Abstract
Background While polygenic risk scores hold significant promise in estimating an individual’s risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort.
Methods The PRS model was developed trained and tested at the Center for Applied Genomics (CAG) of The Children’s Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis.
Results We show that in the absence of a well powered trans-ethnic GWAS from which to derive SNPs and effect estimates, trans-ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred to adjust the summary statistics using trans-ethnic linkage disequilibrium reference panels. The ported trans-ethnic scores outperform population specific-PRS across all non-European ancestry populations investigated including East Asians and three-way admixed Brazilian cohort.
Conclusions Widespread use of PRS in the clinic is hampered by a lack of genotyping data in individuals of non-European ancestry for the vast majority of traits. Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans-ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three-way admixed Brazilians.
Competing Interest Statement
A.S.B declares grants outside of this work from AstraZeneca, Bayer, Biogen, BioMarin, Merck and Sanofi. All other authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding Statement
All authors are supported by the International HundredK+ Cohorts Consortium (IHCC), which has been created in collaboration with the Global Alliance for Genomics and Health (GA4GH) and the Global Genomics Medicine Collaborative (G2MC) with support from the National Institute of Health and the Wellcome Trust. CHOP funding: Institutional Development Funds from the Children's Hospital of Philadelphia to the Center for Applied Genomics, and The Children's Hospital of Philadelphia Endowed Chair in Genomic Research. The Shanghai Women's Health Study (US NIH, R37CA070867, UM1CA182910), and the Shanghai Men's Health Study (US NIH, R01CA082729, UM1CA173640), are funded by the National Institutes of Health. ELSA-Brasil is funded by the Brazilian Ministry of Health (Department of Science and Technology) and the Ministry of Science, Technology and Innovation (FINEP, Financiadora de Estudos e Projetos), and CNPq (the National Council for Scientific and Technological Development). The Norwegian Mother, Father and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authorities and Stiftelsen Kristian Gerhard Jebsen. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities. Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant (www.nhsbt.nhs.uk), which has supported fieldwork and other elements of the trial. DNA extraction and genotyping were co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR Cambridge Biomedical Research Centre (BRC) (no. BRC-1215-20014). The academic coordinating centre for INTERVAL was supported by core funding from the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (no. NIHR BTRU-2014-10024), UK Medical Research Council (MRC) (no. MR/L003120/1), British Heart Foundation (nos SP/09/002, RG/13/13/30194 and RG/18/13/33946) and the NIHR Cambridge BRC (no. BRC-1215-20014). A complete list of the investigators and contributors to the INTERVAL trial is provided in ref.17. The academic coordinating centre thanks blood donor centre staff and blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK, which is funded by the UK MRC, Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. The views expressed in this manuscript are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
This study was exempted by the Institutional Review Board (IRB) of the Children's Hospital of Philadelphia. Human participants and personal information are inaccessible to the research group due to sample and data deidentification. All human subjects or their proxies provided written informed consent for the respective studies involved.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.
Yes
Data Availability
Supporting data from this study can be obtained by emailing the corresponding author Dr. Hakon Hakonarson.