Genetic Risk in Families with Age-Related Macular Degeneration.

Content Provider	Europe PMC
Author	de Breuk, Anita Lechanteur, Yara T.E. Heesterbeek, Thomas J. Fauser, Sascha Klaver, Caroline C.W. Hoyng, Carel B. den Hollander, Anneke I.
Copyright Year	2021
Abstract	PurposeTo determine the contribution of common and rare genetic risk variants in families with age-related macular degeneration (AMD).DesignCase-control study.ParticipantsA family cohort (355 affected and 342 unaffected family members from 144 families with AMD) and an unrelated case-control cohort (1078 patients, 952 controls), recruited from the European Genetic Database.MethodsGenetic data of both cohorts were filtered for carriership of rare genetic variants in the coding and splice-site regions of the complement factor H (CFH) and complement factor I (CFI) genes, and 52 AMD-associated variants were extracted for calculation of genetic risk scores (GRS). To compare GRSs between familial and nonfamilial rare CFH and CFI variant carriers and noncarriers and between AMD disease stages, we performed a 2-way analysis of variance, with Bonferroni correction for multiple testing. Within families with AMD carrying rare CFH and CFI variants, we analyzed segregation patterns by calculating the proportion of affected among carriers.Main Outcome MeasuresGRSs and segregation of rare CFH and CFI variants.ResultsWe observed higher GRSs in familial versus nonfamilial individuals without rare CFH and CFI variants: mean GRS, 1.76 (standard error [SE], 0.08) versus 0.83 (SE, 0.03; P < 0.001). In 51 of 144 families (35.4%), rare CFH and CFI variants were identified. Within the AMD family cohort, carriers of rare CFH and CFI variants showed lower GRSs compared with noncarriers (mean GRS, 1.05 [SE, 0.23] vs. 1.76 [SE, 0.08]; P = 0.02). The proportion of affected family members with a high GRS was 57.3% (176/307). Of the affected family members with a low or intermediate GRS, 40.0% carried rare CFH or CFI variants. Among carriers of 11 rare CFH or CFI variants, the proportion affected by AMD was more than 75%.ConclusionsGenetic risk in families with AMD often is attributed to high GRSs based on common variants. However, in part of the families with a low or intermediate GRS, rare CFH and CFI variants contributed to disease development. We recommend computing GRSs and sequencing the CFH and CFI genes in families with AMD, in particular in the light of ongoing gene-specific clinical trials.
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Journal	Ophthalmology Science [Ophthalmol Sci]
Volume Number	1
DOI	10.1016/j.xops.2021.100087
PubMed Central reference number	PMC9562327
Issue Number	4
PubMed reference number	36246952
e-ISSN	26669145
Language	English
Publisher	Elsevier
Publisher Date	2021-12-06
Access Restriction	Open
Rights License	This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). © 2021 by the American Academy of Ophthalmology.
Subject Keyword	Age-related macular degeneration Complement factor H Complement factor I Complement system Genetic risk score AMD, age-related macular degeneration CCP, complement control protein CFH, complement factor H CFI, complement factor I CI, confidence interval CIRCL, Cologne Image Reading Center and Laboratory CNV, choroidal neovascularization GA, geographic atrophy GRS, genetic risk score GWAS, genome-wide association study IQR, interquartile range RC, Rotterdam Classification SE, standard error
Content Type	Text
Resource Type	Article
Subject	Ophthalmology