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Assessing efficiency of fine-mapping obesity-associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB cohorts

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Abstract

Inadequate representation of non-European ancestry populations in genome-wide association studies (GWAS) has limited opportunities to isolate functional variants. Fine-mapping in multi-ancestry populations should improve the efficiency of prioritizing variants for functional interrogation. To evaluate this hypothesis, we leveraged ancestry architecture to perform comparative GWAS and fine-mapping of obesity-related phenotypes in European ancestry populations from the UK Biobank (UKBB) and multi-ancestry samples from the Population Architecture for Genetic Epidemiology (PAGE) consortium with comparable sample sizes. In the investigated regions with genome-wide significant associations for obesity-related traits, fine-mapping in our ancestrally diverse sample led to 95% and 99% credible sets (CS) with fewer variants than in the European ancestry sample. Lead fine-mapped variants in PAGE regions had higher average coding scores, and higher average posterior probabilities for causality compared to UKBB. Importantly, 99% CS in PAGE loci contained strong expression quantitative trait loci (eQTLs) in adipose tissues or harbored more variants in tighter linkage disequilibrium (LD) with eQTLs. Leveraging ancestrally diverse populations with heterogeneous ancestry architectures, coupled with functional annotation, increased fine-mapping efficiency and performance, and reduced the set of candidate variants for consideration for future functional studies. Significant overlap in genetic causal variants across populations suggests generalizability of genetic mechanisms underpinning obesity-related traits across populations.

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Data availability

PAGE accession numbers are: phs000356 PAGE collectively; phs000223 PAGE-ARIC and phs000280 ARIC Cohort; phs000555 PAGE-HCHS/SOL and phs000810 HCHS/SOL Cohort; phs000220 PAGE-MEC; phs000227 PAGE-WHI and phs000200 WHI Cohort; phs000925 PAGE-IPM-BioMe.

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Acknowledgements

We thank Dr. Masahiro. Kanai (mkanai@broadinstitute.org) for his contribution to data analyses, particularly with implementation of SLALOM.

Funding

This work was supported by UK Biobank application 25953. The PAGE Study is funded by the National Human Genome Research Institute with co-funding from the National Institute on Minority Health and Health Disparities. Assistance with data management, data integration, data dissemination, genotype imputation, ancestry deconvolution, population genetics, analysis pipelines and general study coordination was provided by the PAGE Coordinating Center (NI-HU01HG007419). Genotyping services were provided by the Center for Inherited Disease Research, which is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, contract number HHSN268201200008I. Genotype data quality control and quality assurance services were provided by the Genetic Analysis Center in the Biostatistics Department of the University of Washington, through support provided by the Center for Inherited Disease Research contract. PAGE was also funded by grants R56HG010297 and R01HG010297. PAGE data and materials included in this report were funded through the following studies and organizations: The Mount Sinai BioMe Biobank is supported by The Andrea and Charles Bronfman Philanthropies. We thank all participants and all our recruiters who have assisted and continue to assist in data collection and management. We are grateful for the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sina. The MEC characterization of epidemiological architecture is funded through the NHGRI PAGE program (U01HG004802 and its NHGRI ARRA supplement). The MEC study is funded by the National Cancer Institute (R37CA54281, R01CA63, P01CA33619, U01CA136792 and U01CA98758). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004 and 75N92021D00005. The HCHS/SOL is a collaborative study supported by contracts from the National Heart, Lung and Blood Institute (NHLBI) to the University of North Carolina (HHSN268201300001I/N01-HC-65233), University of Miami (HHSN268201300004I/N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I / N01-HC 65235), University of Illinois at Chicago (HHSN268201300003I/N01-HC-65236 Northwestern University), and San Diego State University (HHSN268201300005I/N01-HC-65237). The following Institutes/Centers/Offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities; National Institute on Deafness and Other Communication Disorders; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; and NIH Institution-Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03. The Atherosclerosis Risk in Communities (ARIC) study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Coronary Artery Risk Development in Young Adults Study (CARDIA): The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201800003I, HHSN268201800004I, HHSN268201800005I, HHSN268201800006I, and HHSN268201800007I from the National Heart, Lung, and Blood Institute (NHLBI). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). GWAS genotyping and data analyses were funded in part by grants U01-HG004729 and R01-HL093029 from the National Institutes of Health to Dr. Myriam Fornage. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005. MYA is funded by NIDDK grant # 3R01DK122503-02W1. Kari North is supported by R01HD057194, R01 DK122503, R01HG010297, R01HL142302, R01HL143885, R01HG009974, and R01DK101855. The following grants supported this study: R01HL151152 (North, Graff), R01HG011345 (North, Graff).

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Authors and Affiliations

  1. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Mohammad Yaser Anwar, Mariaelisa Graff, Heather M. Highland, Victoria L. Buchanan, Kristin L. Young, Kim Daeeun & Kari E. North

  2. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Roelof Smit, Zhe Wang & Ruth J. F. Loos

  3. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Eimear E. Kenny

  4. Department of Biobehavioral Health, College of Health and Human Development, Pennsylvania State University, University Park, PA, 16802, USA

    Lindsay Fernandez-Rhodes

  5. Department of Epidemiology and Center for Global Cardiometabolic Health, School of Public Health, Brown University, Providence, RI, 02903, USA

    Simin Liu

  6. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Themistocles Assimes

  7. Department of Health Promotion Sciences, Mel & Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, 85724, USA

    David O. Garcia

  8. Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA

    Christopher R. Gignoux

  9. Department of Population Health Sciences, Geisinger Health, Danville, PA, 17822, USA

    Anne E. Justice

  10. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA

    Christopher A. Haiman

  11. Department of Statistics, Rutgers University, Piscataway, NJ, 08854, USA

    Steve Buyske

  12. Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA

    Ulrike Peters & Charles Kooperberg

Authors
  1. Mohammad Yaser Anwar
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  2. Mariaelisa Graff
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  3. Heather M. Highland
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  4. Roelof Smit
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  5. Zhe Wang
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  6. Victoria L. Buchanan
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  7. Kristin L. Young
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  12. David O. Garcia
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  13. Kim Daeeun
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  15. Anne E. Justice
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  18. Ulrike Peters
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  19. Ruth J. F. Loos
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  21. Kari E. North
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Contributions

MYA, MG, KEN participated in the study conception. MYA and MG performed data analyses. MYA, MG, and KEN drafted the manuscript. All co-authors performed critical reviews. KEN and MG supervised the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Mohammad Yaser Anwar.

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Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethics approval and consent to participate

All study participants provided written informed consent and each study was approved by relevant institutional review board. All methods were performed in accordance with the relevant guidelines and regulations set by Declaration of Helsinki. HCHS/SOL- The institutional review board at the coordinating center (University of North Carolina Office of Human Research Ethics, 07-1003) and Board Office, 200601-0471; University of California-San Diego Human Research Protection Program, 3677; University of Miami Human Subject Research Office, FWA00002247) approved study protocols. All participants gave informed consent. BioMe- Program for the Protection of Human Subjects, Mount Sinai Health System, Icahn School of Medicine at Mount Sinai. CARDIA- University of Texas Health Science Center at Houston. WHI- Fred Hutchison Cancer Research Center. ARIC- The Johns Hopkins Medicine Institutional Review Board. Cameron County- Committee for the Protection of Human Subjects at the University of Teas Health Sciences Center at Houston; Human Research Protections Program at Vanderbilt University. MEC- USC Institutional Review Board.

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Anwar, M.Y., Graff, M., Highland, H.M. et al. Assessing efficiency of fine-mapping obesity-associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB cohorts. Hum. Genet. 142, 1477–1489 (2023). https://doi.org/10.1007/s00439-023-02593-7

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