Integrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degeneration

Xikun Han; Ines Lains; Jun Li; Jinglun Li; Yiheng Chen; Bing Yu; Qibin Qi; Eric Boerwinkle; Robert Kaplan; Bharat Thyagarajan; Martha Daviglus; Charlotte E Joslin; Jianwen Cai; Marta Guasch-Ferré; Deirdre K Tobias; Eric Rimm; Alberto Ascherio; Karen Costenbader; Elizabeth Karlson; Lorelei Mucci; A Heather Eliassen; Oana Zeleznik; John Miller; Demetrios G Vavvas; Ivana K Kim; Rufino Silva; Joan Miller; Frank Hu; Walter Willett; Jessica Lasky-Su; Peter Kraft; J Brent Richards; Stuart MacGregor; Deeba Husain; Liming Liang

doi:10.1016/j.xcrm.2023.101085

Integrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degeneration

Cell Rep Med. 2023 Jul 18;4(7):101085. doi: 10.1016/j.xcrm.2023.101085. Epub 2023 Jun 21.

Authors

Xikun Han¹, Ines Lains², Jun Li³, Jinglun Li⁴, Yiheng Chen⁵, Bing Yu⁶, Qibin Qi⁷, Eric Boerwinkle⁶, Robert Kaplan⁸, Bharat Thyagarajan⁹, Martha Daviglus¹⁰, Charlotte E Joslin¹¹, Jianwen Cai¹², Marta Guasch-Ferré³, Deirdre K Tobias¹³, Eric Rimm³, Alberto Ascherio³, Karen Costenbader¹⁴, Elizabeth Karlson¹⁴, Lorelei Mucci¹⁵, A Heather Eliassen¹⁶, Oana Zeleznik¹⁷, John Miller², Demetrios G Vavvas¹⁸, Ivana K Kim², Rufino Silva¹⁹, Joan Miller², Frank Hu³, Walter Willett³, Jessica Lasky-Su²⁰, Peter Kraft²¹, J Brent Richards²², Stuart MacGregor²³, Deeba Husain²⁴, Liming Liang²⁵

Affiliations

¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: xikun_han@hsph.harvard.edu.
² Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
³ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada.
⁶ Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁷ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁸ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
⁹ Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center, Minneapolis, MN, USA.
¹⁰ Institute for Minority Health Research, University of Illinois at Chicago, Chicago, IL, USA.
¹¹ Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA.
¹² Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁴ Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁸ Retina Service, Ines and Fredrick Yeatts Retinal Research Laboratory, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
¹⁹ Ophthalmology Unit, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal; University Clinic of Ophthalmology, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.
²⁰ Systems Genetics and Genomics Unit, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
²¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²² Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada; Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal, QC, Canada; Department of Twin Research, King's College London, London, UK; Five Prime Sciences Inc, Montréal, QC, Canada.
²³ Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
²⁴ Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA. Electronic address: deeba_husain@meei.harvard.edu.
²⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: lliang@hsph.harvard.edu.

Abstract

Age-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.

Keywords: AMD; 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; metabolomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Bayes Theorem
Genome-Wide Association Study*
Humans
Macular Degeneration* / genetics
Macular Degeneration* / metabolism
Metabolome / genetics
Metabolomics

Abstract

Publication types

MeSH terms

Grants and funding