Protective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration.
Hum Mol Genet
; 25(23): 5276-5285, 2016 12 01.
Article
em En
| MEDLINE
| ID: mdl-28011711
Although numerous common age-related macular degeneration (AMD) alleles have been discovered using genome-wide association studies, substantial disease heritability remains unexplained. We sought to identify additional common and rare variants associated with advanced AMD. A total of 4,332 cases and 25,268 controls of European ancestry from three different populations were genotyped using the Illumina Infinium HumanExome BeadChip. We performed meta-analyses to identify associations with common variants, and single variant and gene-based burden tests to identify rare variants. Two protective, low-frequency, non-synonymous variants were significantly associated with a decrease in AMD risk: A307V in PELI3 (odds ratio [OR] = 0.14, P = 4.3 × 10-10) and N1050Y in CFH (OR = 0.76, P = 6.2 × 10-12). The new variants have a large effect size, similar to some rare mutations we reported previously in a targeted sequencing study, which remain significant in this analysis: CFH R1210C (OR = 18.82, P = 3.5 × 10-07), C3 K155Q (OR = 3.27, P = 1.5 × 10-10) and C9 P167S (OR = 2.04, P = 2.8 × 10-07). We also identified a strong protective signal for a common variant (rs8056814) near CTRB1 associated with a decrease in AMD risk (logistic regression: OR = 0.71, P = 1.8 × 10-07). Suggestive protective loci were identified in the COL4A3 and APOH genes. Our results support the involvement of common and low-frequency protective variants in this vision-threatening condition. This study expands the roles of the innate immune pathway as well as the extracellular matrix and high-density lipoprotein pathways in the aetiology of AMD.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quimotripsina
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Fator H do Complemento
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Ubiquitina-Proteína Ligases
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Degeneração Macular
Tipo de estudo:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
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Systematic_reviews
Limite:
Female
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Humans
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Male
Idioma:
En
Revista:
Hum Mol Genet
Assunto da revista:
BIOLOGIA MOLECULAR
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GENETICA MEDICA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos