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

This is the final version. Available on open access from Nature Research via the DOI in this record. Data availability: Individual cohorts contributing to the meta-analysis should be contacted directly as each cohort has different data access policies. GWAS summary statistics from this study are available via the EGG website (https://egg-consortium.org/placental-weight-2023.html, https://www.ebi.ac.uk/gwas/), as well as the GWAS catalog (https://www.ebi.ac.uk/gwas/, accession numbers GCST90275189, GCST90275190, GCST90275191, GCST90275192, GCST90275193, GCST90275194, GCST90275195, GCST90275196, GCST90275197, GCST90275198, GCST90275199). Access to personal-level information from Gen3G (including methylation array data) is subject to controlled access according to participants’ consent concerning sharing of personal data. Request for conditions of access and for data access should be addressed to Center Hospitalier Universitaire de Sherbrooke institutional ethics committee: [email protected] availability: Analysis code is available from https://github.com/EarlyGrowthGenetics/placental_weight_codeA well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.Wellcome Trus

Winner's Curse Correction and Variable Thresholding Improve Performance of Polygenic Risk Modeling Based on Genome-Wide Association Study Summary-Level Data

Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winner's-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied our methods to GWAS summary-level data of 14 complex diseases. Across all diseases, a simple winner's curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25-50% increase in the prediction R2) for 5 of 14 diseases. As an example, for GWAS of type 2 diabetes, winner's curse correction improved prediction R2 from 2.29% based on the standard PRS to 3.10% (P = 0.0017) and incorporating functional annotation data further improved R2 to 3.53% (P = 2×10-5). Our simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure

A capacity building approach to increase sports participation in disadvantaged urban communities: a multilevel analysis

Recent evidence showed that community capacity building is one of the key methods to reach health improvements within disadvantaged communities. Physical activity and sports participation are important means to reach health improvements. This study investigates a capacity building method which aims at increasing sports participation in the community, especially for individuals at higher risk of sports deprivation. The main aims of the present study, are the following: (1) to examine differences in sports participation between individuals living in communities implementing a sports-based capacity building program and individuals living in communities without such capacity building program and (2) to investigate if the community sports program reaches the individuals known to experience higher barriers to engage in sports. In Flanders, Belgium, five disadvantaged urban communities implementing the community capacity building program (program communities) and four without (control communities) were selected based on similarity of sociodemographic and environmental characteristics. Two hundred adults (aged 18-56 years) per community were randomly selected and visited at home to fill out a questionnaire on sociodemographics, sports participation, and the community sports program. A sample of 414 adults participated in the study. Results showed that adults from program communities reported on average 96 min/week more participation in sports than their counterparts living in control communities. Furthermore, 61.3 % of the individuals of program communities indicated to engage in sports, whereas in control communities, this was only 42.4 %. Respondents at higher risk of sports deprivation also engaged in significantly more sports participation in program communities than those in control communities. This difference was also noted for groups that are not related with sports deprivation. These results are promising and plead for a community capacity building approach to increase sports participation in disadvantaged communities