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

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

Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. Methods: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. Findings: Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021. Interpretation: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. Funding: Bill & Melinda Gates Foundation

Face au handicap: action syndicale et cadrages juridiques

peer reviewedLes travailleurs en situation de handicap forment une catégorie invisibilisée et discriminée. Cet article examine la façon dont les militants syndicaux, en France, utilisent le droit et la justice pour défendre les travailleurs handicapés et, par ce biais, pour rendre ce public visible, aux yeux des employeurs et de leurs propres organisations syndicales. Il montre tout d’abord comment les syndicalistes font émerger la cause des travailleurs handicapés. Ensuite, il examine leurs usages du droit, très contrastés en fonction des arènes mobilisées et des buts poursuivis. Il met enfin en évidence les cadrages pluriels du handicap au sein des organisations syndicales, qui allient leur action pour la protection des emplois des salariés à des revendications d'égalité professionnelle. Plus généralement, cette étude renouvelle les travaux sur les usages syndicaux du droit en portant attention aux rôles du droit dans la visibilisation d’un public.Workers with disabilities are invisible and discriminated against. This article examines how labor unions representatives, in France, mobilize the law and the labor court to make this public visible among employers and members of unions. First, it shows how labor unions started to make the cause of disabled workers visible in their mobilization. Then, it examines their mobilization of the law and the court and how it varies according to the arenas and goals. Through this analysis, it shows the various framings of disability within labor unions, which combine mobilization to protect their members’ rights and claims for equal opportunity. More broadly, this study suggests new ways to analyze labor unions’ mobilization, by examining the role of the law in making a public visible.Handicap et aménagements raisonnables au travail: importation et usages d'une catégorie juridique en France et en Belgiqu

Logiques, contraintes et effets du recours aux comparutions immédiates. Etude de cinq juridictions de la Cour d’appel de Douai.

La comparution immédiate (CI) a connu une forte croissance de son usage au cours des années 2000. La procédure s’est par ailleurs largement diffusée dans l’ensemble des juridictions, alors qu’elle a longtemps été surtout mobilisée dans les grandes juridictions. Une telle croissance interroge sur les ressorts du recours aux comparutions immédiates. Plusieurs réformes ont été adoptées au cours de cette décennie mais ne suffisent pas à expliquer la diffusion de la procédure. Par ailleurs, le volume de jugements en CI invite à mieux caractériser la procédure, ses cibles et ses effets en termes de peine, dans la mesure où elle concerne aujourd’hui un nombre relativement important de cas. Etudier les comparutions immédiates est ainsi une façon de questionner les pratiques judiciaires et leur évolution de façon plus large. Trois objectifs ont ainsi été fixés à la recherche, au-delà de l’analyse de la croissance du nombre de comparutions immédiates : préciser le profil des individus jugés en comparution immédiate, tester l’hypothèse selon laquelle les comparutions immédiates conduisent à des peines plus sévères, identifier et expliquer la variété des pratiques. Ce dernier point visait notamment à dépasser une analyse en termes de critères présidant au choix de la CI, ou de telle peine dans le cadre de la CI, pour tenter de saisir les contraintes ou conditions spécifiques façonnant l’usage de la procédure. L’analyse s’appuie sur l’étude de 5 juridictions de la Cour d’appel de Douai (Lille, Béthune, Arras, Hazebrouck et Avesnes-sur-Helpe). Un échantillon de minutes de jugement (7882 affaires) a fait l’objet d’une analyse statistique, en vue de l’analyse des peines et du profil des prévenus. Une trentaine d’entretiens a par ailleurs été réalisé auprès de magistrats et d’avocats, et des observations ont été réalisées dans deux salles de permanence du parquet.Les résultats relatifs au profil des prévenus et aux peines prononcées à l’issue d’un jugement en CI confirment largement ceux d’autres travaux portant sur d’autres juridictions. Un autre résultat important de la recherche est la mise en évidence de la variabilité des pratiques, pour ce qui est de la fréquence du recours aux comparutions immédiates, des affaires susceptibles d’être traitées par la voie de cette procédure et des jugements prononcés. Ce deuxième résultat renforce paradoxalement le premier : les différences constatées dans l’usage des comparutions immédiates n’empêchent pas que cette procédure concerne un « public » aux caractéristiques bien identifiables (individus ayant un « passé pénal » et/ou en situation de précarité) ; elles ne contrecarrent pas non plus un effet propre de la procédure, qui favorise le prononcé de peines plus sévères que d’autres procédures.L’attention portée aux variations observables d’une juridiction à l’autre met en évidence des profils de magistrats, des conditions matérielles et des configurations locales freinant ou encourageant le recours aux comparutions immédiates. Par ailleurs, l’analyse localisée de pratiques met en évidence un certain nombre de facteurs structurant le recours aux comparutions immédiate : ainsi la logique de « l’ordre public », principe dont le contenu est défini localement, ou encore l’attractivité et la taille des juridictions, qui ont des effets sur le profil des magistrats en poste et sur la nature des relations entre les professionnels qui interviennent en matière de CI

Handicap et aménagements raisonnables: importation et usages d'une catégorie juridique en France et en Belgique

La notion d’aménagement raisonnable désigne toute tentative, dans une société, de s’accommoder ou de s’ajuster aux besoins d’un individu qui découlent de son appartenance à une minorité, dans le respect de l’égalité de traitement entre tous les êtres humains et des libertés fondamentales. Centrée sur les aménagements à destination des travailleurs en situation de handicap, cette enquête interroge l’émergence de cette catégorie en droit, ainsi que les usages qu’en font les acteurs sociaux dans le domaine du travail. Ce rapport examine les législations en vigueur, la jurisprudence et la doctrine. Il donne à voir les conditions d’importation de cette catégorie juridique en France et en Belgique et son articulation avec d’autres législations qui encadrent les relations de travail (obligation de reclassement, bien-être au travail, etc.). Il présente, ensuite, les résultats d’une enquête inédite menée auprès de professionnels – syndicalistes, avocats et agents des organismes publics de lutte contre les discriminations –, d’employeurs et de travailleurs avec un handicap, et met en lumière la façon dont cette catégorie juridique est mobilisée, contournée ou évitée. Les mobilisations syndicales et professionnelles, ainsi que les expériences du handicap au travail, s’inscrivent dans des configurations de relations professionnelles et des catégorisations administratives et juridiques du handicap différentes en France et en Belgique. Plus généralement, cette recherche montre les effets produits par l’introduction de cette obligation légale. Les acteurs du monde du travail se réfèrent peu aux législations en matière d’aménagement raisonnable, le pouvoir contraignant de ces normes étant contrebalancé par d’autres impératifs et logiques : discours managérial, droit du travail, etc. Néanmoins, ceci ne veut pas dire que le droit aux aménagements raisonnables n’a aucune effectivité, ni qu’il ne produit aucun effet. Les discours changent, les employeurs et les travailleurs se saisissent des cadres juridiques existants, les intègrent dans leurs discours et parfois dans leurs pratiques, lui donnent sens, et contribuent ainsi à remodeler les contours des normes juridiques

Research data supporting: "Understanding the genetic complexity of puberty timing across the allele frequency spectrum"

This dataset is made up of GWAS meta-analysis for age at menarche (AAM), in up to 799,845 women. All studies provided GWAS data imputed to at least 1000 Genomes reference panel density, yielding a total of ~12.7 million genetic variants in the final meta-analysis. Variants were meta-analysed using a fixed-effects inverse-variance-weighted model in METAL and filtered to include minor allele frequency (MAF) >= 0.1%. Summary statistics made available for download are from an analysis excluding 23andMe (ancestry combined up to n=723,014 and European-only up to n=556,124) and following all the filtering steps as outlined above. Datasets available for download: 1) Ancestry combined GWAS summary statistics Menarche2024_AncestryCombined_RELEASE_EXC23andMe.txt.gz 2) European-only GWAS summary statistics Menarche2024_EuropeanOnly_RELEASE_EXC23andMe.txt.gz Both tab-delimited files, with one row per SNP including the same columns as the above. For further information please check the supplied readme file or the associated publication.MC_UU_00006/

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

Acknowledgements: This research was supported by the UK Medical Research Council (MRC; Unit program MC_UU_00006/2) and has been conducted using the UK Biobank Resource under application 9905. Other study-specific acknowledgements can be found in the Supplementary Information.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

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

Acknowledgements: This research was supported by the UK Medical Research Council (MRC; Unit program MC_UU_00006/2) and has been conducted using the UK Biobank Resource under application 9905. Other study-specific acknowledgements can be found in the Supplementary Information.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