for birth weight and offspring neurodevelopmental difficulties conditional on offspring allele scores. Exposures: Birth weight and maternal allele scores for birth weight (derived from genetic variants robustly associated with birth weight) were the exposures in the observational and mendelian randomization analyses, respectively. Main Outcomes and Measures: Clinically relevant maternal ratings of offspring neurodevelopmental difficulties at 6 months, 18 months, 3 years, 5 years, and 8 years of age assessing language and motor difficulties, inattention and hyperactivity-impulsivity, social communication difficulties, and repetitive behaviors. Results: The conventional epidemiological sample included up to 46 970 offspring, whereas the mendelian randomization sample included up to 44 134 offspring (median offspring birth year, 2005 [range, 1999-2009]; mean [SD] maternal age at birth, 30.1 [4.5] years; mean [SD] paternal age at birth, 32.5 [5.1] years). The conventional epidemiological analyses found evidence that birth weight was negatively associated with several domains at multiple offspring ages (outcome of autism-related trait scores: Social Communication Questionnaire [SCQ]–full at 3 years, β = −0.046 [95% CI, −0.057 to −0.034]; SCQ–Restricted and Repetitive Behaviors subscale at 3 years, β = −0.049 [95% CI, −0.060 to −0.038]; attention-deficit/hyperactivity disorder [ADHD] trait scores: Child Behavior Checklist [CBCL]–ADHD subscale at 18 months, β = −0.035 [95% CI, −0.045 to −0.024]; CBCL-ADHD at 3 years, β = −0.032 [95% CI, −0.043 to −0.021]; CBCL-ADHD at 5 years, β = −0.050 [95% CI, −0.064 to −0.037]; Rating Scale for Disruptive Behavior Disorders [RS-DBD]–ADHD at 8 years, β = −0.036 [95% CI, −0.049 to −0.023]; RS-DBD–Inattention at 8 years, β = −0.037 [95% CI, −0.050 to −0.024]; RS-DBD–Hyperactive-Impulsive Behavior at 8 years, β = −0.027 [95% CI, −0.040 to −0.014]; Conners Parent Rating Scale–Revised [Short Form] at 5 years, β = −0.041 [95% CI, −0.054 to −0.028]; motor scores: Ages and Stages Questionnaire–Motor Difficulty [ASQ-MOTOR] at 18 months, β = −0.025 [95% CI, −0.035 to −0.015]; ASQ-MOTOR at 3 years, β = −0.029 [95% CI, −0.040 to −0.018]; and Child Development Inventory–Gross and Fine Motor Skills at 5 years, β = −0.028 [95% CI, −0.042 to −0.015]). Mendelian randomization analyses did not find any evidence for an association between maternal allele scores for birth weight and offspring neurodevelopmental difficulties. Conclusions and Relevance: This study found that the maternal intrauterine environment, as proxied by maternal birth weight genetic variants, is unlikely to be a major determinant of offspring neurodevelopmental outcomes. This cohort study investigates the association between lower birth weight and neurodevelopmental difficulties, as well as the causal association of intrauterine growth with measures of offspring neurodevelopmental difficulties. [ABSTRACT FROM AUTHOR]

Published
2024
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42. Hyperglycaemia is a causal risk factor for upper limb pathologies.

Author

Green, Harry D, Burden, Ella, Chen, Ji, Evans, Jonathan, Patel, Kashyap, Wood, Andrew R, Beaumont, Robin N, Tyrrell, Jessica, Frayling, Timothy M, Hattersley, Andrew T, Oram, Richard A, Bowden, Jack, Barroso, Inês, Smith, Christopher, and Weedon, Michael N

Subjects
CARPAL tunnel syndrome, HYPERGLYCEMIA, MUSCULOSKELETAL system diseases, FAT, DIABETES complications, GENETIC techniques
Abstract

Background Diabetes (regardless of type) and obesity are associated with a range of musculoskeletal disorders. The causal mechanisms driving these associations are unknown for many upper limb pathologies. We used genetic techniques to test the causal link between glycemia, obesity and musculoskeletal conditions. Methods In the UK Biobank's unrelated European cohort (N  = 379 708) we performed mendelian randomisation (MR) analyses to test for a causal effect of long-term high glycaemia and adiposity on four musculoskeletal pathologies: frozen shoulder, Dupuytren's disease, carpal tunnel syndrome and trigger finger. We also performed single-gene MR using rare variants in the GCK gene. Results Using MR, we found evidence that long-term high glycaemia has a causal role in the aetiology of upper limb conditions. A 10-mmol/mol increase in genetically predicted haemoglobin A1C (HbA1c) was associated with frozen shoulder: odds ratio (OR) = 1.50 [95% confidence interval (CI), 1.20–1.88], Dupuytren's disease: OR = 1.17 (95% CI, 1.01–1.35), trigger finger: OR = 1.30 (95% CI, 1.09–1.55) and carpal tunnel syndrome: OR = 1.20 (95% CI, 1.09–1.33). Carriers of GCK mutations have increased odds of frozen shoulder: OR = 7.16 (95% CI, 2.93–17.51) and carpal tunnel syndrome: OR = 2.86 (95% CI, 1.50–5.44) but not Dupuytren's disease or trigger finger. We found evidence that an increase in genetically predicted body mass index (BMI) of 5 kg/m2 was associated with carpal tunnel syndrome: OR = 1.13 (95% CI, 1.10–1.16) and associated negatively with Dupuytren's disease: OR = 0.94 (95% CI, 0.90–0.98), but no evidence of association with frozen shoulder or trigger finger. Trigger finger (OR 1.96 (95% CI, 1.42–2.69) P  =   3.6e-05) and carpal tunnel syndrome [OR 1.63 (95% CI, 1.36–1.95) P  =   8.5e-08] are associated with genetically predicted unfavourable adiposity increase of one standard deviation of body fat. Conclusions Our study consistently demonstrates a causal role of long-term high glycaemia in the aetiology of upper limb musculoskeletal conditions. Clinicians treating diabetes patients should be aware of these complications in clinic, specifically those managing the care of GCK mutation carriers. Upper limb musculoskeletal conditions should be considered diabetes complications. [ABSTRACT FROM AUTHOR]

Published
2024
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44. Identification and analysis of individuals who deviate from their genetically-predicted phenotype

Author

Hawkes, Gareth, Yengo, Loic, Vedantam, Sailaja, Marouli, Eirini, Beaumont, Robin N, Tyrrell, Jessica, Weedon, Michael N, Hirschhorn, Joel, Frayling, Timothy M, and Wood, Andrew R

Subjects
Article
Abstract

Findings from genome-wide association studies have facilitated the generation of genetic predictors for many common human phenotypes. Stratifying individuals misaligned to a genetic predictor based on common variants may be important for follow-up studies that aim to identify alternative causal factors. Using genome-wide imputed genetic data, we aimed to classify 158,951 unrelated individuals from the UK Biobank as either concordant or deviating from two well-measured phenotypes. We first applied our methods to standing height: our primary analysis classified 244 individuals (0.15%) as misaligned to their genetically predicted height. We show that these individuals are enriched for self-reporting being shorter or taller than average at age 10, diagnosed congenital malformations, and rare loss-of-function variants in genes previously catalogued as causal for growth disorders. Secondly, we apply our methods to LDL cholesterol. We classified 156 (0.12%) individuals as misaligned to their genetically predicted LDL cholesterol and show that these individuals were enriched for both clinically actionable cardiovascular risk factors and rare genetic variants in genes previously shown to be involved in metabolic processes. Individuals whose LDL-C was higher than expected based on the genetic predictor were also at higher risk of developing coronary artery disease and type-two diabetes, even after adjustment for measured LDL-C, BMI and age, suggesting upward deviation from genetically predicted LDL-C is indicative of generally poor health. Our results remained broadly consistent when performing sensitivity analysis based on a variety of parametric and non-parametric methods to define individuals deviating from polygenic expectation. Our analyses demonstrate the potential importance of quantitatively identifying individuals for further follow-up based on deviation from genetic predictions.Author SummaryHuman genetics is becoming increasingly useful to help predict human traits across a population owing to findings from large-scale genetic association studies and advances in the power of genetic predictors. This provides an opportunity to potentially identify individuals that deviate from genetic predictions for a common phenotype under investigation. For example, an individual may be genetically predicted to be tall, but be shorter than expected. It is potentially important to identify individuals who deviate from genetic predictions as this can facilitate further follow-up to assess likely causes. Using 158,951 unrelated individuals from the UK Biobank, with height and LDL cholesterol, as exemplar traits, we demonstrate that approximately 0.15% & 0.12% of individuals deviate from their genetically predicted phenotypes respectively. We observed these individuals to be enriched for a range of rare clinical diagnoses, as well as rare genetic factors that may be causal. Our analyses also demonstrate several methods for detecting individuals who deviate from genetic predictions that can be applied to a range of continuous human phenotypes.

Published
2023
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45. L'émergence des partis islamistes

Author

Vannetzel, Marie, Beaumont, Robin, Vannetzel, Marie, Florence Haegel, and Simon Persico

Subjects
gouvernement islamiste, islamisme, Partis politiques, hizbiyya, [SHS.SCIPO] Humanities and Social Sciences/Political science, genèse partisane
Published
2023

46. Genetic evidence that high BMI in childhood has a protective effect on intermediate diabetes traits, including measures of insulin sensitivity and secretion

Author

Hawkes, Gareth, primary, Beaumont, Robin N, additional, Tyrrell, Jessica, additional, Power, Grace M, additional, Wood, Andrew, additional, Laakso, Markku, additional, Silva, Lilian Fernandes, additional, Boehnke, Michael, additional, Yin, Xianyong, additional, Richardson, Tom G, additional, Davey Smith, George, additional, and Frayling, Timothy M, additional

Published
2023
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48. Response to Prakash et al.

Author

Tuke, Marcus A., Ruth, Katherine S., Wood, Andrew R., Beaumont, Robin N., Tyrrell, Jessica, Jones, Samuel E., Yaghootkar, Hanieh, Turner, Claire L. S., Donohoe, Mollie E., Brooke, Antonia M., Collinson, Morag N., Freathy, Rachel M., Weedon, Michael N., Frayling, Timothy M., and Murray, Anna

Published
2019
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49. Using Mendelian Randomisation methods to understand whether diurnal preference is causally related to mental health

Author

O’Loughlin, Jessica, Casanova, Francesco, Jones, Samuel E., Hagenaars, Saskia P., Beaumont, Robin N., Freathy, Rachel M., Watkins, Edward R., Vetter, Céline, Rutter, Martin K., Cain, Sean W., Phillips, Andrew J. K., Windred, Daniel P., Wood, Andrew R., Weedon, Michael N., and Tyrrell, Jessica

Abstract

Late diurnal preference has been linked to poorer mental health outcomes, but the understanding of the causal role of diurnal preference on mental health and wellbeing is currently limited. Late diurnal preference is often associated with circadian misalignment (a mismatch between the timing of the endogenous circadian system and behavioural rhythms), so that evening people live more frequently against their internal clock. This study aims to quantify the causal contribution of diurnal preference on mental health outcomes, including anxiety, depression and general wellbeing and test the hypothesis that more misaligned individuals have poorer mental health and wellbeing using an actigraphy-based measure of circadian misalignment. Multiple Mendelian Randomisation (MR) approaches were used to test causal pathways between diurnal preference and seven well-validated mental health and wellbeing outcomes in up to 451,025 individuals. In addition, observational analyses tested the association between a novel, objective measure of behavioural misalignment (Composite Phase Deviation, CPD) and seven mental health and wellbeing outcomes. Using genetic instruments identified in the largest GWAS for diurnal preference, we provide robust evidence that early diurnal preference is protective for depression and improves wellbeing. For example, using one-sample MR, a twofold higher genetic liability of morningness was associated with lower odds of depressive symptoms (OR: 0.92, 95% CI: 0.88, 0.97). It is possible that behavioural factors including circadian misalignment may contribute in the chronotype depression relationship, but further work is needed to confirm these findings.

Published
2024
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