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Cited by 788Retinal Diseases and TreatmentsGenetic Associations and EpidemiologyRetinal Development and Disorders

Seven new loci associated with age-related macular degeneration

Open access
The AMD Gene Consortium·2013·Nature Genetics
DOI 10.1038/ng.2578PMC PMC3739472
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Abstract

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10−8. These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10−8 for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

AI snapshot

Written from the paper’s full text.

TL;DR

This collaborative genome-wide association meta-analysis identified 19 AMD-associated loci at p<5×10−8, including 7 new loci, in >17,100 advanced AMD cases and >60,000 controls. The findings implicate complement, lipid metabolism, extracellular matrix remodeling, and angiogenesis pathways and provide a genetic risk score that distinguishes cases from controls.

Key findings

  • The study identified 19 genomic loci associated with AMD at p<5×10−8, including 7 loci reaching that threshold for the first time: COL8A1/FILIP1L, IER3/DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9/MIR548A2, and B3GALTL.
  • A genetic risk score combining SNPs from all loci had AUC=.52 using only new loci and AUC=.74 including new and previously reported loci.
  • The 19 loci accounted for 10–30% of variability in disease risk depending on assumed AMD prevalence (1–10%), corresponding to 15–65% of total genetic contribution; new loci accounted for 0.5–1.0% of total heritability, and secondary signals accounted for 1.5–3.0%.
  • Subtype analyses showed ARMS2 risk alleles preferentially associated with neovascular AMD (ORNV=2.97, ORGA=2.50, pdifference=.0008), whereas CFH risk alleles preferentially associated with geographic atrophy (ORNV=2.34, ORGA=2.80, pdifference=.0006).

Methods

  • The AMD Gene Consortium, 18 research groups, performed a meta-analysis of genome-wide association scans combining >7,600 advanced AMD cases and >50,000 controls, followed by genotyping of 32 promising variants in >9,500 additional cases and >8,200 controls, for a total of >17,100 cases and >60,000 controls.
  • Discovery and follow-up results were meta-analyzed using inverse-variance weighted fixed effects in METAL, with genomic control correction; analyses included age adjustment, sex stratification, AMD subtype stratification, and European- versus Asian-ancestry samples.
  • Extended analyses included conditional analysis for independent signals, pairwise interaction tests among 19 index SNPs, genetic risk score construction with leave-one-out cross-validation, RNA-sequencing expression analysis in retina and RPE, and pathway enrichment using Ingenuity Pathway Analysis and INRICH.

Limitations

  • The paper states that differences in genotyping methods, quality control steps, and imputation strategies between samples might have a minor effect on results, and that more uniform approaches across larger sample sizes might uncover more signals.
  • The paper states that disease prevalence is difficult to estimate in this sample because it includes cases and controls of different ages and collected through a variety of ascertainment schemes, which affects estimates of explained risk.
  • The paper notes that the data do not directly answer whether HTRA1 or ARMS2 is the causal gene in the 10q26 locus; an evident limitation is that the risk score using only the new loci had low discrimination (AUC=.52).

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Integrity signals

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Crossref · 10.1038/ng.2578

Cites

63 of 63 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 56 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The set includes seven loci reaching p<5×10−8 for the first time.

    “In addition, the set includes seven loci reaching p<5×10−8 for the first time.”
    Quote in the paperSubstantial claim
  • Findingcitation

    Separate analysis of NV and GA cases showed ARMS2 risk alleles preferentially associated with risk of NV (ORNV=2.97, ORGA=2.50, pdifference=.0008).

    “Consistent with previous reports17,29,30, separate analysis of NV and GA cases showed ARMS2 risk alleles preferentially associated with risk of NV (ORNV=2.97, ORGA=2.50, pdifference=.0008)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Chen, W. et al. Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration. Proc. Natl. Acad. Sci. USA 107, 7401–7406 (2010). source

      Not checked in the free run.

    • cites [29] Sobrin, L. et al. ARMS2/HTRA1 locus can confer differential susceptibility to the advanced subtypes of age-related macular degeneration. Am. J. Ophthalmol. 151, 345–352 (2011). source

      Not checked in the free run.

    • cites [30] Seddon, J.M. et al. Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. J. Am. Med. Assoc. 297, 1793–1800 (2007). source

      Not checked in the free run.

  • Findingown data

    Joint analysis of discovery and follow-up studies resulted in 19 loci reaching p<5×10−8.

    “Joint analysis of discovery and follow-up studies27 resulted in 19 loci reaching p<5×10−8 (Figure 1, Table 2, Supplementary Table 5).”
    Quote in the paperSubstantial claim
  • Findingown data

    Sub-analyses of the full GWAS dataset (age-adjustment, separating NV and GA cases, men and women, and European- and Asian-ancestry samples separately) did not uncover additional loci reaching p<5×10−8.

    “These sub-analyses of the full GWAS dataset did not uncover additional loci reaching p<5×10−8; furthermore heterogeneity near CFH and ARMS2 remained significant in all sub-analyses (I2>65%, p <.001).”
    • Also stated in: § Abstract · plain
      “In our sample, subtype specific GWAS analyses considering GA or NV cases only did not identify additional loci.”
    Quote in the paperSubstantial claim
  • Findingown data

    These 19 loci include all susceptibility loci previously reaching p<5×10−8, except the 4q12 gene cluster for which association was reported in a Japanese population.

    “These 19 loci include all susceptibility loci previously reaching p<5×10−8, except the 4q12 gene cluster for which association was reported in a Japanese population.”
    Quote in the paperSubstantial claim
  • May combine two claims. 25
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    Although ARMS2 and CFH loci were significantly associated in every sample examined, the magnitude of association varied more than expected.

    “Although these two loci were significantly associated in every sample examined, the magnitude of association varied more than expected.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A risk score combining information across our 19 loci can distinguish cases and controls relatively well (AUC=.52 including only new loci or AUC=.74 including new and previously reported loci).

    “In contrast to most other complex diseases, a risk score combining information across our 19 loci, can distinguish cases and controls relatively well (Figure 4, area under the ROC curve [AUC]=.52 including only new loci or AUC=.74 including new and previously reported loci; Supplementary Figure 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Interaction analysis resulted in 171 tests of interaction, of which 9 were nominally significant (p<.05), consistent with chance expectations.

    “This analysis resulted in 171 tests of interaction, of which 9 were nominally significant (p<.05, see Supplementary Table 11), consistent with chance expectations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    INRICH analyses showed enrichment for genes encoding collagen and extra-cellular region proteins (both p=10−5 and padjust=.0006), complement and coagulation cascades (p=.0002, padjust=.03), lipoprotein metabolism (p=.0003, padjust=.04), and regulation of apoptosis (p=.0009, padjust=.09).

    “The INRICH analyses showed enrichment for genes encoding collagen and extra-cellular region proteins (both with p=10−5 and after adjustment for multiple testing padjust=.0006), complement and coagulation cascades (p=.0002, padjust=.03), lipoprotein metabolism (p=.0003, padjust=.04), and regulation of apoptosis (p=.0009, padjust=.09)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Our data reveal 19 susceptibility loci, including 7 loci reaching p<5×10−8 for the first time, nearly doubling the number of known AMD loci outside the complement pathway.

    “Our data reveal 19 susceptibility loci, including 7 loci reaching p<5×10−8 for the first time, nearly doubling the number of known AMD loci outside the complement pathway.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Although a common deletion of CFHR1 and CFHR3 has been proposed, there was only modest signal in this study, likely due to linkage disequilibrium with the most significantly associated variants in the locus (r2=.31 between rs10737680 and 1000 Genomes Project MERGED_DEL_2_6731).

    “Although a common deletion of the CFHR1 and CFHR3 genes has been proposed42,43, there was only modest signal in this study which is likely due to linkage disequilibrium with our most significantly associated variants in the locus (r2=.31 between rs10737680 and 1000 Genomes Project MERGED_DEL_2_6731) as previously suggested34.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Hughes, A.E. et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat. Genet. 38, 1173–1177 (2006). source

      Not checked in the free run.

    • cites [43] Fritsche, L.G. et al. An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Hum. Mol. Genet. 19, 4694–4704 (2010). source

      Not checked in the free run.

    • cites [34] Raychaudhuri, S. et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat. Genet. 43, 1232–1236 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In 50 control sets drawn from the NHGRI GWAS catalog, Ingenuity enrichment p-values for complement system and atherosclerosis signaling genes were exceeded 16% and 32% of the time respectively, although these two specific pathways were never implicated in a control dataset.

    “In these 50 control sets, Ingenuity enrichment p-values for the complement system and for atherosclerosis signaling genes were exceeded 16% and 32% of the time respectively (although these two specific pathways were never implicated in a control dataset).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362–9367 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    rs1061170 (CFH p.His402Tyr) was not in disequilibrium with rs10737680, the most strongly associated SNP in the CFH region, but was tagged by a secondary and weaker association signal.

    “Interestingly, rs1061170 (NP_000177.2[CFH]:p.His402Tyr) was not in disequilibrium with rs10737680, the most strongly associated SNP in the CFH region but, instead, was tagged by a secondary and weaker association signal (Supplementary Tables 6&7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Large differences in effect sizes were observed when stratifying by ethnicity, with variants near CFH exhibiting stronger evidence for association among Europeans (p=.0000001) and those near TNFRSF10A among East Asians (p=.002).

    “We also observed large differences in effect sizes when stratifying by ethnicity, with variants near CFH exhibiting stronger evidence for association among Europeans (p=.0000001) and those near TNFRSF10A among East Asians (p=.002).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Conditioning on the risk alleles and examining each of the 19 implicated loci for variants with independent association resulted in identification of previously well documented independently associated variants near CFH and C2/CFB and additional independent signals near C3, CETP, LIPC, FRK/COL10A1, IER3/DDR1, RAD51B.

    “This analysis resulted in the identification of the previously well documented independently associated variants near CFH and C2/CFB8,10,31,32 and of additional independent signals near C3, CETP, LIPC, FRK/COL10A1, IER3/DDR1, RAD51B (Supplementary Table 6).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [8] Gold, B. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat. Genet. 38, 458–462 (2006). source

      Not checked in the free run.

    • cites [10] Hageman, G.S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl. Acad. Sci. USA 102, 7227–7232 (2005). source

      Not checked in the free run.

    • cites [31] Li, M. et al. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat. Genet. 38, 1049–1054 (2006). source

      Not checked in the free run.

    • cites [32] Maller, J. et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat. Genet. 38, 1055–1059 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The strongest observed interaction involved risk alleles at rs10737680 (near CFH) and rs429608 (near C2/CFB), the only association that remained significant after adjusting for multiple testing (p=.000052, <0.05/171=.00029).

    “The strongest observed interaction involved risk alleles at rs10737680 (near CFH) and rs429608 (near C2/CFB), the only association that remained significant after adjusting for multiple testing (p=.000052, <0.05/171=.00029).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two genes showed differential expression between post-mortem retina of young (ages 17-35) and elderly (ages 75 and 77) individuals: CFH (p=.009) and VEGFA (p=.003), both with increased expression in older individuals.

    “Two genes showed differential expression between post-mortem retina of young (ages 17–35) and elderly (ages 75 and 77) individuals: CFH (p=.009) and VEGFA (p=.003), both with increased expression in older individuals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    The new loci identified here account for 0.5-1.0% of the total heritability of AMD whereas secondary signals at novel and known loci account for 1.5-3.0% of the total heritability.

    “the new loci identified here account for 0.5–1.0% of the total heritability of AMD whereas secondary signals at novel and known loci account for 1.5–3.0% of the total heritability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Genes in the complement pathway and a region of chromosome 10 have been implicated as the major genetic contributors to AMD.

    “Genes in the complement pathway4–11 and a region of chromosome 10 12,13 have now been implicated as the major genetic contributors to disease.”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [4] Edwards, A.O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424 (2005). source

      Not checked in the free run.

    • cites [5] Haines, J.L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005). source

      Not checked in the free run.

    • cites [6] Klein, R.J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005). source

      Not checked in the free run.

    • cites [7] Yates, J.R. et al. Complement C3 variant and the risk of age-related macular degeneration. N. Engl. J. Med. 357, 553–561 (2007). source

      Not checked in the free run.

    • cites [8] Gold, B. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat. Genet. 38, 458–462 (2006). source

      Not checked in the free run.

    • cites [9] Fagerness, J.A. et al. Variation near complement factor I is associated with risk of advanced AMD. Eur. J. Hum. Genet. 17, 100–104 (2009). source

      Not checked in the free run.

    • cites [10] Hageman, G.S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl. Acad. Sci. USA 102, 7227–7232 (2005). source

      Not checked in the free run.

    • cites [11] Maller, J.B. et al. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat. Genet. 39, 1200–1201 (2007). source

      Not checked in the free run.

    • cites [12] Rivera, A. et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum. Mol. Genet. 14, 3227–3236 (2005). source

      Not checked in the free run.

    • cites [13] Jakobsdottir, J. et al. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am. J. Hum. Genet. 77, 389–407 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [14] Klaver, C.C. et al. Genetic association of apolipoprotein E with age-related macular degeneration. Am. J. Hum. Genet. 63, 200–206 (1998). source

      Not checked in the free run.

    • cites [15] Souied, E.H. et al. The ɛ4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am. J. Ophthalmol. 125, 353–359 (1998). source

      Not checked in the free run.

    • cites [16] McKay, G.J. et al. Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies. Hum. Mutat. 32, 1407–1416 (2011). source

      Not checked in the free run.

    • cites [17] Chen, W. et al. Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration. Proc. Natl. Acad. Sci. USA 107, 7401–7406 (2010). source

      Not checked in the free run.

    • cites [18] Neale, B.M. et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc. Natl. Acad. Sci. USA 107, 7395–7400 (2010). source

      Not checked in the free run.

    • cites [19] Yu, Y. et al. Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum. Mol. Genet. 20, 3699–3709 (2011). source

      Not checked in the free run.

    • cites [20] Arakawa, S. et al. Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population. Nat. Genet. 43, 1001–1004 (2011). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Each study was subject to GWAS quality control filters customized taking into account study-specific features and standardized to the HapMap reference panel and statistical genotype imputation.

    “Each study was first subject to GWAS quality control filters (customized taking into account study specific features21 as detailed in Supplementary Table 2) and standardized to the HapMap reference panel and statistical genotype imputation22–25.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [21] McCarthy, M.I. et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat. Rev. Genet. 9, 356–369 (2008). source

      Not checked in the free run.

    • cites [22] Li, Y., Willer, C.J., Sanna, S. & Abecasis, G.R. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009). source

      Not checked in the free run.

    • cites [23] Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007). source

      Not checked in the free run.

    • cites [24] Browning, B.L. & Browning, S.R. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am. J. Hum. Genet. 84, 210–223 (2009). source

      Not checked in the free run.

    • cites [25] Li, Y., Willer, C.J., Ding, J., Scheet, P. & Abecasis, G.R. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010). source

      Not checked in the free run.

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

    Premisecitation

    AMD is a highly heritable progressive neurodegenerative disease that leads to loss of central vision through death of photoreceptors.

    “AMD is a highly heritable progressive neurodegenerative disease that leads to loss of central vision through death of photoreceptors1,2.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Swaroop, A., Chew, E.Y., Rickman, C.B. & Abecasis, G.R. Unravelling a late-onset multifactorial disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration. Annu. Rev. Genomics Hum. Genet. 10, 19–43 (2009). source

      Not checked in the free run.

    • cites [2] Seddon, J.M., Cote, J., Page, W.F., Aggen, S.H. & Neale, M.C. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch. Ophthalmol. 123, 321–327 (2005). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Before meta-analysis, all study-specific files underwent quality control procedures to check for completeness and plausible descriptive statistics on all variables as well as for compliance of allele frequencies with HapMap.

    “Before meta-analysis, all study-specific files underwent quality control procedures to check for completeness and plausible descriptive statistics on all variables as well as for compliance of allele frequencies with HapMap59.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Nyholt, D.R. A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am. J. Hum. Genet. 74, 765–769 (2004). source

      Not checked in the free run.

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

    Study design and conductown data

    Meta-analyses used inverse variance weighted fixed effect model; alternative weighted z-score method gave very similar test statistics (correlation of −log10(p-value) >0.98).

    “For both discovery and follow-up, we performed meta-analyses using the inverse variance weighted fixed effect model, which pools the effect size and standard error of each participated GWAS. Using an alternative weighted z-score method, which is based on a weighted sum of z-score statistics, we obtained a very similar set of test statistics (correlation of −log10(p-value) >0.98).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010). source

      Not checked in the free run.

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

    Study design and conductown data

    Second signal analysis used logistic regression containing all identified index SNPs, quality control, effective sample size weighted z-score meta-analysis, two rounds of genomic control correction, and a Bonferroni-adjusted significance threshold.

    “using a logistic regression model containing all identified index SNPs. Quality control procedures were performed as before.”
    • Also stated in: § EXTENDED ANALYSES FOR THE IDENTIFIED AMD LOCI · plain
      “The significance threshold (p<0.05) for an independent association signal within any of the identified loci was Bonferroni-adjusted using the average effective number of SNPs involved across the identified loci determined by SNPSpD60.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Some coding variants point to well-studied genes (ARMS2, C3 and APOE) while others help prioritize nearby genes for further study.

    “Some coding variants point to well-studied genes (ARMS2, C3 and APOE) while others help prioritize nearby genes for further study.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All results were analyzed and validated among four independent teams.

    “All results were analyzed and validated among four independent teams.”
    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

    Interaction analysis used pre-specified R-scripts, quality control checks, and inverse variance weighted fixed effect model in METAL.

    “Utilizing a pre-specified R-scripts (see URLs), GWAS partners performed 171 logistic regression analyses modeling the pair-wise interaction of the 19 index SNPs assuming an additive model for main and interaction effects.”
    • Also stated in: § EXTENDED ANALYSES FOR THE IDENTIFIED AMD LOCI · plain
      “SNPs with low imputation quality measures and pairs with |beta|>5 or standard errors >5 were excluded before meta-analyzing the interaction effects with the inverse variance weighted fixed effect model in METAL.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Study-specific control for population stratification was conducted for all analyses.

    “For all analyses, study-specific control for population stratification was conducted (Supplementary Table 4).”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    SNP results were excluded from meta-analysis for discovery if imputation quality measures were too low or if effect sizes or standard errors were too extreme, and for follow-up if Hardy-Weinberg equilibrium was violated.

    “In addition, we excluded SNP results of a study into meta-analysis (i) for discovery: if imputation quality measures were too low (MACH & PLINK <0.3; SNPTEST <0.4) or if effect sizes (|beta|) or standard errors were too extreme (≥5) indicating instability of the estimates, (ii) for follow-up: if Hardy-Weinberg equilibrium was violated (p<0.05/32).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Our results show some susceptibility alleles exhibit different association across ethnic groups and may be preferentially associated with specific subtypes of disease.

    “Our results show some susceptibility alleles exhibit different association across ethnic groups and may be preferentially associated with specific subtypes of disease.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Two rounds of genomic control corrections were applied to each individual GWAS and the combined meta results.

    “For the discovery, we applied two rounds of genomic control corrections to each individual GWAS and the combined meta results, respectively 51.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    CFH, VEGFA and C3 are up-regulated with aging, and their role in AMD may indicate an accelerated aging process.

    “CFH, VEGFA and C3 are thus up-regulated with aging, and their role in AMD may indicate an accelerated aging process.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    Consistent with observations for other complex diseases, the majority of common disease susceptibility alleles do not alter protein sequences and are not associated with insertions or deletions of coding sequence or with copy number variation.

    “Consistent with observations for other complex diseases39, the majority of common disease susceptibility alleles do not alter protein sequences and are not associated with insertions or deletions of coding sequence or with copy number variation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] 1000 Genomes Project Consortium. A map of human genome variation from population scale sequencing. Nature 467, 1061–1073 (2010). source

      Not checked in the free run.

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

    Study design and conductown data

    Genetic risk score used leave-one-out cross-validation to assess prediction.

    “For each study, we used a leave-one-out cross-validation to access the prediction of the risk score.”
    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

    Pathway analyses used control sets and INRICH permutations to evaluate significance.

    “To evaluate significance of observed enrichment, we repeated our Ingenuity analysis starting with 50 lists of 19 SNPs randomly drawn from the NHGRI GWAS catalog46 and, again, using the INRICH tool63.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362–9367 (2009). source

      Not checked in the free run.

    • cites [63]

      Not checked in the free run.

31 of 31

  • The authors state this as an assumption.

    An underlying normally distributed but unobserved disease risk score (liability) underlies AMD risk.

    “Using a model that assumes an underlying normally distributed but unobserved disease risk score or liability49, the nineteen loci described here account for between 10% (if AMD prevalence is close to 1%) and 30% (if AMD prevalence is closer to 10%) of the variability in disease risk (corresponding to 15–65% of the total genetic contribution to AMD).”
1 of 1

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?

  • Variants of SLC16A8 are risk factors for AMD.

    “A genome-wide association study (GWAS) showed that variants of SLC16A8 are risk factors for AMD (Fritsche et al., 2013, 2016).”

    From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Fritsche et al., 2013

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Related

Authors
The AMD Gene Consortium
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2013-03-03
Volume
45
Issue
4
Pages
433-439
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.2578
PMC
PMC3739472
OpenAlex
W2035310463
Semantic Scholar
6fdcda9d7a79b5197ed12da43c2a5c4f8ad34db1
Cited by
788
References
63
Citations by year
2026: 19 · 2025: 21 · 2024: 24 · 2023: 39 · 2022: 39 · 2021: 56 · 2020: 51 · 2019: 59 · 2018: 58 · 2017: 75 · 2016: 89 · 2015: 113 · 2014: 100 · 2013: 44 · 2012: 1
FWCI
113.56
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion)
  • National University of Singapore (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • HAL (submittedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • University of Thessaly Institutional Repository (University of Thessaly) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • Site cant be reached (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
  • Research Portal (Queen's University Belfast) (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
  • Hirsla (Landspítali University Hospital) (submittedVersion)
Funders
  • Wellcome Trust
  • National Institute for Health and Care Research (NF-SI-0507-10204, NF-SI-0507-10094)
  • Agence Nationale de la Recherche (ANR-10-INBS-0001)
  • Moorfields Eye Hospital NHS Foundation Trust
  • Medical Research Council (MR/K006584/1)
  • National Human Genome Research Institute (R01HG007022)
  • National Eye Institute (R01EY022005, R01EY013435, P30EY019007, R24EY019861, R01EY022310, R01EY021163, R01EY011309, P30EY014800)
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
age-related macular degeneration, genetic loci, genome-wide association study, complement system, lipid metabolism, extracellular matrix remodeling, angiogenesis, TGFBR1, RAD51B, ADAMTS9, polygenic risk score
MeSH terms
Female, Humans, Macular Degeneration, Male, Risk Factors, Meta-Analysis as Topic, Biomarkers, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci

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.

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