Purpose: Age-related macular degeneration (AMD) is a common multifactorial disease in the elderly with a prominent genetic basis. Many risk variants have been identified, but the interpretation remains challenging. We investigated the genetic distribution of AMD-associated risk variants in a large European consortium, calculated attributable and pathway-specific genetic risks, and assessed the influence of lifestyle on genetic outcomes. Design: Pooled analysis of cross-sectional data from the European Eye Epidemiology Consortium. Participants: Seventeen thousand one hundred seventy-four individuals 45 years of age or older participating in 6 population-based cohort studies, 2 clinic-based studies, and 1 case-control study. Methods: Age-related macular degeneration was diagnosed and graded based on fundus photographs. Data on genetics, lifestyle, and diet were harmonized. Minor allele frequencies and population-attributable fraction (PAF) were calculated. A total genetic risk score (GRS) and pathway-specific risk scores (complement, lipid, extra-cellular matrix, other) were constructed based on the dosage of SNPs and conditional β values; a lifestyle score was constructed based on smoking and diet. Main Outcome Measures: Intermediate and late AMD. Results: The risk variants with the largest difference between late AMD patients and control participants and the highest PAFs were located in ARMS2 (rs3750846) and CHF (rs570618 and rs10922109). Combining all genetic variants, the total genetic risk score ranged from –3.50 to 4.63 and increased with AMD severity. Of the late AMD patients, 1581 of 1777 (89%) showed a positive total GRS. The complement pathway and ARMS2 were by far the most prominent genetic pathways contributing to late AMD (positive GRS, 90% of patients with late disease), but risk in 3 pathways was most frequent (35% of patients with late disease). Lifestyle was a strong determinant of the outcome in each genetic risk category; unfavorable lifestyle increased the risk of late AMD at least 2-fold. Conclusions: Genetic risk variants contribute to late AMD in most patients. However, lifestyle factors have a strong influence on the outcome of genetic risk and should be a strong focus in patient management. Genetic risks in ARMS2 and the complement pathway are present in most late AMD patients but are mostly combined with risks in other pathways.
Bibliographical noteFunding Information:
Supported by the European Union (Horizon 2020 grant no.: 634479 [EYE-RISK]). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; The biobank CORRBI of both Department of Ophthalmology and the Rotterdam Eye Hospital is financed through the CORR (Combined Ophthalmic Research Rotterdam) Foundation; The ophthalmic research within the Rotterdam Study was supported by Uitzicht grant number: 2015-36, Oogfonds, MaculaFonds, LSBS, Novartis Fonds. The sponsors and funding organization had no role in the design or conduct of this research; the Netherlands Organization for the Health Research and Development; the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The Alienor-3C study received financial support from Laboratoires Th?a (Clermont-Ferrand, France), Fondation Voir et Entendre (Paris, France), and Caisse Nationale de Solidarit? pour l'Autonomie (Paris, France). Laboratoires Th?a participated in the design of the study, but no sponsor participated in the collection, management, statistical analysis and interpretation of the data, nor in the preparation, review or approval of the present manuscript. The genome-wide association study genotype data for the Alienor-3C study are managed by the RID-AGE (Risk factors and molecular determinants of aging-related diseases) group of University of Lille, Institut Pasteur de Lille, and INSERM U1167 (Lille, France). MONRACHET funding was provided by an Inter-regional grant (Programme Hospitalier de Recherche Clinique [PHRC]) and the Regional Council of Burgundy. This study was also funded by INRA, CNRS, Universit? de Bourgogne, Regional Council of Burgundy France (PARI Agrale 1), FEDER (European Funding for Regional Economic Development) and French Government grant managed by the French National Research Agency (ANR) as part of the ?Investissements d'Avenir? program (reference ANR-11-LABX-0021-01-LipSTIC Labex). The funding organizations had no role in the design or conduct of this research. The Coimbra Eye Study is an Investigator-Initiated Study sponsored by AIBILI that was financially supported by Novartis Pharma AG. The funding organization played no role in the design or conduct of this research. Supported in part by grants from Deutsche Forschungsgemeinschaft HE 2293/5-1, 5-2, 5-3; the Intramural IMF fund of the University of Muenster; the Pro Retina Foundation; and the Jackstaedt Foundation. EUGENDA was funded by grants from the Oogfonds, MaculaFonds, Landelijke Stiching voor Blinden en Slechtzienden, Stichting Blindenhulp, Stichting A.F. Deutman Oogheelkunde Researchfonds, the Netherlands Organization for Scientific Research (Vidi Innovational Research Award 016.096.309), and the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) (ERC Grant Agreement no. 310644 MACULA). This research was supported by the Dutch Organization for Scientific Research (016.Vici.170.024 to AIdH). The ophthalmic research within the Rotterdam Study was supported by Uitzicht grant number: 2015-36, Oogfonds, MaculaFonds, LSBS, Novartis Fonds. The sponsors and funding organization had no role in the design or conduct of this research. B.M.J.M.: Consultant ? Thea Pharma, Bausch & Lomb; Financial support Thea Pharma, Synadiet A.C.-G.: Financial support ? Thea Pharma C.C.-G.: Financial support ? Allergan, Bayer, Roche, Bausch & Lomb, Novartis, Th?a, Horus; Nonfinancial support ? Bayer The generation and management of GWAS genotype data for the Rotterdam Study (I, II, and III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nos.: 175.010.2005.011 and 911-03-012); the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; the Research Institute for Diseases in the Elderly (grant no.: 014-93-015 [RIDE2]); the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research and Netherlands Consortium for Healthy Aging (grant no.: 050-060-810). Obtained funding: Ueffing, Klaver, Delcourt, den Hollander, Hoyng
© 2020 American Academy of Ophthalmology