The power of TOPMed imputation for the discovery of Latino-enriched rare variants associated with type 2 diabetes
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Aims/hypothesis: The Latino population has been systematically underrepresented in large-scale genetic analyses, and previous studies have relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) released the largest multi-ancestry genotype reference panel representing a unique opportunity to analyse rare genetic variations in the Latino population. We hypothesise that a more comprehensive analysis of low/rare variation using the TOPMed panel would improve our knowledge of the genetics of type 2 diabetes in the Latino population. Methods: We evaluated the TOPMed imputation performance using genotyping array and whole-exome sequence data in six Latino cohorts. To evaluate the ability of TOPMed imputation to increase the number of identified loci, we performed a Latino type 2 diabetes genome-wide association study (GWAS) meta-analysis in 8150 individuals with type 2 diabetes and 10,735 control individuals and replicated the results in six additional cohorts including whole-genome sequence data from the All of Us cohort. Results: Compared with imputation with 1000G, the TOPMed panel improved the identification of rare and low-frequency variants. We identified 26 genome-wide significant signals including a novel variant (minor allele frequency 1.7%; OR 1.37, p=3.4 × 10−9). A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improved the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance. Conclusions/interpretation: Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variants in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores. Data availability: Full summary statistics are available through the Common Metabolic Diseases Knowledge Portal (https://t2d.hugeamp.org/downloads.html) and through the GWAS catalog (https://www.ebi.ac.uk/gwas/ , accession ID: GCST90255648). Polygenic score (PS) weights for each ancestry are available via the PGS catalog (https://www.pgscatalog.org , publication ID: PGP000445, scores IDs: PGS003443, PGS003444 and PGS003445). Graphical abstract: [Figure not available: see fulltext.]
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Diabetologia |
| Vol/bind | 66 |
| Sider (fra-til) | 1273-1288 |
| Antal sider | 16 |
| ISSN | 0012-186X |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
SIGMA was partially supported by a joint USA–Mexico project funded by the Carlos Slim Health Institute. The UNAM/INCMNSZ Diabetes Study was supported by Consejo Nacional de Ciencia y Tecnología grants (138826, 128877, SALUD 2009-01-115250) and a grant from Dirección General de Asuntos del Personal Académico (UNAM, IT 214711). The Mexico City Diabetes Study was supported by the NHLBI (grant ROHL24799) and the Consejo Nacional de Ciencia y Tecnología (grants 2099, M9303, F671-M9407, 251M, 2005-CO1-14502 and SALUD 2010-2-15-1165). SIGMA was also supported by funds from the Fundación Carlos Slim (to JCF). GERA was supported by a grant (RC2 AG033067; principal investigators C. Schaefer and N. Risch) awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics. GERA was also supported by grants from the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Northern California Community Benefit Programs. The PAGE programme is funded by the National Human Genome Research Institute (NHGRI) with co-funding from the National Institute on Minority Health and Health Disparities (NIMHD), supported by U01HG007416 (Causal Variants Across the Life Course [CALiCo]), U01HG007417 (Icahn School of Medicine at Mount Sinai [ISMMS]), U01HG007397 (Multiethnic Cohort Study [MEC]), U01HG007376 (Women’s Health Initiative [WHI]), U01HG007419 (Coordinating Center), R01HG010297 and R01HL151152. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Funding Information:
The Urban American Indians and Arizona Pima Indians cohort studies were supported by the intramural research programme of NIDDK. Parts of this research were conducted using the UK Biobank Resource under Application Number 27892.
Funding Information:
The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA : AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276.
Funding Information:
The data and materials included in this report result from collaboration between the following studies and organisations: The HCHS/SOL was carried out as a collaborative study supported by contracts from the NHLBI to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236) and San Diego State University (N01-HC65237). The following Institutes/Centres/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: NIMHD; 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. Samples and data of The Charles Bronfman Institute for Personalized Medicine (IPM) BioMe Biobank used in this study were provided by The Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai (New York). Phenotype data collection was supported by The Andrea and Charles Bronfman Philanthropies. Funding support for the PAGE IPM BioMe Biobank study was provided through the NHGRI (U01 HG007417). The datasets used for the analyses described in this manuscript were obtained from dbGaP under accession phs000925. The Multiethnic Cohort study (MEC) characterisation of epidemiological architecture is funded through the NHGRI PAGE programme (U01 HG007397). The MEC study is funded through the National Cancer Institute (R37CA54281, R01CA63, P01CA33619, U01CA136792 and U01CA98758). The datasets used for the analyses described in this manuscript were obtained from dbGaP under accession phs000220. Funding support for the ‘Exonic variants and their relation to complex traits in minorities of the WHI’ study is provided through the NHGRI PAGE programme (U01HG007376). The WHI programme is funded by the NHLBI, NIH, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the programme possible. The datasets used for the analyses described in this manuscript were obtained from dbGaP under accession phs000227.
Funding Information:
JMM is supported by ADA Innovative and Clinical Translational Award 1-19-ICTS-068, ADA grant no. 11-22-ICTSPM-16 and by NHGRI, grant FAIN no. U01HG011723. MC is supported by the Fonds National de la Recherche Scientifique (FNRS), the Walloon Region SPW-EER Win2Wal project BetaSource, and the FWO and FRS-FNRS under the Excellence of Science (EOS) programme, project Pandarome, Belgium. XY is supported by the Foundation ULB and the China Scholarship Council. DLE acknowledges the support of grants from the Welbio-FNRS (WELBIO-CR-2019C-04), Belgium. DLE, PM and MC acknowledge the support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreements 115797 (INNODIA) and 945268 (INNODIA HARVEST), supported by the European Union’s Horizon 2020 research and innovation programme. These joint undertakings receive support from the European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations (EFPIA), JDRF, and the Leona M. and Harry B. Helmsley Charitable Trust. PM and LM acknowledge the support of European Union’s Horizon 2020 research and innovation programme T2Dsystems under grant agreement no. 667191. HMH is supported by the NHLBI training grant T32 HL129982, ADA grant no. 1-19-PDF-045 and R01HL142825. JB acknowledges the support of grants R01DK127084, U01HG011723, R01HL142302 and R01GM133169. The Mexican Biobank (MXBB) project was supported by CONACYT (grant FONCICYT/50/2016) and the Newton Fund (grant MR/N028937/1) awarded to A.M.E. JHL is partially supported by a MGH ECOR Fund for Medical Discovery Clinical Research Fellowship Award. YL is supported by grants R56HL150186 and R01HL158884. AD is supported by NIDDK T32DK007028. JCF is supported by UM1 DK078616, K24 HL157960, UM1 DK126185, R01 HL151855, U01 HG011723 and UM1 DK105554. TT is supported by Fundación Gonzálo Río Arronte Project No. S.678. JBC is supported by NIDDK K99DK127196. AL was supported by grant 2020096 from the Doris Duke Charitable Foundation ( https://www.ddcf.org ).
Publisher Copyright:
© 2023, The Author(s).
ID: 350992820