Rare Variants in the Functional Domains of Complement Factor H Are Associated With Age-Related Macular Degeneration.
OBJECTIVE
Age-related macular degeneration (AMD) has a substantial genetic risk component, as evidenced by the risk from common genetic variants uncovered in the first genome-wide association studies. More recently, it has become apparent that rare genetic variants also play an independent role in AMD risk. We sought to determine if rare variants in complement factor H (CFH) played a role in AMD risk.


METHODS
We had previously collected DNA from a large population of patients with advanced age-related macular degeneration (A-AMD) and controls for targeted deep sequencing of candidate AMD risk genes. In this analysis, we tested for an increased burden of rare variants in CFH in 1665 cases and 752 controls from this cohort.


RESULTS
We identified 65 missense, nonsense, or splice-site mutations with a minor allele frequency ≤ 1%. Rare variants with minor allele frequency ≤ 1% (odds ratio [OR] = 1.5, P = 4.4 × 10⁻²), 0.5% (OR = 1.6, P = 2.6 × 10⁻²), and all singletons (OR = 2.3, P = 3.3 × 10⁻²) were enriched in A-AMD cases. Moreover, we observed loss-of-function rare variants (nonsense, splice-site, and loss of a conserved cysteine) in 10 cases and serum levels of FH were decreased in all 5 with an available sample (haploinsufficiency). Further, rare variants in the major functional domains of CFH were increased in cases (OR = 3.2; P = 1.4 × 10⁻³) and the magnitude of the effect correlated with the disruptive nature of the variant, location in an active site, and inversely with minor allele frequency.


CONCLUSIONS
In this large A-AMD cohort, rare variants in the CFH gene were enriched and tended to be located in functional sites or led to low serum levels. These data, combined with those indicating a similar, but even more striking, increase in rare variants found in CFI, strongly implicate complement activation in A-AMD etiopathogenesis as CFH and CFI interact to inhibit the alternative pathway.
Washington University School of Medicine Department of Internal Medicine, Division of Rheumatology, St. Louis, Missouri, United States.
Michael P
MP
Triebwasser
Washington University School of Medicine Department of Internal Medicine, Division of Rheumatology, St. Louis, Missouri, United States 2Washington University School of Medicine, Department of Genetics, St. Louis, Missouri, United States.
Elisha D O
ED
Roberson
Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, Massachusetts, United States.
Yi
Y
Yu
Washington University School of Medicine Department of Internal Medicine, Division of Rheumatology, St. Louis, Missouri, United States.
Elizabeth C
EC
Schramm
Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, Massachusetts, United States 4Department of Ophthalmology, Tufts University School of Medicine, Sackler School of Graduate Medical Sciences, Tufts Universi.
Erin K
EK
Wagner
Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, Massachusetts, United States 4Department of Ophthalmology, Tufts University School of Medicine, Sackler School of Graduate Medical Sciences, Tufts Universi.
Soumya
S
Raychaudhuri
Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, Massachusetts, United States 4Department of Ophthalmology, Tufts University School of Medicine, Sackler School of Graduate Medical Sciences, Tufts Universi.
Johanna M
JM
Seddon
Washington University School of Medicine Department of Internal Medicine, Division of Rheumatology, St. Louis, Missouri, United States.
John P
JP
Atkinson
D000368:Aged; D018389:Codon, Nonsense; D017242:Complement Factor H / Q000032:analysis / Q000235:genetics; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008268:Macular Degeneration / Q000097:blood / Q000235:genetics*; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
C493495:CFH protein, human; D018389:Codon, Nonsense; D017242:Complement Factor H