TY - JOUR
T1 - Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration
AU - Seddon, Johanna M.
AU - Yu, Yi
AU - Miller, Elizabeth C.
AU - Reynolds, Robyn
AU - Tan, Perciliz L.
AU - Gowrisankar, Sivakumar
AU - Goldstein, Jacqueline I.
AU - Triebwasser, Michael
AU - Anderson, Holly E.
AU - Zerbib, Jennyfer
AU - Kavanagh, David
AU - Souied, Eric
AU - Katsanis, Nicholas
AU - Daly, Mark J.
AU - Atkinson, John P.
AU - Raychaudhuri, Soumya
PY - 2013/11
Y1 - 2013/11
N2 - To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within all reported AMD loci and related pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (odds ratio (OR) = 3.6; P = 2 × 10 -8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in 5,115 independent samples confirmed associations with AMD of an allele in C3 encoding p.Lys155Gln (replication P = 3.5 × 10 -5, OR = 2.8; joint P = 5.2 × 10 -9, OR = 3.8) and an allele in C9 encoding p.Pro167Ser (replication P = 2.4 × 10 -5, OR = 2.2; joint P = 6.5 × 10 -7, OR = 2.2). Finally, we show that the allele of C3 encoding Gln155 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.
AB - To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within all reported AMD loci and related pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (odds ratio (OR) = 3.6; P = 2 × 10 -8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in 5,115 independent samples confirmed associations with AMD of an allele in C3 encoding p.Lys155Gln (replication P = 3.5 × 10 -5, OR = 2.8; joint P = 5.2 × 10 -9, OR = 3.8) and an allele in C9 encoding p.Pro167Ser (replication P = 2.4 × 10 -5, OR = 2.2; joint P = 6.5 × 10 -7, OR = 2.2). Finally, we show that the allele of C3 encoding Gln155 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.
UR - http://www.scopus.com/inward/record.url?scp=84887080613&partnerID=8YFLogxK
U2 - 10.1038/ng.2741
DO - 10.1038/ng.2741
M3 - Letter
C2 - 24036952
AN - SCOPUS:84887080613
SN - 1061-4036
VL - 45
SP - 1366
EP - 1373
JO - Nature Genetics
JF - Nature Genetics
IS - 11
ER -