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Cited by 254Retinal Diseases and TreatmentsGenetic Associations and EpidemiologyRetinal Development and Disorders

Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Open access
Yu, Yi, Bhangale, Tushar R., Fagerness, Jesen, Ripke, Stephan, Thorleifsson, Gudmar, Tan, Perciliz L., Souied, Eric H., Richardson, Andrea J. +37 more·2011·Human Molecular Genetics
DOI 10.1093/hmg/ddr270PMC PMC3159552
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Abstract

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

AI snapshot

Written from the paper’s full text.

TL;DR

This large meta-analysis of genome-wide association studies for advanced age-related macular degeneration (AMD) identified two novel common susceptibility loci, near FRK/COL10A1 and VEGFA, and confirmed 10 previously reported loci. The findings implicate angiogenesis and extracellular collagen matrix pathways in advanced AMD.

Key findings

  • rs1999930 near FRK/COL10A1 was associated with reduced risk of advanced AMD (combined OR 0.87, 95% CI 0.83–0.91, P = 1.1 × 10−8); rs4711751 near VEGFA was associated with increased risk (combined OR 1.15, 95% CI 1.10–1.21, P = 8.7 × 10−9).
  • Ten previously reported loci were confirmed with genome-wide significant signals in the combined analysis, including ARMS2/HTRA1 (rs10490924, P = 3.6 × 10−322), CFH (rs1061170, P = 1.3 × 10−261; rs1410996, P = 7.4 × 10−235), CFB (rs641153, P = 5.5 × 10−31), C3 (rs2230199, P = 4.6 × 10−29), C2 (rs9332739, P = 2.4 × 10−23), CFI (rs10033900, P = 4.1 × 10−10), LIPC (rs10468017, P = 2.7 × 10−12), TIMP3 (rs9621532, P = 2.2 × 10−15), and CETP (rs3764261, P = 6.9 × 10−9).
  • Both novel variants had similar effect sizes for geographic atrophy and neovascular AMD subtypes in the TMMG samples.
  • A risk score using 14 validated or suggested variants estimated a >50-fold difference in advanced AMD risk between high-risk (score >2) and low-risk (score <−2) individuals; the associated loci explained ∼39% of total variance, or 55% of the heritability, of advanced AMD.

Methods

  • Meta-analysis of GWAS in the TMMG data set: 2594 advanced AMD cases and 4134 controls of European ancestry, with 6,036,699 high-quality SNPs imputed using 1000 Genomes Project reference genotypes.
  • Replication in 5640 cases and 52,174 controls from 10 independent cohorts; top signals were tested with fixed-effects meta-analysis, and heterogeneity was assessed by Cochran’s Q-test.
  • Cases had advanced AMD (geographic atrophy or neovascular disease); controls were without macular degeneration. Analyses adjusted for genotyping platform and genetic ancestry principal components.

Limitations

  • The paper states that discovery effect sizes for both novel SNPs were larger than replication effect sizes, possibly due to a “winner’s curse” phenomenon.
  • The paper notes that the genome-wide significance threshold assumes ∼1,000,000 independent SNPs, but 1000 Genomes imputation tested many more correlated SNPs, and no empirical studies address genome-wide significance for 1000 Genomes-derived data.
  • The paper states that the genetic risk score’s clinical utility needs further evaluation in independent samples, and that associations may exist for other endophenotypes such as macular drusen; evident from the text, all cohorts were of European ancestry, limiting generalizability, and not all replication cohorts contributed to every SNP analysis (e.g., Rotterdam Study was not genotyped for rs4711751).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/hmg/ddr270

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 23 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The risk allele (T) of rs4711751 had a similar magnitude of effect on geographic atrophy (OR = 1.23, 95% CI 1.08-1.40, P = 2.0 × 10−3) and neovascular AMD (OR = 1.20, 95% CI 1.09-1.32, P = 2.5 × 10−4).

    “The risk allele (T) of rs4711751 also had a similar magnitude of effect on GA [OR = 1.23 (1.08–1.40), P = 2.0 × 10−3] and NV [OR = 1.20 (1.09–1.32), P = 2.5 × 10−4].”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Using a standard liability threshold model, the previously reported loci combined with the new loci discovered in this study explain ∼39% of the total variance (or 55% of the heritability) of advanced AMD.

    “Using a standard liability threshold model (25), the previously reported loci combined with the new loci discovered in this study explain ∼39% of the total variance (or 55% of the heritability) of advanced AMD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Barrett, 2008, Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease, Nat. Genet. source

      Not checked in the free run.

  • Findingcitation

    ARMS2/HTRA1 was more strongly related to neovascular AMD compared with geographic atrophy, as previously reported.

    “ARMS2/HTRA1 was more strongly related to NV compared with GA as previously reported (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Sobrin, 2011, ARMS2/HTRA1 locus can confer differential susceptibility to the advanced subtypes of age-related macular degeneration, Am. J. Ophthalmol. source

      Not checked in the free run.

  • Findingown data

    In the TMMG meta-analysis, SNPs at previously reported loci ARMS2/HTRA1, CFH, CFB, C3, C2, CFI and LIPC showed highly statistically significant association with advanced AMD.

    “As expected, we observed highly statistically significant association signals at SNPs in six previously published loci, including ARMS2/HTRA1 (rs10490924, P = 1.2 × 10−144), CFH (rs1061170, P = 5.6 × 10−138, and rs1410996, P = 2.1 × 10−134), CFB (rs641153, P = 2.9 × 10−22), C3 (rs2230199, P = 1.4 × 10−18), C2 (rs9332739, P = 4.3 × 10−12), CFI (rs10033900, P = 2.4 × 10−11) and LIPC (rs1532085, P =”
    Quote in the paperNot a substantial claim
  • Findingown data

    Variants in ABCA1 (rs1883025) and COL8A1 (rs13095226) showed suggestive evidence of association with advanced AMD in the combined analysis (P = 1.2 × 10−7 and P = 9.7 × 10−7, respectively).

    “Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD.”
    • Also stated in: § RESULTS · plain
      “Two other variants in ABCA1 (rs1883025, P = 1.2 × 10−7) and COL8A1 (rs13095226, P = 9.7 × 10−7) which were reported in our previous GWAS (15) are also still noteworthy candidates”
    Quote in the paperNot a substantial claim
  • May combine two claims. 14
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 21

  • May combine two claims.

    Findingown data

    In the TMMG meta-analysis, the T allele of rs4711751 had an allele frequency of 0.54 in cases and 0.50 in controls and was associated with increased risk of advanced AMD (OR = 1.21, 95% CI 1.11-1.32).

    “The T allele of rs4711751, with an allele frequency of 0.54 in cases and 0.50 in controls, was associated with increased risk of advanced AMD [OR = 1.21 (95% CI:1.11–1.32)].”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The T allele of rs4711751 near VEGFA is associated with increased risk of advanced AMD in the combined analysis (OR = 1.15, 95% CI 1.10-1.21, P = 8.7 × 10−9).

    “rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10−9)”
    • Also stated in: § RESULTS · plain
      “This SNP reached genome-wide significance [OR = 1.15 (95% CI: 1.10–1.21), P = 8.7 × 10−9] in the combined analysis”
    • Also stated in: § DISCUSSION · plain
      “We also identified a novel locus (rs4711751, P = 8.7 × 10−9) for advanced AMD near VEFGA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The allele (G) at rs9488843 creates a possible transcription factor-binding site for PAX3 near the promoter region of COL10A1 and is on the same haplotype as the allele (T) at rs1999930.

    “The allele (G) at rs9488843, which creates a possible transcription factor-binding site for paired box 3 (PAX3) near the promoter region of COL10A1, is on the same haplotype as the allele (T) at rs1999930.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    rs4711751 is in strong LD with rs943080 (R2 = 1.0 in 1000 Genomes CEU data), a variant that resides in a highly evolutionarily conserved region.

    “Finally, we note that the newly identified SNP rs4711751 is in strong LD with rs943080 (R2 = 1.0 in 1000 Genomes CEU data), a variant that resides in a highly evolutionarily conserved region (Fig. 3).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    rs4711751 is in moderate LD with nearby genome-wide significant variants reported in type 2 diabetes, waist-hip ratio and chronic kidney disease (R2 = 0.31, D′ = 0.91 to rs881858).

    “In addition, rs4711751 is in moderate LD with nearby genome-wide significant variants reported in type 2 diabetes, waist–hip ratio and chronic kidney disease (R2= 0.31, D′ = 0.91 to rs881858).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    rs881858 was not significantly associated with advanced AMD in the TMMG meta-analysis (P = 0.11) and cannot explain the association observed at rs4711751.

    “However, rs881858 was not significantly associated with advanced AMD in the TMMG meta-analysis (P = 0.11) and cannot explain the association we observe in rs4711751.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    After quality control, the merged TMMG data set contained 6728 samples, of which 4300 were genotyped by AFFY 6.0 and 2428 were genotyped by ILMN 370.

    “the merged data set of TMMG contained 6728 samples, of which 4300 were genotyped by AFFY 6.0 and 2428 were genotyped by ILMN 370.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    The replication data sets consisted of 5640 cases and 52 174 controls from 10 independent cohorts.

    “The replication data sets consisted of 5640 cases and 52 174 controls from 10 independent cohorts from JHU, COL, Genentech, Iceland, Wash-U, AUS, RS, FR-CRET, Irish and an independent replication sample from Tufts/MGH.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Findingcitation

    The TMMG meta-analysis data set consisted of 1242 cases and 492 controls from the Tufts/MGH GWAS Cohort Study, 1355 cases and 1076 controls from the MMAP Cohort Study, 1188 controls from the MIGen Consortium Study, and 1378 controls from the GAIN Schizophrenia Study.

    “The TMMG meta-analysis data set consisted of: (i) 1242 cases and 492 controls from the Tufts/MGH GWAS Cohort Study (15), which were derived from ongoing AMD study protocols as described previously (8,15,24,35–37); (ii) 1355 cases and 1076 controls from the MMAP Cohort Study (16); (iii) 1188 controls from the (MIGen) Consortium Study (21) and (iv) 1378 controls from the GAIN Schizophrenia Study (22”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Neale, 2010, Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC), Proc. Natl Acad. Sci. USA source

      Not checked in the free run.

    • cites [16] Chen, 2010, Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration, Proc. Natl Acad. Sci. USA source

      Not checked in the free run.

    • cites [21] Kathiresan, 2009, Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants, Nat. Genet. source

      Not checked in the free run.

  • May combine two claims.

    Findingreasoning

    The effect sizes of both rs1999930 and rs4711751 in the replication cohorts are smaller than the effect sizes estimated in the TMMG analysis.

    “The effect sizes of both rs1999930 and rs4711751 in the replication cohorts are smaller than the effect sizes estimated in the TMMG analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The association of rs4711751 near VEGFA is in a novel region and is not likely due to linkage disequilibrium with SNPs in the VEGFA promoter region.

    “However, SNP rs4711751 appears to be independent of the rs2010963 variant (R2 = 0.015, D′ = 0.14 in samples of European ancestry); therefore, the association we identified near VEGFA was in a novel region and is not likely due to LD with SNPs in the VEGFA promoter region.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

    “The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    All samples included in this study met quality control measures.

    “All samples included in this study met quality control measures as described previously (15,16).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Neale, 2010, Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC), Proc. Natl Acad. Sci. USA source

      Not checked in the free run.

    • cites [16] Chen, 2010, Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration, Proc. Natl Acad. Sci. USA source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The association analysis controlled for genotyping platform and genetic ancestry based on principal component analysis.

    “A consensus set of 6 036 699 high-quality SNPs from each imputed data set was analyzed by PLINK, using a generalized linear model controlling for the genotyping platform and genetic ancestry based on principal component analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The novel findings are not likely caused by population admixture or population substructure because subjects in all cohorts are of European ancestry and the analysis adjusted for genetic ancestry components.

    “Our novel findings are not likely caused by population admixture or population substructure, because subjects in all cohorts are of European ancestry, and we adjusted for the genetic ancestry components in our study.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The top 40 SNPs were validated using Sequenom genotyping on 1600 samples that were also part of the Tufts/MGH GWAS.

    “The top 40 SNPs were validated using Sequenom genotyping on 1600 samples that were also part of the Tufts/MGH GWAS.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In patients with osteoarthritis, expression of COL10A1 was significantly downregulated.

    “In patients with osteoarthritis, expression of COL10A1 was significantly downregulated (28).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Lamas, 2010, Large-scale gene expression in bone marrow mesenchymal stem cells: a putative role for COL10A1 in osteoarthritis, Ann. Rheum. Dis. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    CRX is an essential transcription factor highly expressed in RPE and retinal ganglion cells.

    “cone–rod homeobox (CRX), which is an essential transcription factor highly expressed in RPE and retinal ganglion cells (27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Corbo, 2010, CRX ChIP-seq reveals the cis-regulatory architecture of mouse photoreceptors, Genome Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All replication studies applied the same criteria for the diagnosis of cases.

    “All replication studies applied the same criteria for the diagnosis of cases.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A major advantage of the study design is the careful diagnosis of cases across all cohorts.

    “A major advantage of the study design is the careful diagnosis of cases across all cohorts.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Only imputed genotypes of common variants (MAF >0.01) were included in the analysis.

    “we only included imputed genotypes of common variants (MAF >0.01) in the analysis”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Because the prediction model included only genetic risk factors, the performance of advanced AMD risk assessment is expected to improve with additional environmental and demographic factors in prospective studies.

    “As this prediction model only included genetic risk factors, we expect an improvement of the performance of advanced AMD risk assessment with additional environmental and demographic factors in prospective studies as in our previous calculations (18,19).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Seddon, 2011, Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors, Ophthalmology source

      Not checked in the free run.

    • cites [19] Seddon, 2009, Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables, Invest. Ophthalmol. Vis. Sci. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    For the meta-analysis of GWAS, only imputed genotypes with imputation quality scores >0.6 were included.

    “For the meta-analysis of GWAS, we included only imputed genotypes with imputation quality scores >0.6, where the score is defined as the ratio-of-variances (empirical/asymptotic) of each genotype.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The larger effect size observed in the discovery cohort (TMMG) could be due to a 'winner's curse' phenomenon where association is often exaggerated relative to the estimated effect in follow-up studies.

    “The larger effect size observed in the discovery cohort (TMMG) could be due to a ‘winner's curse’ phenomenon where association is often exaggerated relative to the estimated effect in follow-up studies (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Lohmueller, 2003, Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease, Nat. Genet. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    The sample size of this study is the largest of all published association studies for advanced AMD to date.

    “The sample size of this study is the largest of all published association studies for advanced AMD to date.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    rs12204816 failed the genotyping quality criteria in the replication phase, but rs1999930 was successfully genotyped in all 10 replication cohorts.

    “Of the two SNPs we selected for replication in FRK/COL10A1 locus, rs12204816 failed the genotyping quality criteria in the replication phase, but rs1999930 was successfully genotyped in all 10 replication cohorts.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The imputation quality score (ratio-of-variances) is commonly applied as a quality filter for imputed genotypes and is equivalent to the RSQR_HAT value by MACH and the information content (INFO) measure by PLINK.

    “This score is commonly applied as a quality filter for imputed genotypes and is equivalent to the RSQR_HAT value by MACH and the information content (INFO) measure by PLINK (44).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] de Bakker, 2008, Practical aspects of imputation-driven meta-analysis of genome-wide association studies, Hum. Mol. Genet. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The genetic loci associated with AMD suggest that the disease process may be explained in part by dysregulation of the alternative complement pathway (CFH, C2, CFB, C3, CFI), HDL cholesterol metabolism (LIPC, CETP, ABCA1), angiogenesis (VEGFA) and degradation of extracellular matrix (COL10A1, COL8A1, FRK, TIMP3, and possibly ARMS2).

    “The genetic loci associated with AMD suggest that the disease process may be explained in part by dysregulation of the alternative complement pathway (CFH, C2, CFB, C3, CFI), HDL cholesterol metabolism (LIPC, CETP, ABCA1), angiogenesis (VEGFA) and degradation of extracellular matrix (COL10A1, COL8A1, FRK, TIMP3, and possibly ARMS2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Owing to the larger size of the Icelanders data set, imputation based on the Icelanders data set is more reliable than imputation based on the HapMap or 1000 Genomes Project.

    “Owing to the larger size of the Icelanders data set, the imputation is more reliable based on the Icelanders data set than the imputation based on the HapMap or 1000 Genomes Project.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Compared with other complex diseases, the associated risk variants for advanced AMD are more informative in terms of predicting risk of disease.

    “Compared with other complex diseases, the associated risk variants for advanced AMD are more informative in terms of predicting risk of disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    rs2010963 in the VEGFA promoter region has been reported to be associated with AMD.

    “The newly identified SNP (rs4711751) is 60 kb downstream of VEGFA and >90 kb away from a SNP (rs2010963) in the VEGFA promoter region which has been reported to be associated with AMD (26).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Haines, 2006, Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6, Invest. Ophthalmol. Vis. Sci. source

      Not checked in the free run.

31 of 31

  • The authors state this as an assumption.

    There are no empirical studies that address levels of genome-wide significance for 1000 Genomes Project-derived data.

    “To our knowledge, there are no empirical studies that address levels of genome-wide significance for the 1000 Genomes Project-derived data.”

  • The paper relies on this without support.

    The generally accepted genome-wide significance threshold of P < 5 × 10−8 is appropriate for this study despite the larger number of SNPs tested.

    “For this study, we utilized the generally accepted genome-wide level of significance (P < 5 × 10−8) as our threshold for association.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Association has been demonstrated with several additional loci, each providing an entry-point into AMD biology and potential therapeutic targets.

    “Association has also been demonstrated with several additional loci14–20, each providing an entry-point into AMD biology and potential therapeutic targets.”

    From Seven new loci associated with age-related macular degeneration (2013) · cites this paper as [19]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Figure 3 gives a different identifier for the putative CRX-site variant

    Minor

    The discussion identifies the variant in strong linkage disequilibrium with rs4711751 as rs943080, whereas the Figure 3 caption calls it rs934080.

1 of 1

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Authors
Yu, Y., Bhangale, T. R., Fagerness, J., Ripke, S., Thorleifsson, G., Tan, P. L., Souied, E. H., Richardson, A. J., Merriam, J. E., Buitendijk, G. H. S., Reynolds, R., Raychaudhuri, S., Chin, K. A., Sobrin, L., Evangelou, E., Lee, P. H., Lee, A. Y., Leveziel, N., Zack, D. J., Campochiaro, B., Campochiaro, P., Smith, R. T., Barile, G. R., Guymer, R. H., Hogg, R., Chakravarthy, U., Robman, L. D., Gustafsson, O., Sigurdsson, H., Ortmann, W., Behrens, T. W., Stefansson, K., Uitterlinden, A. G., van Duijn, C. M., Vingerling, J. R., Klaver, C. C. W., Allikmets, R., Brantley, M. A., Baird, P. N., Katsanis, N., Thorsteinsdottir, U., Ioannidis, J. P. A., Daly, M. J., Graham, R. R., & Seddon, J. M.
Affiliations
  • Tufts University (US)
  • Broad Institute (US)
  • Duke University (US)
  • Université Paris-Est Créteil (FR)
  • The University of Melbourne (AU)
  • Columbia University (US)
  • Tufts Medical Center (US)
  • Massachusetts Eye and Ear Infirmary (US)
  • Washington University in St. Louis (US)
  • Institut de la Vision (FR)
  • Johns Hopkins University (US)
  • Queen's University Belfast (GB)
  • Genentech (US)
  • Erasmus MC (NL)
Corresponding author
Seddon, Johanna M.
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2011-06-10
Volume
20
Issue
18
Pages
3699-3709
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddr270
PMC
PMC3159552
OpenAlex
W2099989980
Semantic Scholar
97301598fe7bc85d8c49c0c3a586fa1ead9afa0e
Cited by
254
References
54
Citations by year
2026: 3 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 12 · 2021: 14 · 2020: 10 · 2019: 18 · 2018: 7 · 2017: 15 · 2016: 23 · 2015: 27 · 2014: 32 · 2013: 41 · 2012: 27
FWCI
5.92
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • Research Portal (Queen's University Belfast) (submittedVersion)
  • Hirsla (Landspítali University Hospital) (submittedVersion)
Funders
  • Research to Prevent Blindness
  • Brigham and Women's Hospital
  • Tufts Medical Center
  • Macula Vision Research Foundation
  • Northwestern University
  • Massachusetts Lions Eye Research Fund
  • State Government of Victoria
  • National Institutes of Health (5k12ey016335-17, K12EY16335, RO1-EY11309)
  • Tufts University School of Medicine
  • Medical Research Council
  • National Health and Medical Research Council (529923)
  • National Institute of Mental Health (MH59566, R01 MH61675, U01-MH79470, MH-60870, R01 MH-59571, R01MH59588, U01MH46276, R01-MH59566, R01-MH60879, U01MH046276, R01-MH60870, MH-59586, R01-MH59586, R01MH059566, MH79470, MH60879, R01 MH81800, R01MH59587, U01MH046318, R01-MH59565, MH81800, R01MH059571, MH 61675, R01MH060879, R01MH059565, U01MH46289, MH67257, MH46289, R01MH081800, R01 MH-67257, MH46318, R01MH060870, U01MH079469, R01MH061675, R01MH059586, MH59571, R01MH059588, R01MH067257, U01MH079470, MH59588, MH79469, U01MH46318, MH-59587, MH59565, R01MH059587, MH-46276, U01MH-79469)
  • National Eye Institute (K12 EY16335, EY-017404, R01EY013435, R01 EY13435, EY16335, EY-13435, K12-EY016335, R01 EY 11309, EY11309, P30EY001765, R01EY011309, R24EY017404)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR055688)
  • Alcon Research Institute
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Keywords
advanced age-related macular degeneration, genetic susceptibility, common genetic variants, VEGF-A, angiogenesis, collagen matrix, complement factor H, complement system, hepatic lipase, TIMP-3, cholesteryl ester transfer protein, ABCA1, COL8A1, genetic loci
MeSH terms
Female, Genotype, Humans, Macular Degeneration, Male, Neoplasm Proteins, Protein-Tyrosine Kinases, Genetic Variation, Cohort Studies, Case-Control Studies, Polymorphism, Single Nucleotide, Collagen Type X, Vascular Endothelial Growth Factor A, White People, Genome-Wide Association Study

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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