Instrumental variable meta-analysis of randomised trials of epidural analgesia in labour to adjust for non-compliance

Objective: Intention-to-treat analysis of randomised controlled trials may cause bias towards the null where non-compliance with the allocated intervention occurs. Instrumental variable analysis allows estimation of the causal effect adjusted for non-compliance. The aim of this study is to compare intention-to-treat and instrumental variable meta-analysis of the association between epidural analgesia in labour and caesarean section. Study design and Setting: The study was restricted to 27 trials in a recent Cochrane Systematic Review. For trials with data on compliance, the association between epidural analgesia in labour and caesarean section was calculated using intention-to-treat analysis and instrumental variable analysis. Fixed-effects meta-analysis was used to calculate pooled risk ratios. Results: In 18 trials with data on compliance, 23% of women allocated to epidural analgesia did not comply and 27% of women allocated to the control received epidural analgesia. Data on outcomes in non-compliant groups were available for 10 trials. The pooled risk ratio for caesarean section following epidural analgesia in labour was 1.37 (95% CI 1.00-1.89, p=0.049) using instrumental variable analysis compared to 1.19 (95% CI 0.93-1.51, p=0.16) using intention-to-treat analysis. Conclusion: Intention-to-treat meta-analysis underestimates the effect of receiving epidural analgesia in labour on caesarean section compared to instrumental variable meta-analysis.NHMR

Intrahepatic cholestasis of pregnancy is not associated with stillbirth in an Australian maternity population

Dissertação de mestrado em Relações Internacionais (Estudos da Paz e da Segurança), apresentada à Faculdade de Economia da Universidade de CoimbraNo seguimento de experiências de violência extrema, no contexto de regimes políticos autoritários e violações sistemáticas de direitos humanos, algumas sociedades são confrontadas com questões relativas ao legado desse passado de violência, cujo impacto se faz sentir diretamente ao nível dos seus processos de (re)conciliação e reconstrução pós-conflito: o que será lembrado e esquecido, na construção da memória e verdade(s) sobre o conflito, e na transmissão do conhecimento às gerações futuras? O que deve acontecer aos indivíduos que planearam e aos que exerceram a violência? Que tipo de crimes serão julgados? Que tipo de processos judiciais e mecanismos de reparação serão estabelecidos e com que propósitos? Como é que uma sociedade pode (re)estabelecer os seus laços sociais intra-comunitários e até que ponto é que indivíduos que se percecionam mutuamente como inimigos alguma vez se poderão reconciliar? Estas são questões relacionadas com o fenómeno de justiça de transição, que se tem vindo a estabelecer enquanto norma global para as sociedades lidarem com o passado. A justiça de transição não só é uma área pouco teorizada como a sua teoria e prática dependem, em larga medida, de pressupostos adquiridos e partilhados com o modelo liberal internacional de construção da paz (peacebuilding). Esta dissertação procura problematizar mais especificamente um destes pressupostos, a dicotomia “vítimaperpetrador” e os processos de categorização inerentes ao modelo dominante de justiça de transição, em geral, tal como este é pensado e implementado ao nível internacional e nacional. Com base no estudo de caso do Ruanda, o nosso objetivo é demonstrar as insuficiências e limitações desta visão dicotómica para interpretar dinâmicas profundas de conflito considerando, ao invés, a diversidade de experiências de violência e vitimização que esta dicotomia exclui e refletindo sobre o seu impacto nas perspectivas de (re)conciliação pós-conflito, em particular da sociedade Ruandesa. De forma a atingir o objetivo a que nos propomos, a análise desta dissertação será orientada pela seguinte pergunta de partida: de que forma, no contexto de sociedades pós-conflito, como o Ruanda, pode uma narrativa de vitimização dominante ser desafiada por excluir uma diversidade de experiências de vitimização e violência, e que repercussões pode esta contestação originar para as perspectivas de (re)conciliação nesta sociedade? A nossa análise estará alicerçada em três hipóteses: (i) a dicotomia “vítima-perpetrator” é um elemento fundamental das iniciativas de transição pós-conflito apoiados pela ONU e implementados no contexto de intervenções internacionais; (ii) o Ruanda no pósgenocídio é caracterizado por uma narrativa nacional dominante de vitimização, baseada numa dicotomia “vítima-perpetrator” que é insuficiente para compreender a diversidade de experiências de violência e vitimização vivida por diferentes grupos sociais, excluindoas e deslegitimando-as; e (iii) os processos de justiça de transição orientados segundo esta dicotomia provocam novas formas de re-vitimização, por um lado, invisibilizando e deslegitimando certas experiências de violência e vitimização e, por outro lado, tomando estas categorias socio-políticas como absolutas, limitando assim a agência política dos indivíduos e a sua (re)integração social, colocando em causa o processo de (re)conciliação em sociedades divididas em geral, e na Ruandesa em particular. A validação destas hipóteses será baseada numa abordagem qualitativa à investigação, com base na interpretação qualitativa de informação textual recolhida através de fontes primárias e secundárias, e também na análise de discurso. O enquadramento teórico e conceptual com base no qual articularemos a nossa crítica combina contributos teóricos de duas disciplinas distintas mas complementares: a psicologia social, mais precisamente o trabalho de Carlos Beristain sobre a abordagem psicosocial, e a teoria das relações internacionais, especificamente a vertente mais crítica da abordagem construtivista. Da nossa análise decorreu a validação das nossas hipóteses iniciais, sendo que demonstrámos assim como a dicotomia “vítima-perpetrator” se tem tornado um elemento fundamental nas iniciativas de justiça de transição apoiadas pela ONU; discutimos e detalhámos as narrativas dominantes de justiça de transição e vitimização estabelecidas no Ruanda e as suas dinâmicas de exclusão e, por último, refletimos sobre como os processos de justiça de transição orientados por esta dicotomia promovem processos de revitimização e limitam as perspectivas de longo prazo de reconciliação em sociedades divididas, como exemplificado pelo Ruanda no pós-genocídio.Following experiences of extreme violence, in the context of authoritarian political regimes and systematic human rights violations, societies are faced with questions regarding the legacy of that past of violence, which directly impact on the processes of (re)conciliation and post-conflict rebuilding: what will be remembered and forgotten, in the construction of memory and truth(s) relating to the conflict, and in the transmission of knowledge to younger generations? What should happen to those individuals who planned and those who enacted the violence? What will be the range of crimes under investigation? What kind of judicial processes and mechanisms for reparations will be established and with what purposes? How can a community (re)establish its social intra-community ties and to what extent and in which way can individuals who perceive each other as enemies ever reconcile? These questions fall within the scope of the phenomenon of transitional justice, which has been establishing itself as a global norm on how societies should deal with the past. Not only is the field of transitional justice under theorized but its dominant discourse on theory and praxis relies heavily on core assumptions taken for granted, many of which borrowed from liberal peacebuilding. Our dissertation seeks to problematize one of these, in particular, the “victim-perpetrator” dichotomy and the categorizing inherent to the dominant transitional justice model thought of and implemented at both international and national levels. Drawing on Rwanda as a case study, this dissertation will aim at demonstrating the insufficiencies and limitations of this dichotomised view in understanding deeper conflict dynamics, by looking into the diversity of violence and victimhood experiences that this dichotomy excludes and by reflecting upon its impact on the prospects of post-conflict (re)conciliation, specifically with regards to contemporary Rwandan society. In order to achieve our proposed aim, the analysis in this dissertation will be guided by the following research question: In what way, in the context of a post-conflict society such as Rwanda, can an established dominant victimhood narrative be challenged for excluding the diversity of victimization and violence experiences, and what repercussions may that dispute have on the prospects of (re)conciliation in this society? Our analysis will be grounded on three working hypotheses: (i) the dichotomy “victim-perpetrator” is a fundamental element in UN-sanctioned post-conflict transition Initiatives implemented in the context of international interventions; (ii) post -genocide Rwanda is characterized by a national dominant victimhood narrative, based on a “victim-perpetrator” dichotomy which is insufficient to understand the full diversity of violence and victimhood experiences from different social groups, therefore excluding and delegitimizing them; and (iii) transitional justice processes framed by this dichotomy promote new forms of victimization, on the one hand, by making invisible (and, therefore, illegitimate) certain experiences of violence and victimhood and, on the other hand, by essentializing these sociopolitical categories, which ends up limiting individuals’ political agency and social reintegration, hindering the reconciliation process in divided societies and, particularly, in Rwanda. The validation of these hypotheses will be based on a qualitative research approach, in this way relying on the qualitative interpretation of textual (qualitative) data collected both from the literature and from primary evidence as well as discourse analysis. The theoretical and conceptual framework supporting our critique combines contributions from two distinct but, complementary fields of study: social psychology, in particular the work of Carlos Beristain on the psychosocial approach, and international relations theory, drawing on the more critical strand of constructivism. Our discussion successfully validated our three initial hypotheses, therefore asserting how the “victim-perpetrator” dichotomy has become a fundamental element in UN-sanctioned transit ional justice initiatives; discussing and detailing the dominant transitional justice and victimhood narratives in Rwanda and their dynamics of exclusion and, finally, reflecting on how transitional justice processes framed by this dichotomy promote re-victimization and hinder long-term reconciliation in divided societies such as post-genocide Rwanda

Partial Deletion of Chromosome 8 β-defensin Cluster Confers Sperm Dysfunction and Infertility in Male Mice

β-defensin peptides are a family of antimicrobial peptides present at mucosal surfaces, with the main site of expression under normal conditions in the male reproductive tract. Although they kill microbes in vitro and interact with immune cells, the precise role of these genes in vivo remains uncertain. We show here that homozygous deletion of a cluster of nine β-defensin genes (DefbΔ9) in the mouse results in male sterility. The sperm derived from the mutants have reduced motility and increased fragility. Epididymal sperm isolated from the cauda should require capacitation to induce the acrosome reaction but sperm from the mutants demonstrate precocious capacitation and increased spontaneous acrosome reaction compared to wild-types but have reduced ability to bind the zona pellucida of oocytes. Ultrastructural examination reveals a defect in microtubule structure of the axoneme with increased disintegration in mutant derived sperm present in the epididymis cauda region, but not in caput region or testes. Consistent with premature acrosome reaction, sperm from mutant animals have significantly increased intracellular calcium content. Thus we demonstrate in vivo that β-defensins are essential for successful sperm maturation, and their disruption leads to alteration in intracellular calcium, inappropriate spontaneous acrosome reaction and profound male infertility

Is Adipose Tissue a Place for Mycobacterium tuberculosis Persistence?

BACKGROUND: Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), has the ability to persist in its human host for exceptionally long periods of time. However, little is known about the location of the bacilli in latently infected individuals. Long-term mycobacterial persistence in the lungs has been reported, but this may not sufficiently account for strictly extra-pulmonary TB, which represents 10–15% of the reactivation cases. METHODOLOGY/PRINCIPAL FINDINGS: We applied in situ and conventional PCR to sections of adipose tissue samples of various anatomical origins from 19 individuals from Mexico and 20 from France who had died from causes other than TB. M. tuberculosis DNA could be detected by either or both techniques in fat tissue surrounding the kidneys, the stomach, the lymph nodes, the heart and the skin in 9/57 Mexican samples (6/19 individuals), and in 8/26 French samples (6/20 individuals). In addition, mycobacteria could be immuno-detected in perinodal adipose tissue of 1 out of 3 biopsy samples from individuals with active TB. In vitro, using a combination of adipose cell models, including the widely used murine adipose cell line 3T3-L1, as well as primary human adipocytes, we show that after binding to scavenger receptors, M. tuberculosis can enter within adipocytes, where it accumulates intracytoplasmic lipid inclusions and survives in a non-replicating state that is insensitive to the major anti-mycobacterial drug isoniazid. CONCLUSIONS/SIGNIFICANCE: Given the abundance and the wide distribution of the adipose tissue throughout the body, our results suggest that this tissue, among others, might constitute a vast reservoir where the tubercle bacillus could persist for long periods of time, and avoid both killing by antimicrobials and recognition by the host immune system. In addition, M. tuberculosis-infected adipocytes might provide a new model to investigate dormancy and to evaluate new drugs for the treatment of persistent infection

Fifteen years of the Australian imaging, biomarkers and lifestyle (AIBL) study: Progress and observations from 2,359 older adults spanning the spectrum from cognitive normality to Alzheimer\u27s disease

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer\u27s disease dementia (AD)) as an \u27Inception cohort\u27 who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an \u27Enrichment cohort\u27 (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Funding Information: Researchers were funded by investment from the European Regional Development Fund (ERDF) and the European Social Fund (ESF) Convergence Programme for Cornwall and the Isles of Scilly [J.T.]; European Research Council (ERC) [grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M.F., A.R.W.], [ERC Consolidator Grant, ERC-2014-CoG-648916 to V.W.V.J.], [P.R.N.]; University of Bergen, KG Jebsen and Helse Vest [P.R.N.]; Wellcome Trust Senior Investigator Awards [A.T.H. (WT098395), M.I.M. (WT098381)]; National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0611–10219); Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150) [R.M.F., R.N.B.]; 4-year studentship (Grant Code: WT083431MF) [R.C.R]; the European Research Council under the European Union’s Seventh Framework Programme (FP/2007– 2013)/ERC Grant Agreement (grant number 669545; Develop Obese) [D.A.L.]; US National Institute of Health (grant: R01 DK10324) [D.A.L, C.L.R]; Wellcome Trust GWAS grant (WT088806) [D.A.L] and NIHR Senior Investigator Award (NF-SI-0611–10196) [D.A.L]; Wellcome Trust Institutional Strategic Support Award (WT097835MF) [M.A.T.]; The Diabetes Research and Wellness Foundation Non-Clinical Fellowship [J.T.]; Australian National Health and Medical Research Council Early Career Fellowship (APP1104818) [N.M.W.]; Daniel B. Burke Endowed Chair for Diabetes Research [S.F.A.G.]; UK Medical Research Council Unit grants MC_UU_12013_5 [R.C.R, L.P, S.R, C.L.R, D.M.E., D.A.L.] and MC_UU_12013_4 [D.M.E.]; Medical Research Council (grant: MR/M005070/1) [M.N.W., S.E.J.]; Australian Research Council Future Fellowship (FT130101709) [D.M.E] and (FT110100548) [S.E.M.]; NIHR Oxford Biomedical Research Centre (BRC); Oak Foundation Fellowship and Novo Nordisk Foundation (12955) [B.F.]; FRQS research scholar and Clinical Scientist Award by the Canadian Diabetes Association and the Maud Menten Award from the Institute of Genetics– Canadian Institute of Health Research (CIHR) [MFH]; CIHR— Frederick Banting and Charles Best Canada Graduate Scholarships [C.A.]; FRQS [L.B.]; Netherlands Organization for Health Research and Development (ZonMw–VIDI 016.136.361) [V.W.V.J.]; National Institute on Aging (R01AG29451) [J.M.M.]; 2010–2011 PRIN funds of the University of Ferrara—Holder: Prof. Guido Barbujani, Supervisor: Prof. Chiara Scapoli—and in part sponsored by the European Foundation for the Study of Diabetes (EFSD) Albert Renold Travel Fellowships for Young Scientists, ‘5 per mille’ contribution assigned to the University of Ferrara, income tax return year 2009 and the ENGAGE Exchange and Mobility Program for ENGAGE training funds, ENGAGE project, grant agreement HEALTH-F4–2007-201413 [L.M.]; ESRC (RES-060–23-0011) [C.L.R.]; National Institute of Health Research ([S.D., M.I.M.], Senior Investigator Award (NF-SI-0611–10196) [D.A.L]); Australian NHMRC Fellowships Scheme (619667) [G.W.M]. For study-specific funding, please see Supplementary Material. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Funding to pay the Open Access publication charges for this article was provided by the Charity Open Access Fund (COAF). Funding Information: We are extremely grateful to the participants and families who contributed to all of the studies and the teams of investigators involved in each one. These include interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. This research has been conducted using the UK Biobank Resource (Application numbers 7036 and 12703). For additional study-specific acknowledgements, please see Supplementary Material. Conflict of Interest statement. D.A.L. has received support from Roche Diagnostics and Medtronic for biomarker research unrelated to the work presented here. Funding Researchers were funded by investment from the European Regional Development Fund (ERDF) and the European Social Fund (ESF) Convergence Programme for Cornwall and the Isles of Scilly [J.T.]; European Research Council (ERC) [grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M.F., A.R.W.], [ERC Consolidator Grant, ERC-2014-CoG-648916 to V.W.V.J.], [P.R.N.]; University of Bergen, KG Jebsen and Helse Vest [P.R.N.]; Wellcome Trust Senior Investigator Awards [A.T.H. (WT098395), M.I.M. (WT098381)]; National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0611-10219); Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150) [R.M.F., R.N.B.]; 4-year studentship (Grant Code: WT083431MF) [R.C.R]; the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement (grant number 669545; Develop Obese) [D.A.L.]; US National Institute of Health (grant: R01 DK10324) [D.A.L, C.L.R]; Wellcome Trust GWAS grant (WT088806) [D.A.L] and NIHR Senior Investigator Award (NF-SI-0611-10196) [D.A.L]; Wellcome Trust Institutional Strategic Support Award (WT097835MF) [M.A.T.]; The Diabetes Research and Wellness Foundation Non-Clinical Fellowship [J.T.]; Australian National Health and Medical Research Council Early Career Fellowship (APP1104818) [N.M.W.]; Daniel B. Burke Endowed Chair for Diabetes Research [S.F.A.G.]; UK Medical Research Council Unit grants MC_UU_12013_5 [R.C.R, L.P, S.R, C.L.R, D.M.E., D.A.L.] and MC_UU_12013_4 [D.M.E.]; Medical Research Council (grant: MR/M005070/1) [M.N.W., S.E.J.]; Australian Research Council Future Fellowship (FT130101709) [D.M.E] and (FT110100548) [S.E.M.]; NIHR Oxford Biomedical Research Centre (BRC); Oak Foundation Fellowship and Novo Nordisk Foundation (12955) [B.F.]; FRQS research scholar and Clinical Scientist Award by the Canadian Diabetes Association and the Maud Menten Award from the Institute of Genetics-Canadian Institute of Health Research (CIHR) [MFH]; CIHR-Frederick Banting and Charles Best Canada Graduate Scholarships [C.A.]; FRQS [L.B.]; Netherlands Organization for Health Research and Development (ZonMw-VIDI 016.136.361) [V.W.V.J.]; National Institute on Aging (R01AG29451) [J.M.M.]; 2010-2011 PRIN funds of the University of Ferrara-Holder: Prof. Guido Barbujani, Supervisor: Prof. Chiara Scapoli-and in part sponsored by the European Foundation for the Study of Diabetes (EFSD) Albert Renold Travel Fellowships for Young Scientists, '5 per mille' contribution assigned to the University of Ferrara, income tax return year 2009 and the ENGAGE Exchange and Mobility Program for ENGAGE training funds, ENGAGE project, grant agreement HEALTH-F4-2007-201413 [L.M.]; ESRC (RES-060-23-0011) [C.L.R.]; National Institute of Health Research ([S.D., M.I.M.], Senior Investigator Award (NFSI-0611-10196) [D.A.L]); Australian NHMRC Fellowships Scheme (619667) [G.W.M]. For study-specific funding, please see Supplementary Material. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Funding to pay the Open Access publication charges for this article was provided by the Charity Open Access Fund (COAF). Publisher Copyright: © The Author(s) 2018.Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5 x 10(-8). In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.Peer reviewe

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

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 ($\textit{P}$  < 5 × 10$^{-8}$). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure ($\textit{R}$ $_{g}$ = -0.22, $\textit{P}$  = 5.5 × 10$^{-13}$), T2D ($\textit{R}$ $_{g}$ = -0.27, $\textit{P}$  = 1.1 × 10$^{-6}$) and coronary artery disease ($\textit{R}$ $_{g}$ = -0.30, $\textit{P}$  = 6.5 × 10$^{-9}$). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions ($\textit{P}$ = 1.9 × 10$^{-4}$). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.For a full list of the funders pelase visit the publisher's website and look at the supplemetary material provided. Some of the funders are: British Heart Foundation, Cancer Research UK, Medical Research Council, National Institutes of Health, Royal Society and Wellcome Trust

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

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.The Fenland Study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust

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

Birth weight (BW) is influenced by both foetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P <5x10-8). Overall, ˜15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg-0.22, P =5.5x10-13), T2D (rg-0.27, P =1.1x10-6) and coronary artery disease (rg-0.30, P =6.5x10-9) and, in large cohort data sets, demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P =1.9x10-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated