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.
Highlights
In 57.3% (176/307) of the affected family members in the familial Age-related macular degeneration (AMD) cohort, a high genetic risk scores (GRS) contributed to AMD development, whereas rare complement factor H (CFH) and complement factor I (CFI) variants contributed to AMD development in 40.0% (36/90) of the affected family members with a low and intermediate GRS
We showed that the identification of rare CFH and CFI variants in addition to common variants is important because in some families with AMD, the genetic risk is mainly determined by a high genetic load based on common genetic variants (Fig 2), whereas in other families with AMD, the GRS is low and a rare CFH or CFI variant segregates with the disease and contribute to AMD development (Fig 3)
Some families have an even higher genetic burden. They demonstrate a high GRS based on common variants, and in addition, a highly penetrant rare CFH or CFI variant runs in the family
Summary
We aimed to evaluate differences in GRSs between familial and nonfamilial AMD and between rare CFH or CFI variant carriers and noncarriers, and included the 96 families from the family cohort and the case-control cohort
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