Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/112203
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dc.contributor.authorHan, Xikun-
dc.contributor.authorLaíns, Inês-
dc.contributor.authorLi, Jun-
dc.contributor.authorLi, Jinglun-
dc.contributor.authorChen, Yiheng-
dc.contributor.authorYu, Bing-
dc.contributor.authorQi, Qibin-
dc.contributor.authorBoerwinkle, Eric-
dc.contributor.authorKaplan, Robert-
dc.contributor.authorThyagarajan, Bharat-
dc.contributor.authorDaviglus, Martha-
dc.contributor.authorJoslin, Charlotte E.-
dc.contributor.authorCai, Jianwen-
dc.contributor.authorGuasch-Ferré, Marta-
dc.contributor.authorTobias, Deirdre K.-
dc.contributor.authorRimm, Eric-
dc.contributor.authorAscherio, Alberto-
dc.contributor.authorCostenbader, Karen-
dc.contributor.authorKarlson, Elizabeth-
dc.contributor.authorMucci, Lorelei-
dc.contributor.authorEliassen, A Heather-
dc.contributor.authorZeleznik, Oana-
dc.contributor.authorMiller, John-
dc.contributor.authorVavvas, Demetrios G.-
dc.contributor.authorKim, Ivana K.-
dc.contributor.authorSilva, Rufino-
dc.contributor.authorMiller, Joan-
dc.contributor.authorHu, Frank-
dc.contributor.authorWillett, Walter-
dc.contributor.authorLasky-Su, Jessica-
dc.contributor.authorKraft, Peter-
dc.contributor.authorRichards, J. Brent-
dc.contributor.authorMacGregor, Stuart-
dc.contributor.authorHusain, Deeba-
dc.contributor.authorLiang, Liming-
dc.date.accessioned2024-01-24T12:12:06Z-
dc.date.available2024-01-24T12:12:06Z-
dc.date.issued2023-07-18-
dc.identifier.issn26663791pt
dc.identifier.urihttps://hdl.handle.net/10316/112203-
dc.description.abstractAge-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal AMD-associated metabolites. We find limited evidence linking urine metabolites to AMD risk. Our study emphasizes the contribution of plasma metabolites, particularly lipid-related pathways and genes, to AMD risk and uncovers numerous putative causal associations between metabolites and AMD risk.pt
dc.description.sponsorshipWe would like to thank the research participants in the NHS, NHSII, and HPFS, the CLSA, the METSIM, the HCHS/SOL, the urinary metabolomic data from Schlosser et al.,16 and the AMD Biomarkers Study for making this work possible. The opinions expressed in this manuscript are the authors’ own and do not reflect the views of the CLSA or any affiliated institution. This research was made possible using the data/biospecimens collected by the CLSA. Funding for the CLSA is provided by the government of Canada through the Canadian Institutes of Health Research (CIHR) under grant reference LSA 94473 and the Canada Foundation for Innovation, as well as the following provinces: Newfoundland, Nova Scotia, Quebec, Ontario, Manitoba, Alberta, and British Columbia. This research has been conducted using a CLSA dataset (Baseline Comprehensive Dataset v.6.0, Follow-up 1 Comprehensive Dataset v.3.0, Genome-wide Genetic Data v.3.0, and Metabolomics v.1.0) under application number 2006016. The CLSA is led by Drs. Parminder Raina, Christina Wolfson, and Susan Kirkland. 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), the University of Miami (HHSN268201300004I/N01-HC-65234), the Albert Einstein College of Medicine (HHSN268201300002I/N01-HC-65235), the 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: the National Institute on Minority Health and Health Disparities, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the 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). Support for metabolomics data was graciously provided by the JLH Foundation (Houston, TX, USA). The authors thank all of the participants who took part in the UK Biobank and the International AMD Genomics Consortium and support staff who made this study possible. This lipid GWAS work was conducted using the UK Biobank Resource (application number 25331). For the AMD datasets, all contributing sites and additional funding information are acknowledged in this publication: Fritsche et al.,7 The International AMD Genomics consortium’s web page is http://eaglep.case.edu/iamdgc_web/, and additional information is available at http://csg.sph.umich.edu/abecasis/public/amd2015/. The AMD case-control datasets used for the analyses described in this manuscript were obtained from the NEI Study of Age-Related Macular Degeneration (NEI-AMD) Database found at https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi? study_id=phs001039.v1.p1 through dbGaP accession number 20740. Funding support for NEI-AMD was provided by the National Eye Institute. We would like to thank NEI-AMD participants and the NEI-AMD Research Group for their valuable contribution to this research. S.M. is supported by a research fellowship and program grant (1150144) from the Australian National Healthand Medical Research Council (NHMRC). The Richards research group is supported by the Canadian Institutes of Health Research (CIHR: 365825, 409511, and 100558), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK, Genome Que´ bec, the Public Health Agency of Canada, Genome Que´ bec, McGill University, and the Fonds de Recherche Que´ bec Sante´ (FRQS). J.B.R. is supported by an FRQS Clinical Research Scholarship. Support from Calcul Que´ bec and Compute Canada is acknowledged. This work was supported by Cancer Research UK (grant number C18281/A29019). TwinsUK is funded by the Wellcome Trust, the Medical Research Council, the European Union, the National Institute for Health Research (NIHR)-funded BioResource, and the Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. This work is supported by MSL Renewed Hope Foundation and Ines and Fredrick Yeatts Foundation Award. These funding agencies had no role in the design, implementation, or interpretation of this study. The NHS study is funded by UM1 CA186107 and R01 CA49449, the NHSII is funded by U01 CA176726 and R01 CA67262, and the HPFS study is funded by U01 CA167552. This study was supported by RO1EY030088 (D.H.), the Miller Retina Research Fund (Mass. Eye and Ear), the Champalimaud Vision Award (Joan Miller), the Portuguese Foundation for Science and Technology/Harvard Medical School Portugal Program (HMSP-ICJ/006/2013) (I.L.), and R01 AR049880 (K.C.).pt
dc.language.isoengpt
dc.publisherElsevierpt
dc.rightsopenAccesspt
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt
dc.subjectAMD; CLSA; Canadian Longitudinal Study of Aging; GWASs; HCHS/SOL; HPFS; Health Professionals Follow Up Study; Hispanic Community Health Study/Study of Latinos; MR; Mendelian randomization; NHS; Nurses’ Health Study; UK Biobank; age-related macular degeneration; genome-wide association studies; genomics; metabolomicspt
dc.subject.meshHumanspt
dc.subject.meshAgedpt
dc.subject.meshBayes Theorempt
dc.subject.meshMetabolomicspt
dc.subject.meshMetabolomept
dc.subject.meshGenome-Wide Association Studypt
dc.subject.meshMacular Degenerationpt
dc.titleIntegrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degenerationpt
dc.typearticle-
degois.publication.firstPage101085pt
degois.publication.issue7pt
degois.publication.titleCell Reports Medicinept
dc.peerreviewedyespt
dc.identifier.doi10.1016/j.xcrm.2023.101085pt
degois.publication.volume4pt
dc.date.embargo2023-07-18*
uc.date.periodoEmbargo0pt
item.grantfulltextopen-
item.cerifentitytypePublications-
item.languageiso639-1en-
item.openairetypearticle-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.fulltextCom Texto completo-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.orcid0000-0001-8676-0833-
Appears in Collections:FMUC Medicina - Artigos em Revistas Internacionais
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