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      Understanding the genetic complexity of puberty timing across the allele frequency spectrum

      research-article
      1 , 1 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 5 , 6 , 14 , 5 , 6 , 4 , 11 , 12 , 2 , 15 , 7 , 1 , 1 , 1 , 8 , 16 , 17 , 18 , 13 , 19 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 1 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 31 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 13 , 74 , 40 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 25 , 85 , 86 , 87 , 88 , 89 , 56 , 42 , 90 , 91 , 13 , 92 , 93 , 94 , 95 , 78 , 96 , 97 , 98 , 99 , 100 , 75 , 101 , 56 , 102 , 103 , 70 , 104 , 105 , 106 , 107 , 108 , 109 , 42 , 110 , 111 , 21 , 26 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 68 , 95 , 120 , 75 , 7 , 94 , ABCTB Investigators 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 48 , 50 , 136 , 137 , 138 , 42 , 139 , 140 , 141 , 142 , 143 , 144 , 46 , 13 , 145 , 7 , 119 , 146 , 147 , 148 , 64 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 157 , 164 , 107 , 165 , 31 , 166 , 167 , 7 , 168 , 169 , 170 , 53 , 171 , 172 , 152 , 173 , 173 , 174 , 175 , 46 , 32 , 94 , 95 , 119 , 176 , 94 , 177 , 178 , 163 , 179 , 94 , 180 , 181 , 13 , 182 , 183 , 184 , 112 , 185 , 186 , 93 , 187 , 64 , 188 , 189 , 68 , 190 , 53 , 171 , 48 , 56 , 57 , 45 , 106 , 107 , 191 , 26 , 27 , 28 , 112 , 192 , 61 , 62 , 65 , 54 , 55 , 94 , 180 , 58 , 59 , 48 , 193 , 42 , 66 , 67 , 194 , 25 , 31 , 64 , 35 , 195 , 46 , 107 , 196 , 24 , 197 , 58 , 59 , 60 , 22 , 23 , 31 , 173 , 1 , 163 , 40 , The Lifelines Cohort Study, The Danish Blood Donor Study, The Ovarian Cancer Association Consortium, The Breast Cancer Association Consortium, The Biobank Japan Project, The China Kadoorie Biobank Collaborative Group, 13 , 96 , 198 , 199 , 13 , 96 , 2 , 200 , 11 , 44 , 201 , 202 , 203 , 204 , 205 , 10 , 206 , 207 , 208 , 209 , 11 , 62 , 210 , 7 , 4 , 5 , 6 , 2 , 15 , 1 , 1 , 211 , , 1 , 212
      Nature Genetics
      Nature Publishing Group US
      Genome-wide association studies, Obesity

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

          Abstract

          A multi-ancestry genome-wide association study for age at menarche followed by fine mapping and downstream analysis implicates 665 pubertal timing genes, such as the G-protein-coupled receptor 83 ( GPR83) and other genes expressed in the ovaries involved in the DNA damage response.

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          PLINK: a tool set for whole-genome association and population-based linkage analyses.

          Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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            • Article: found
            Is Open Access

            The mutational constraint spectrum quantified from variation in 141,456 humans

            Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
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              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age

              Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.
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                Author and article information

                Contributors
                john.perry@mrc-epid.cam.ac.uk
                Journal
                Nat Genet
                Nat Genet
                Nature Genetics
                Nature Publishing Group US (New York )
                1061-4036
                1546-1718
                1 July 2024
                1 July 2024
                2024
                : 56
                : 7
                : 1397-1411
                Affiliations
                [1 ]MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK
                [2 ]Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, ( https://ror.org/03zga2b32) Bergen, Norway
                [3 ]Department of Genetics and Bioinformatics, Health Data and Digitalization, Norwegian Institute of Public Health, ( https://ror.org/046nvst19) Oslo, Norway
                [4 ]GRID grid.120073.7, ISNI 0000 0004 0622 5016, University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, , Addenbrooke’s Hospital, ; Cambridge, UK
                [5 ]GRID grid.8515.9, ISNI 0000 0001 0423 4662, Division of Endocrinology, Diabetology, and Metabolism, , Lausanne University Hospital, ; Lausanne, Switzerland
                [6 ]Faculty of Biology and Medicine, University of Lausanne, ( https://ror.org/019whta54) Lausanne, Switzerland
                [7 ]Nuffield Department of Population Health, University of Oxford, ( https://ror.org/052gg0110) Oxford, UK
                [8 ]Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, ( https://ror.org/04mb6s476) Yokohama, Japan
                [9 ]Department of General Pediatrics, University of Münster, ( https://ror.org/00pd74e08) Münster, Germany
                [10 ]GRID grid.475435.4, Department of Growth and Reproduction, , Copenhagen University Hospital—Rigshospitalet, ; Copenhagen, Denmark
                [11 ]GRID grid.421812.c, ISNI 0000 0004 0618 6889, deCODE Genetics/Amgen, Inc., ; Reykjavik, Iceland
                [12 ]School of Engineering and Natural Sciences, University of Iceland, ( https://ror.org/01db6h964) Reykjavik, Iceland
                [13 ]Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, ( https://ror.org/013meh722) Cambridge, UK
                [14 ]Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, ( https://ror.org/001w7jn25) Berlin, Germany
                [15 ]Department of Medical Genetics, Haukeland University Hospital, ( https://ror.org/03np4e098) Bergen, Norway
                [16 ]Clinical Research Center, Shizuoka General Hospital, ( https://ror.org/0457h8c53) Shizuoka, Japan
                [17 ]Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, ( https://ror.org/04rvw0k47) Shizuoka, Japan
                [18 ]Department of Gynecology, Duke University Medical Center, ( https://ror.org/04bct7p84) Durham, NC USA
                [19 ]Research Center of the Sainte-Justine University Hospital, University of Montreal, ( https://ror.org/0161xgx34) Montreal, Quebec Canada
                [20 ]Quantinuum Research, Wayne, PA USA
                [21 ]Center for Applied Genomics, Children’s Hospital of Philadelphia, ( https://ror.org/01z7r7q48) Philadelphia, PA USA
                [22 ]Department of Internal Medicine, Erasmus MC, ( https://ror.org/018906e22) Rotterdam, The Netherlands
                [23 ]Department of Epidemiology, Erasmus MC, ( https://ror.org/018906e22) Rotterdam, The Netherlands
                [24 ]Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, ( https://ror.org/01nrxwf90) Edinburgh, UK
                [25 ]Division of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, ( https://ror.org/04b6nzv94) Boston, MA USA
                [26 ]Division of Human Genetics, Children’s Hospital of Philadelphia, ( https://ror.org/01z7r7q48) Philadelphia, PA USA
                [27 ]Department of Genetics, University of Pennsylvania, ( https://ror.org/00b30xv10) Philadelphia, PA USA
                [28 ]Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, ( https://ror.org/01z7r7q48) Philadelphia, PA USA
                [29 ]Department of Epidemiology, University of North Carolina, ( https://ror.org/0130frc33) Chapel Hill, NC USA
                [30 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Genetics, University of Groningen, , University Medical Center Groningen, ; Groningen, The Netherlands
                [31 ]GRID grid.418712.9, ISNI 0000 0004 1760 7415, Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’, ; Trieste, Italy
                [32 ]Department of Medicine, Surgery and Health Sciences, University of Trieste, ( https://ror.org/02n742c10) Trieste, Italy
                [33 ]Department of Internal Medicine, Division of Medical Oncology, University of Kentucky College of Medicine, ( https://ror.org/02k3smh20) Lexington, KY USA
                [34 ]GRID grid.266539.d, ISNI 0000 0004 1936 8438, Cancer Prevention and Control Research Program, Markey Cancer Center, , University of Kentucky, ; Lexington, KY USA
                [35 ]Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, ( https://ror.org/041kmwe10) London, UK
                [36 ]Institute of Health Sciences, University of Oulu, ( https://ror.org/03yj89h83) Oulu, Finland
                [37 ]Biocenter Oulu, University of Oulu, ( https://ror.org/03yj89h83) Oulu, Finland
                [38 ]Unit of Primary Care, Oulu University Hospital, ( https://ror.org/045ney286) Oulu, Finland
                [39 ]GRID grid.14758.3f, ISNI 0000 0001 1013 0499, Department of Children and Young People and Families, , National Institute for Health and Welfare, ; Oulu, Finland
                [40 ]Centre for Global Health Research, Usher Institute, University of Edinburgh, ( https://ror.org/01nrxwf90) Edinburgh, Scotland
                [41 ]Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, ( https://ror.org/057zh3y96) Tokyo, Japan
                [42 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, ( https://ror.org/056d84691) Stockholm, Sweden
                [43 ]Department of Biostatistics, Boston University School of Public Health, ( https://ror.org/05qwgg493) Boston, MA USA
                [44 ]NHLBI’s and Boston University’s Framingham Heart Study, ( https://ror.org/05qwgg493) Framingham, MA USA
                [45 ]Institute of Genomics, University of Tartu, ( https://ror.org/03z77qz90) Tartu, Estonia
                [46 ]Department of Twin Research and Genetic Epidemiology, King’s College London, ( https://ror.org/0220mzb33) London, UK
                [47 ]GRID grid.420545.2, ISNI 0000 0004 0489 3985, NIHR Biomedical Research Centre at Guy’s and St. Thomas’ Foundation Trust, ; London, UK
                [48 ]QIMR Berghofer Medical Research Institute, ( https://ror.org/004y8wk30) Brisbane, Queensland Australia
                [49 ]School of Psychology, University of Queensland, ( https://ror.org/00rqy9422) Brisbane, Queensland Australia
                [50 ]Faculty of Medicine, University of Queensland, ( https://ror.org/00rqy9422) Brisbane, Queensland Australia
                [51 ]Epidemiology, Medical Faculty, University of Augsburg, University Hospital of Augsburg, ( https://ror.org/03p14d497) Augsburg, Germany
                [52 ]Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, ( https://ror.org/05xvt9f17) Leiden, The Netherlands
                [53 ]GRID grid.5326.2, ISNI 0000 0001 1940 4177, Institute of Genetics and Biophysics ‘A. Buzzati-Traverso’, , CNR, ; Naples, Italy
                [54 ]University of Split School of Medicine, ( https://ror.org/00m31ft63) Split, Croatia
                [55 ]Algebra University College, ( https://ror.org/019m6wk21) Zagreb, Croatia
                [56 ]GRID grid.5326.2, ISNI 0000 0001 1940 4177, Institute of Genetics and Biomedical Research, , National Research Council, ; Sardinia, Italy
                [57 ]Department of Biomedical Sciences, University of Sassari, ( https://ror.org/01bnjbv91) Sassari, Italy
                [58 ]GRID grid.5337.2, ISNI 0000 0004 1936 7603, MRC Integrative Epidemiology Unit, , University of Bristol, ; Bristol, UK
                [59 ]Population Health Science, Bristol Medical School, University of Bristol, ( https://ror.org/0524sp257) Bristol, UK
                [60 ]Division of Genetics and Cell Biology, San Raffele Hospital, Milano, Italy
                [61 ]Icelandic Heart Association, ( https://ror.org/051snsd81) Kopavogur, Iceland
                [62 ]Faculty of Medicine, University of Iceland, ( https://ror.org/01db6h964) Reykjavik, Iceland
                [63 ]GRID grid.419475.a, ISNI 0000 0000 9372 4913, National Institute on Aging, National Institutes of Health, ; Baltimore, MD USA
                [64 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Epidemiology, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [65 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, MRC Human Genetics Unit, Institute of Genetics and Cancer, , University of Edinburgh, ; Edinburgh, UK
                [66 ]School of Medicine and Public Health, University of Newcastle, ( https://ror.org/00eae9z71) Newcastle, New South Wales Australia
                [67 ]Hunter Medical Research Institute, ( https://ror.org/0020x6414) Newcastle, New South Wales Australia
                [68 ]Department of Biological Psychology, Vrije Universiteit Amsterdam; Amsterdam Public Health (APH) Research Institute, ( https://ror.org/008xxew50) Amsterdam, The Netherlands
                [69 ]Clinic of Gynaecology and Obstetrics, University Medicine Greifswald, ( https://ror.org/025vngs54) Greifswald, Germany
                [70 ]GRID grid.27235.31, Division of Cancer Epidemiology and Genetics National Cancer Institute, National Institutes of Health, , Department of Health and Human Services Bethesda, ; Bethesda, MD USA
                [71 ]Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, ( https://ror.org/05deks119) Toronto, Ontario Canada
                [72 ]Department of Molecular Genetics, University of Toronto, ( https://ror.org/03dbr7087) Toronto, Ontario Canada
                [73 ]Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, ( https://ror.org/04gyf1771) Irvine, CA USA
                [74 ]Division of Biostatistics, Institute for Health and Equity and Cancer Center, Medical College of Wisconsin, ( https://ror.org/00qqv6244) Milwaukee, WI USA
                [75 ]GRID grid.411668.c, ISNI 0000 0000 9935 6525, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, , Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, ; Erlangen, Germany
                [76 ]Division of Genetics and Epidemiology, The Institute of Cancer Research, ( https://ror.org/043jzw605) London, UK
                [77 ]Department of Radiation Oncology, Hannover Medical School, ( https://ror.org/00f2yqf98) Hannover, Germany
                [78 ]Gynaecology Research Unit, Hannover Medical School, ( https://ror.org/00f2yqf98) Hannover, Germany
                [79 ]GRID grid.477553.7, ISNI 0000 0004 0516 9294, N.N. Alexandrov Research Institute of Oncology and Medical Radiology, ; Minsk, Belarus
                [80 ]Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, ( https://ror.org/051dzw862) Herlev, Denmark
                [81 ]Department of Clinical Biochemistry, Herlev and Gentofte Hospital Copenhagen University Hospital, ( https://ror.org/051dzw862) Herlev, Denmark
                [82 ]Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), ( https://ror.org/04cdgtt98) Heidelberg, Germany
                [83 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Division of Preventive Oncology, , German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), ; Heidelberg, Germany
                [84 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [85 ]Genomic Epidemiology Group, German Cancer Research Center (DKFZ), ( https://ror.org/04cdgtt98) Heidelberg, Germany
                [86 ]Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), ( https://ror.org/04cdgtt98) Heidelberg, Germany
                [87 ]GRID grid.412315.0, Cancer Epidemiology Group, , University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany
                [88 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Department of Laboratory Medicine and Pathology, , Mayo Clinic Rochester, ; Rochester, MN USA
                [89 ]Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, ( https://ror.org/05krs5044) Sheffield, UK
                [90 ]Department of Clinical Genetics, Fox Chase Cancer Center, ( https://ror.org/0567t7073) Philadelphia, PA USA
                [91 ]GRID grid.17635.36, ISNI 0000000419368657, Division of Epidemiology and Community Health, School of Public Health, , University of Minnesota, ; Minneapolis, MN USA
                [92 ]Department of Pathology, Leiden University Medical Center, ( https://ror.org/05xvt9f17) Leiden, The Netherlands
                [93 ]Department of Human Genetics, Leiden University Medical Center, ( https://ror.org/05xvt9f17) Leiden, The Netherlands
                [94 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Epidemiology, , Harvard T.H. Chan School of Public Health, ; Boston, MA USA
                [95 ]Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, ( https://ror.org/04b6nzv94) Boston, MA USA
                [96 ]Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, ( https://ror.org/013meh722) Cambridge, UK
                [97 ]School of Life Sciences, University of Westminster, ( https://ror.org/04ycpbx82) London, UK
                [98 ]GRID grid.15485.3d, ISNI 0000 0000 9950 5666, Department of General Practice and Primary Healthcare, , University of Helsinki, Helsinki University Hospital, ; Helsinki, Finland
                [99 ]Yong Loo Lin School of Medicine, Department of Obstetrics and Gynecology and Human Potential Translational Research Programme, National University Singapore, ( https://ror.org/01tgyzw49) Singapore City, Singapore
                [100 ]Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), ( https://ror.org/015p9va32) Singapore City, Singapore
                [101 ]Department of Biobehavioral Health, Pennsylvania State University, ( https://ror.org/04p491231) University Park, PA USA
                [102 ]The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, ( https://ror.org/043jzw605) London, UK
                [103 ]GRID grid.411048.8, ISNI 0000 0000 8816 6945, Genomic Medicine Group, International Cancer Genetics and Epidemiology Group Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, , SERGAS Santiago de Compostela, ; Coruña, Spain
                [104 ]GRID grid.510933.d, ISNI 0000 0004 8339 0058, Medical Oncology Department, Hospital Clínico San Carlos Instituto de Investigación Sanitaria San Carlos (IdISSC), , Centro Investigación Biomédica en Red de Cáncer (CIBERONC), ; Madrid, Spain
                [105 ]Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), ( https://ror.org/00bvhmc43) Madrid, Spain
                [106 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, ( https://ror.org/00cfam450) Neuherberg, Germany
                [107 ]Institute of Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, ( https://ror.org/00cfam450) Neuherberg, Germany
                [108 ]Team ‘Exposome and Heredity’, CESP, Gustave Roussy INSERM, University Paris-Saclay, UVSQ, ( https://ror.org/03xjwb503) Orsay, France
                [109 ]Department of Preventive Medicine, Keck School of Medicine, University of Southern California, ( https://ror.org/03taz7m60) Los Angeles, CA USA
                [110 ]Department of Oncology, Södersjukhuset, ( https://ror.org/00ncfk576) Stockholm, Sweden
                [111 ]Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), ( https://ror.org/04cdgtt98) Heidelberg, Germany
                [112 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Pediatrics, , University of Pennsylvania Perelman School of Medicine, ; Philadelphia, PA USA
                [113 ]Division of Pulmonary Medicine, Children’s Hospital of Philadelphia, ( https://ror.org/01z7r7q48) Philadelphia, PA USA
                [114 ]Division of Obstetrics and Gynaecology, University of Western Australia, ( https://ror.org/047272k79) Crawley, Western Australia Australia
                [115 ]Department of Obstetrics and Gynaecology, University of Melbourne and The Royal Women’s Hospital, ( https://ror.org/03grnna41) Parkville, Victoria Australia
                [116 ]Department of Medical Oncology, Erasmus MC Cancer Institute, ( https://ror.org/03r4m3349) Rotterdam, The Netherlands
                [117 ]Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, ( https://ror.org/02pnjnj33) Stuttgart, Germany
                [118 ]University of Tübingen, ( https://ror.org/03a1kwz48) Tübingen, Germany
                [119 ]Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, ( https://ror.org/01ej9dk98) Melbourne, Victoria Australia
                [120 ]Department of Nutrition, Harvard T.H. Chan School of Public Health School of Public Health, ( https://ror.org/00q16t150) Boston, MA USA
                [121 ]GRID grid.1013.3, ISNI 0000 0004 1936 834X, Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, , University of Sydney, ; Sydney, New South Wales Australia
                [122 ]Oncology, Department of Clinical Sciences in Lund, Lund University, ( https://ror.org/012a77v79) Lund, Sweden
                [123 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Epidemiology and Population Health, , Stanford University School of Medicine Stanford, ; Stanford, CA USA
                [124 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Medicine, Division of Oncology Stanford Cancer Institute, , Stanford University School of Medicine Stanford, ; Stanford, CA USA
                [125 ]GRID grid.38142.3c, ISNI 000000041936754X, Hebrew SeniorLife Institute for Aging Research, ; Boston, MA USA
                [126 ]GRID grid.38142.3c, ISNI 000000041936754X, Harvard Medical School, ; Boston, MA USA
                [127 ]GRID grid.429129.5, Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, ; Ufa, Russia
                [128 ]GRID grid.77269.3d, ISNI 0000 0001 1015 7624, Department of Genetics and Fundamental Medicine, , Bashkir State University, ; Ufa, Russia
                [129 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Medical Genetics, , Oslo University Hospital and University of Oslo, ; Oslo, Norway
                [130 ]Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, ( https://ror.org/01xtthb56) Oslo, Norway
                [131 ]Department of Computational and Quantitative Medicine, City of Hope, ( https://ror.org/00w6g5w60) Duarte, CA USA
                [132 ]City of Hope Comprehensive Cancer Center, City of Hope, ( https://ror.org/00w6g5w60) Duarte, CA USA
                [133 ]Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, ( https://ror.org/05f950310) Leuven, Belgium
                [134 ]GRID grid.511459.d, VIB Center for Cancer Biology, VIB, ; Leuven, Belgium
                [135 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, , National Institutes of Health, ; Bethesda, MD USA
                [136 ]School of Biomedical Sciences, Queensland University of Technology, ( https://ror.org/03pnv4752) Brisbane, Queensland Australia
                [137 ]Department of Molecular Medicine and Surgery, Karolinska Institutet, ( https://ror.org/056d84691) Stockholm, Sweden
                [138 ]Department of Clinical Genetics, Karolinska University Hospital, ( https://ror.org/00m8d6786) Stockholm, Sweden
                [139 ]Translational Cancer Research Area, University of Eastern Finland, ( https://ror.org/00cyydd11) Kuopio, Finland
                [140 ]Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, ( https://ror.org/00cyydd11) Kuopio, Finland
                [141 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Wellcome Trust Centre for Human Genetics, , University of Oxford, ; Oxford, UK
                [142 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Oxford Centre for Diabetes, Endocrinology and Metabolism, , University of Oxford, Churchill Hospital, ; Oxford, UK
                [143 ]NIHR Oxford Biomedical Research Centre, Churchill Hospital, ( https://ror.org/009vheq40) Oxford, UK
                [144 ]GRID grid.15474.33, ISNI 0000 0004 0477 2438, Institute of Human Genetics, , Klinikum rechts der Isar, Technical University of Munich, School of Medicine, ; Munich, Germany
                [145 ]Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, ( https://ror.org/01ggsp920) Nicosia, Cyprus
                [146 ]Cancer Epidemiology Division, Cancer Council Victoria, ( https://ror.org/023m51b03) Melbourne, Victoria Australia
                [147 ]Institute for Molecular Bioscience, The University of Queensland, ( https://ror.org/00rqy9422) Brisbane, Queensland Australia
                [148 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Department of Obstetrics and Gynecology, Helsinki University Hospital, , University of Helsinki, ; Helsinki, Finland
                [149 ]School of Biomedical Sciences, Faculty of Health, Centre for Genomics and Personalised Health, Queensland University of Technology, ( https://ror.org/03pnv4752) Brisbane, Queensland Australia
                [150 ]Institute for Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, ( https://ror.org/01zgy1s35) Hamburg, Germany
                [151 ]Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, ( https://ror.org/01zgy1s35) Hamburg, Germany
                [152 ]Epidemiology Branch, National Institute of Environmental Health Sciences, NIH Research Triangle Park, ( https://ror.org/00j4k1h63) Durham, NC USA
                [153 ]Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, ( https://ror.org/02yrq0923) New York City, NY USA
                [154 ]Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, ( https://ror.org/02yrq0923) New York City, NY USA
                [155 ]GRID grid.4830.f, ISNI 0000 0004 0407 1981, Interdisciplinary Center Psychopathology and Emotion Regulation, University Medical Center Groningen, , University of Groningen, ; Groningen, The Netherlands
                [156 ]GRID grid.475435.4, Department of Clinical Immunology, , Rigshospitalet—University of Copenhagen, ; Copenhagen, Denmark
                [157 ]Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, ( https://ror.org/035b05819) Copenhagen, Denmark
                [158 ]Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, ( https://ror.org/002pd6e78) Boston, MA USA
                [159 ]Medical and Population Genetics Program, Broad Institute of MIT and Harvard, ( https://ror.org/05a0ya142) Cambridge, MA USA
                [160 ]GRID grid.66859.34, ISNI 0000 0004 0546 1623, Stanley Center for Psychiatric Research, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [161 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, ( https://ror.org/05cy4wa09) Hinxton, UK
                [162 ]Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, ( https://ror.org/002pd6e78) Boston, MA USA
                [163 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Institute for Molecular Medicine Finland (FIMM), , University of Helsinki, ; Helsinki, Finland
                [164 ]GRID grid.512923.e, ISNI 0000 0004 7402 8188, Department of Clinical Immunology, , Zealand University Hospital, ; Køge, Denmark
                [165 ]Institute for Medical Information Processing, Biometry and Epidemiology—IBE, Ludwig-Maximilians-Universität München, ( https://ror.org/05591te55) Munich, Germany
                [166 ]Research Centre for Genetic Engineering and Biotechnology ‘Georgi D. Efremov’, MASA, Skopje, Republic of North Macedonia
                [167 ]GRID grid.14758.3f, ISNI 0000 0001 1013 0499, National Institute for Health and Welfare, ; Helsinki, Finland
                [168 ]GRID grid.417893.0, ISNI 0000 0001 0807 2568, Unit of Preventive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS, , Istituto Nazionale dei Tumori (INT), ; Milan, Italy
                [169 ]GRID grid.413469.d, Faculty of Medicine, , Clalit National Cancer Control Center, Carmel Medical Center and Technion, ; Haifa, Israel
                [170 ]Department of Clinical Epidemiology, Leiden University Medical Center, ( https://ror.org/05xvt9f17) Leiden, The Netherlands
                [171 ]IRCCS Neuromed, ( https://ror.org/00cpb6264) Isernia, Italy
                [172 ]Division of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, ( https://ror.org/04v4g9h31) Larissa, Greece
                [173 ]Institute for Community Medicine, University Medicine Greifswald, ( https://ror.org/025vngs54) Greifswald, Germany
                [174 ]Division of Molecular Pathology, The Netherlands Cancer Institute, ( https://ror.org/03xqtf034) Amsterdam, The Netherlands
                [175 ]Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, ( https://ror.org/03xqtf034) Amsterdam, The Netherlands
                [176 ]Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia Perth, ( https://ror.org/047272k79) Perth, Western Australia Australia
                [177 ]Department of Population Health Sciences, Weill Cornell Medicine, ( https://ror.org/02r109517) New York City, NY USA
                [178 ]Department of Population Science, American Cancer Society, ( https://ror.org/02e463172) Atlanta, GA USA
                [179 ]GRID grid.14758.3f, ISNI 0000 0001 1013 0499, Public Health Genomics Unit, Department of Chronic Disease Prevention, , National Institute for Health and Welfare, ; Helsinki, Finland
                [180 ]GRID grid.38142.3c, ISNI 000000041936754X, Program in Genetic Epidemiology and Statistical Genetics, , Harvard T.H. Chan School of Public Health, ; Boston, MA USA
                [181 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Department of Quantitative Health Sciences, Division of Epidemiology, , Mayo Clinic Rochester, ; Rochester, MN USA
                [182 ]Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, ( https://ror.org/03yj89h83) Oulu, Finland
                [183 ]GRID grid.511574.3, ISNI 0000 0004 7407 0626, Laboratory of Cancer Genetics and Tumor Biology, , Northern Finland Laboratory Centre, ; Oulu, Finland
                [184 ]Institute of Environmental Medicine, Karolinska Institutet, ( https://ror.org/056d84691) Stockholm, Sweden
                [185 ]Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, ( https://ror.org/01z7r7q48) Philadelphia, PA USA
                [186 ]GRID grid.152326.1, ISNI 0000 0001 2264 7217, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, , Vanderbilt University School of Medicine, ; Nashville, TN USA
                [187 ]Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, ( https://ror.org/05xvt9f17) Leiden, The Netherlands
                [188 ]Geriatric Unit, Local Health Toscana Centro, Florence, Italy
                [189 ]GRID grid.267308.8, ISNI 0000 0000 9206 2401, Human Genetics Center, , University of Texas Health Science Center at Houston, ; Houston, TX USA
                [190 ]Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
                [191 ]German Center for Diabetes Research (DZD), ( https://ror.org/04qq88z54) Neuherberg, Germany
                [192 ]Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, ( https://ror.org/01z7r7q48) Philadelphia, PA USA
                [193 ]GRID grid.7143.1, ISNI 0000 0004 0512 5013, Institute of Clinical Research, University of Southern Denmark, Department of Obstetrics and Gynecology, , Odense University Hospital, ; Odense, Denmark
                [194 ]Department of Maternity and Gynaecology, John Hunter Hospital, ( https://ror.org/0187t0j49) Newcastle, New South Wales Australia
                [195 ]Department of Obstetrics and Gynaecology, University of Cambridge, ( https://ror.org/013meh722) Cambridge, UK
                [196 ]GRID grid.414279.d, ISNI 0000 0001 0349 2029, State Institute of Health, , Bavarian Health and Food Safety Authority (LGL), ; Oberschleissheim, Germany
                [197 ]Centre for Medical Informatics, Usher Institute, University of Edinburgh, ( https://ror.org/01nrxwf90) Edinburgh, UK
                [198 ]Department of Epidemiology and Biostatistics, School of Public Health, Peking University, ( https://ror.org/02v51f717) Beijing, China
                [199 ]Center for Public Health and Epidemic Preparedness and Response, Peking University, ( https://ror.org/02v51f717) Beijing, China
                [200 ]Children and Adolescent Clinic, Haukeland University Hospital, ( https://ror.org/03np4e098) Bergen, Norway
                [201 ]Boston University Chobanian and Avedisian School of Medicine, Department of Medicine, Section of General Internal Medicine, ( https://ror.org/05qwgg493) Boston, MA USA
                [202 ]GRID grid.416118.b, Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, RILD Level 3, , Royal Devon and Exeter Hospital, ; Exeter, UK
                [203 ]GRID grid.14848.31, ISNI 0000 0001 2292 3357, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, , University of Montreal, ; Montreal, Quebec Canada
                [204 ]Department of Pediatrics, University of Montreal, ( https://ror.org/0161xgx34) Montreal, Quebec Canada
                [205 ]Department of Biochemistry and Molecular Medicine, University of Montreal, ( https://ror.org/0161xgx34) Montreal, Quebec Canada
                [206 ]International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital—Rigshospitalet, ( https://ror.org/03mchdq19) Copenhagen, Denmark
                [207 ]Department of Clinical Medicine, University of Copenhagen, ( https://ror.org/035b05819) Copenhagen, Denmark
                [208 ]Department of Clinical Immunology, Aarhus University Hospital, ( https://ror.org/040r8fr65) Aarhus, Denmark
                [209 ]Department of Clinical Medicine, Aarhus University, ( https://ror.org/01aj84f44) Aarhus, Denmark
                [210 ]Laboratory for Genomics of Diabetes and Metabolism, RIKEN Center for Integrative Medical Sciences, ( https://ror.org/04mb6s476) Yokohama, Japan
                [211 ]GRID grid.5335.0, ISNI 0000000121885934, Metabolic Research Laboratory, Wellcome-MRC Institute of Metabolic Science, , University of Cambridge School of Clinical Medicine, ; Cambridge, UK
                [212 ]Department of Paediatrics, University of Cambridge, ( https://ror.org/013meh722) Cambridge, UK
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                Article
                1798
                10.1038/s41588-024-01798-4
                11250262
                38951643
                13cb45ac-5f98-464b-b8e7-a884fc7ef66a
                © The Author(s) 2024, corrected publication 2024

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                History
                : 12 June 2023
                : 13 May 2024
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100009187, RCUK | MRC | Medical Research Foundation;
                Award ID: MC_UU_00006/2
                Award ID: MC_UU_00006/2
                Award ID: MC_UU_00006/2
                Award ID: MC_UU_00006/2
                Award ID: MC_UU_00006/2
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                © Springer Nature America, Inc. 2024

                Genetics
                genome-wide association studies,obesity
                Genetics
                genome-wide association studies, obesity

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