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Cited by 442Retinal Diseases and TreatmentsGenetic Associations and EpidemiologyRetinal Development and Disorders

Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene ( LIPC )

Open access
Neale, Benjamin M., Fagerness, Jesen, Reynolds, Robyn, Sobrin, Lucia, Parker, Margaret, Raychaudhuri, Soumya, Tan, Perciliz L., Oh, Edwin C. +18 more·2010·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0912019107PMC PMC2867697
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Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene ( LIPC ) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, ( P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci ( ABCA1 , P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3 , P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.

AI snapshot

Written from the paper’s full text.

TL;DR

This GWAS of advanced AMD (979 cases/1,709 controls in discovery; 5,789 cases/4,234 controls in replication) identified a replicated association at *LIPC* rs10468017 (P = 1.34 × 10⁻⁸), with the minor T allele protective (OR = 0.82). Other HDL loci showed weaker or inconsistent associations, suggesting the *LIPC* effect may not be mediated by HDL levels.

Key findings

  • *LIPC* rs493258 was associated in discovery (P = 4.53 × 10⁻⁵) and reached P = 1.61 × 10⁻⁸ after replication; the functional promoter variant rs10468017 gave P = 1.34 × 10⁻⁸, OR = 0.82 (95% CI 0.77–0.88), with minor T allele frequency 25.8% in cases vs 30.0% in controls.
  • rs9621532 near *TIMP3*/*SYN3* showed a protective effect for the minor C allele (OR = 0.62, 95% CI 0.53–0.73, P = 3.71 × 10⁻⁹) in combined analysis.
  • Other HDL loci were weaker and directionally inconsistent: *ABCA1* rs1883025 P = 9.73 × 10⁻⁴, *CETP* rs3764261 P = 1.41 × 10⁻³, *FADS1-3* rs174547 P = 2.69 × 10⁻²; no consistent trend between HDL-raising alleles and AMD risk was observed.
  • CNV analyses found no common CNPs with P < 0.001 except the previously reported *CFHR1* deletion (P = 1 × 10⁻¹⁹), explained by known *CFH* variants, and no genome-wide enrichment of rare CNVs in cases vs controls.

Methods

  • Discovery GWAS used 979 unrelated advanced AMD cases and 1,709 controls genotyped on Affymetrix 6.0; replication included seven additional cohorts totaling 5,789 unrelated cases and 4,234 unrelated controls.
  • Association was assessed by logistic regression in PLINK, with meta-analysis using weighted Z scores; final genomic control λ was 1.036 for 632,932 SNPs after including seven principal components.
  • CNV analysis used Birdsuite/CANARY/Birdseye for 554 common CNPs and rare CNVs >100 kb; LIPC expression was examined by immunoprecipitation, quantitative RT-PCR, and immunohistochemistry in bovine, mouse, and human retinal samples.

Limitations

  • Stated: modest heterogeneity was observed for rs10468017 across replication samples (Breslow–Day P = 0.022); the UT sample lacked association and FR-CRET had higher-than-expected association, though excluding both strengthened the result (P = 6.45 × 10⁻⁹).
  • Stated: the scan did not have sufficient statistical power to conclusively highlight weak or moderate subtype-specific SNP associations between advanced dry and wet AMD.
  • Evident from the text: additional discovery controls were unscreened for AMD status, and the Tufts/MGH replication set included 379 unexamined controls, which could affect phenotype classification; the case-control design also cannot establish causality.

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

Integrity signals

Registry

Crossref · 10.1073/pnas.0912019107

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 13 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The minor T allele of rs10468017 (HDL increasing) has a protective effect for advanced wet and dry AMD.

    “with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD”
    Quote in the paperSubstantial claim
  • Findingown data

    The discovery GWAS data implicated an association between advanced AMD and a variant in the hepatic lipase gene (LIPC) in the HDL pathway (discovery P = 4.53e-05 for rs493258).

    “Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (*LIPC*) in the high-density lipoprotein cholesterol (HDL) pathway (discovery *P* = 4.53e-05 for rs493258).”
    Quote in the paperSubstantial claim
  • Findingown data

    Of 159 SNPs in linkage disequilibrium with the most positively associated variants, 137 showed an improvement in the chi-square statistic with the addition of the additional controls.

    “We examined 159 SNPs that were in linkage disequilibrium (LD) with the most positively associated variants, and of these SNPs, 137 showed an improvement in the χ2 with the addition of these controls.”
    Quote in the paperSubstantial claim
  • Findingown data

    The most significant, replicated association in this study is a functional variation in the hepatic lipase gene (LIPC).

    “our most significant, replicated association is a functional variation in the hepatic lipase gene (*LIPC*)”
    Quote in the paperSubstantial claim
  • Findingown data

    The LIPC association was strongest for the functional promoter variant rs10468017 (P = 1.34e-08).

    “Our *LIPC* association was strongest for a functional promoter variant, rs10468017, (*P* = 1.34e-08)”
    Quote in the paperSubstantial claim
  • May combine two claims. 24
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    rs493258 is located 35 kb upstream of the LIPC gene on chromosome 15q22 and is in linkage disequilibrium (r2 = 0.33; D′ = 0.847) with the functional variant rs10468017.

    “This SNP is located 35 kb upstream of the *LIPC* gene on chromosome 15q22 and is in LD (*r*2 = 0.33; D′ = 0.847) with the previously described functional variant (rs10468017)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The regions of previously reported association are near CFH (rs572515 proxy for rs1061170, r2 = 0.654, P < 10−55; rs10737680 proxy for rs1410996, r2 = 1, P < 10−47), CFI (rs7690921 proxy for rs10033900, r2 = 0.403, P < 10−4), CFB/C2 (rs522162 proxy for rs641153, r2 = 1, P < 10−6), and the ARMS2/HTRA1 locus (rs10490924, P < 10−59).

    “The regions of previously reported association are near *CFH* (rs572515 proxy for rs1061170 with *r*2 = 0.654 and *P* < 10−55; rs10737680 proxy for *CFH* rs1410996 with *r*2 = 1 and *P* < 10−47), *CFI* (rs7690921 proxy for rs10033900 with *r*2 = 0.403 and *P* < 10−4), *CFB/C2* (rs522162 proxy for rs641153 with *r*2 = 1 and *P* < 10−6), and the *ARMS2*/*HTRA1* locus (rs10490924 with *P* < 10−59)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    rs493258 is not associated with AMD conditional on rs10468017, but rs10468017 remains associated with AMD (P < 0.001) conditional on rs493258.

    “Logistic regression analyses conditional on allelic dosage of each SNP indicated that rs493258 is not associated with AMD conditional on rs10468017, but rs10468017 is still associated with AMD (*P <* 0.001) conditional on association at rs493258.”
    Quote in the paperSubstantial claim

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

    Findingown data

    The top end of the QQ plot is dominated by the strong associations of previously reported SNPs, which were excluded to more fully examine the remaining results.

    “The top end of the QQ plot ([Fig. S1*A*](http://www.pnas.org/cgi/data/0912019107/DCSupplemental/Supplemental_PDF#nameddest=sfig01)) is dominated by the strong associations of previously reported SNPs, which were excluded to more fully examine the remaining results”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    With additional replication, rs493258 on chromosome 15 showed significant association with AMD (P = 1.61 × 10−8; independent of the MPM GWAS data, P = 4.92 × 10−7).

    “With additional replication, the SNP that we identified on chromosome 15, rs493258, showed significant association with *P* = 1.61 × 10−8 (independent of the MPM GWAS data *P* = 4.92 × 10−7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No other SNPs reached genome-wide significance of P < 5 × 10−8, but several SNPs of interest in new regions with P values between 10−4 and 10−6 were identified in the discovery scan, including rs493258 (LIPC) with P = 4.5 × 10−5.

    “Although no other SNPs reached genome-wide significance of *P* < 5 × 10−8 (20), we did identify several SNPs of interest in new regions with *P* values between 10−4 and 10−6 in our discovery scan ([Table 1](#t01)), including rs493258 (*LIPC*) with *P* = 4.5 × 10−5”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Weaker associations were observed with other HDL loci: ABCA1 (P = 9.73e-04), cholesterylester transfer protein (P = 1.41e-03), and FADS1-3 (P = 2.69e-02).

    “We observed weaker associations with other HDL loci (*ABCA1*, *P* = 9.73e-04; cholesterylester transfer protein, *P* = 1.41e-03; *FADS1-3*, *P* = 2.69e-02).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The ABCA1 variant rs1883025 (meta P = 9.73 × 10−4) was not genome-wide significant and showed discordant effects between the HDL-increasing allele and protective or risk effects for AMD.

    “The variant, rs12678919, in the lipoprotein lipase precursor gene (*LPL*) with meta *P* = 0.07 as well as rs1883025 in the ATP-binding cassette, subfamily A member 1 (*ABCA1*) gene with meta *P* = 9.73 × 10−4, were also not genome-wide significant, and they showed discordant effects between the HDL-increasing allele and protective or risk effects for AMD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    These rare CNV events were not enriched across the genome among cases compared with controls, nor were there specific regions showing association of a rare CNV (Fisher's exact test P < 0.01).

    “However, these events were not enriched across the genome among cases compared with controls nor were there specific regions showing association of a rare CNV (Fisher's exact test *P* < 0.01).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The SNPs at the LIPC locus were not on the list of top SNPs from the MPM scan, and rs9621532 was not on the authors' list of top SNPs.

    “Of note, the SNPs at the *LIPC* locus were not on the list of top SNPs from the MPM scan, and the SNP rs9621532 was not on our list of top SNPs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Data from the authors' scan suggest that the HDL-raising alleles of ABCA1 and CETP may increase the risk of AMD, although these results are not currently genome-wide significant.

    “In contrast, data from our scan suggest that the HDL-raising alleles of *ABCA1* and *CETP* may increase the risk of AMD, although these results are not currently genome-wide significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Prominent labeling of all retinal neurons was observed, especially in retinal ganglion cells of the central retina; Mueller glial cells were unlabeled, and RPE cells appeared to exhibit significant fluorescence signal beyond intrinsic autofluorescence.

    “Prominent labeling of all retinal neurons was observed, especially in retinal ganglion cells of the central retina. However, Mueller glial cells were unlabeled, and RPE cells appeared to exhibit significant fluorescence signal beyond intrinsic autofluorescence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The HDL-increasing allele A of CETP SNP rs3764261 was in the direction of increased risk for AMD, opposite to the protective effect seen with the functional HDL-increasing LIPC variant.

    “However, the HDL-increasing allele, A, was in the direction of increased risk for AMD, opposite to the protective effect seen with the functional HDL-increasing *LIPC* variant.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    After stringent QC, a set of 150 rare deletions and 278 rare duplications greater than 100 kb was observed.

    “After stringent QC, we observed a set of 150 rare deletions and 278 rare duplications greater than 100 kb.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    SNP rs13095226 on chromosome 3 (P = 2.50 × 10−6 and OR = 1.24 for the C allele) is an intronic SNP in the COL8A1 gene.

    “The SNP rs13095226 on chromosome 3 (*P* = 2.50 × 10−6 and OR = 1.24 for the C allele) is an intronic SNP in the *COL8A1* gene”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The LPL variant rs12678919 (meta P = 0.07) was not genome-wide significant and showed discordant effects between the HDL-increasing allele and protective or risk effects for AMD.

    “The variant, rs12678919, in the lipoprotein lipase precursor gene (*LPL*) with meta *P* = 0.07 as well as rs1883025 in the ATP-binding cassette, subfamily A member 1 (*ABCA1*) gene with meta *P* = 9.73 × 10−4, were also not genome-wide significant, and they showed discordant effects between the HDL-increasing allele and protective or risk effects for AMD.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The role of the alternative complement pathway in AMD pathogenesis was documented by the discovery and replication of the CFH association and by reports of three additional risk loci in this pathway: CFB/C2 on chromosome 6, C3 on chromosome 19, and CFI on chromosome 4.

    “The role of the alternative complement pathway in disease pathogenesis was documented by the discovery ([2](#r2)–[5](#r5)) and replication ([6](#r6), [7](#r7)) of the *CFH* association as well as reports of three additional risk loci in this pathway: *CFB/C2* on chromosome 6 ([6](#r6), [8](#r8)), *C3* on chromosome 19 ([9](#r9), [10](#r10)), and *CFI* on chromosome 4 ([11](#r11)).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Haines JL, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419–421. doi: 10.1126/science.1110359. [[DOI](https://doi.org/10.1126/science.1110359)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/15761120/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Science&title=Complement%20factor%20H%20variant%20increases%20the%20risk%20of%20age-related%20macular%20degeneration&author=JL%20Haines&volume=308&publication_year=2005&pages=419-421&pmid=15761120&doi=10.1126/science.1110359&)] source

      Not checked in the free run.

    • cites [6] 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. 2006;38:1055–1059. doi: 10.1038/ng1873. [[DOI](https://doi.org/10.1038/ng1873)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/16936732/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nat%20Genet&title=Common%20variation%20in%20three%20genes,%20including%20a%20noncoding%20variant%20in%20CFH,%20strongly%20influences%20risk%20of%20age-related%20macular%20degeneration&author=J%20Maller&volume=38&publication_year=2006&pag source

      Not checked in the free run.

    • cites [11] Fagerness JA, et al. Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet. 2009;17:100–104. doi: 10.1038/ejhg.2008.140. [[DOI](https://doi.org/10.1038/ejhg.2008.140)] [[PMC free article](/articles/PMC2985963/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/18685559/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Eur%20J%20Hum%20Genet&title=Variation%20near%20complement%20factor%20I%20is%20associated%20with%20risk%20of%20advanced%20AMD&author=JA%20Fagerness&volume=17&publication_year=2009&pages=100-104&pmid=18685559&doi=10.1038/ejhg.2008 source

      Not checked in the free run.

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

    Premisecitation

    Combined with demographic, ocular, and environmental factors, these loci have potential predictive power.

    “and combined with demographic, ocular, and environmental factors, they have potential predictive power ([14](#r14))”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Seddon JM, et al. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009;50:2044–2053. doi: 10.1167/iovs.08-3064. [[DOI](https://doi.org/10.1167/iovs.08-3064)] [[PMC free article](/articles/PMC3772781/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/19117936/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Invest%20Ophthalmol%20Vis%20Sci&title=Prediction%20model%20for%20prevalence%20and%20incidence%20of%20advanced%20age-related%20macular%20degenerati 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 common, late-onset neurodegenerative disorder modified by covariates including smoking and body mass index, with a 3- to 6-fold higher recurrence ratio in siblings than in the general population.

    “Age-related macular degeneration (AMD) is a common, late-onset neurodegenerative disorder that is modified by covariates including smoking and body mass index, and it has a 3- to 6-fold higher recurrence ratio in siblings than in the general population ([1](#r1)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Seddon JM, Sobrin L. Epidemiology of age-related macular degeneration. In: Albert D, Miller J, Azar D, Blodi B, editors. Albert & Jakobiec's Principles and Practice of Ophthalmology. Philadelphia: Saunders; 2007. pp. 413–422. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Albert%20&%20Jakobiec's%20Principles%20and%20Practice%20of%20Ophthalmology&author=JM%20Seddon&author=L%20Sobrin&publication_year=2007&)]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The variant rs10468017 influences LIPC expression and serum HDL levels.

    “a functional promoter variant, rs10468017, (*P* = 1.34e-08), that influences LIPC expression and serum HDL levels”
    • Also stated in: § Results of Combined Scan and Replication Analysis. · plain
      “the previously described functional variant (rs10468017) reported to influence LIPC expression and serum HDL levels ([23](#r23), [24](#r24))”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Rufibach LE, Duncan SA, Battle M, Deeb SS. Transcriptional regulation of the human hepatic lipase (LIPC) gene promoter. J Lipid Res. 2006;47:1463–1477. doi: 10.1194/jlr.M600082-JLR200. [[DOI](https://doi.org/10.1194/jlr.M600082-JLR200)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/16603721/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Lipid%20Res&title=Transcriptional%20regulation%20of%20the%20human%20hepatic%20lipase%20(LIPC)%20gene%20promoter&author=LE%20Rufibach&author=SA%20Duncan&author=M%20Battle&author=SS%20Deeb&volume=47&publication_year=2006&pages=1463-1477&pm source

      Not checked in the free run.

    • cites [24] Grarup N, et al. The -250G>A promoter variant in hepatic lipase associates with elevated fasting serum high-density lipoprotein cholesterol modulated by interaction with physical activity in a study of 16,156 Danish subjects. J Clin Endocrinol Metab. 2008;93:2294–2299. doi: 10.1210/jc.2007-2815. [[DOI](https://doi.org/10.1210/jc.2007-2815)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/18364377/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Clin%20Endocrinol%20Metab&title=The%20-250G>A%20promoter%20variant%20in%20hepatic%20lipase%20associates%20with%20elevated%20fasting source

      Not checked in the free run.

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

    Premisecitation

    LIPC is a gene involved in triglyceride hydrolysis and high-density lipoprotein cholesterol (HDL) function.

    “a gene involved in triglyceride hydrolysis and high-density lipoprotein cholesterol (HDL) function ([16](#r16))”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Hasham SN, Pillarisetti S. Vascular lipases, inflammation and atherosclerosis. Clin Chim Acta. 2006;372:179–183. doi: 10.1016/j.cca.2006.04.020. [[DOI](https://doi.org/10.1016/j.cca.2006.04.020)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/16765928/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Clin%20Chim%20Acta&title=Vascular%20lipases,%20inflammation%20and%20atherosclerosis&author=SN%20Hasham&author=S%20Pillarisetti&volume=372&publication_year=2006&pages=179-183&pmid=16765928&doi=10.1016/j.cca.2006.04.020&)] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.

    “Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    These diseases may represent parallel responses to tissue injury induced by multiple factors, including genetic variation, impaired immune responses, and oxidative stress.

    “These diseases may represent parallel responses to tissue injury induced by multiple factors, including genetic variation, impaired immune responses, and oxidative stress.”
    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

    The final genomic control λ for the logistic regression included seven significant principal components as covariates and was 1.036 for 632,932 SNPs.

    “The final genomic control λ for the logistic regression included seven significant (for prediction of phenotype status) principal components as covariates, and was 1.036 for 632,932 SNPs.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The authors' 1997 study of the TIMP3 locus and AMD in 38 AMD families did not find evidence of association or linkage between AMD and TIMP3.

    “Our study of the *TIMP3* locus and AMD in 1997, inspired by the association of this gene to Sorsby fundus dystrophy that has similar phenotypic features to advanced AMD, did not find evidence of association or linkage between AMD and *TIMP3* among 38 AMD families.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] De La Paz MA, Pericak-Vance MA, Lennon F, Haines JL, Seddon JM. Exclusion of TIMP3 as a candidate locus in age-related macular degeneration. Invest Ophthalmol Vis Sci. 1997;38:1060–1065. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/9152225/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Invest%20Ophthalmol%20Vis%20Sci&title=Exclusion%20of%20TIMP3%20as%20a%20candidate%20locus%20in%20age-related%20macular%20degeneration&author=MA%20De%20La%20Paz&author=MA%20Pericak-Vance&author=F%20Lennon&author=JL%20Haines&author=JM%20Seddon&volume=38&publication_year=1997&pages=1060-1065&pm

      Not checked in the free run.

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

    Interpretationnone given

    Bands of mobility ∼80 kDa likely represented glycosylated hepatic lipase.

    “Bands of mobility ∼80 kDa likely represented glycosylated hepatic lipase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The minor T allele of rs10468017 is associated with reduced LIPC expression and higher HDL.

    “the minor allele T, previously associated with reduced LIPC expression and higher HDL”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Kathiresan S, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009;41:56–65. doi: 10.1038/ng.291. [[DOI](https://doi.org/10.1038/ng.291)] [[PMC free article](/articles/PMC2881676/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/19060906/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nat%20Genet&title=Common%20variants%20at%2030%20loci%20contribute%20to%20polygenic%20dyslipidemia&author=S%20Kathiresan&volume=41&publication_year=2009&pages=56-65&pmid=19060906&doi=10.1038/ng.291&)] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The association between advanced AMD and LIPC may not represent phenotypic correlation to or a causal effect of serum HDL but could indicate a shared underlying biologic mechanism involving the cholesterol pathway.

    “Thus, the association between advanced AMD and *LIPC* may not represent phenotypic correlation to or a causal effect of serum HDL but could indicate a shared underlying biologic mechanism involving the cholesterol pathway.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: If the LIPC-AMD association were driven by HDL levels, all SNPs associated with HDL would show some association with AMD and in a consistent direction.

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

    Study design and conductnone given

    The study conformed to the tenets of the Declaration of Helsinki and received approval from Institutional Review Boards; informed consent was signed by all participants.

    “This study conformed to the tenets of the Declaration of Helsinki and received approval from Institutional Review Boards; informed consent was signed by all participants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    A preliminary χ2 association analysis observed λ ∼ 1.05, indicating that the samples were generally matched well for population ancestry but with some minor inflation remaining.

    “We conducted a preliminary χ2 association analysis to determine the extent to which population stratification and other biases were affecting the samples and observed λ ∼ 1.05, indicating that the samples were generally matched well for population ancestry but with some minor inflation remaining”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Heterogeneity in rs10468017 association could be attributed to yet to be discovered genotype or phenotype correlations and ascertainment differences between samples.

    “such heterogeneity could be attributed to yet to be discovered genotype or phenotype correlations and ascertainment differences between these samples.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The UT and FR-CRET samples were not discounted based on modest heterogeneity, particularly because both samples showed association to complement loci.

    “These samples were not discounted based on modest heterogeneity, particularly given the fact that both samples showed association to complement loci”
    Quote in the paperSubstantial claim
32 of 32

  • The paper relies on this without support.

    No large sample genome-wide association study had previously been undertaken to explain the remaining heritability of AMD and to identify other susceptibility loci.

    “To date, however, no large sample genome-wide association study (GWAS) has been undertaken to attempt to explain the remaining heritability of AMD and to identify other susceptibility loci.”

  • The paper relies on this without support.

    The T allele of the LIPC SNP increases HDL levels.

    “The T allele of the *LIPC* SNP has been shown to increase HDL levels”

  • The paper relies on this without support.

    If the LIPC-AMD association were driven by HDL levels, all SNPs associated with HDL would show some association with AMD and in a consistent direction.

    “If the association between *LIPC* and AMD was driven by this phenotypic correlation, then all SNPs associated with HDL would likely show some level of association with AMD. Additionally, the direction of the effects would be consistent.”

  • The paper relies on this without support.

    The MPM scan and the authors' scan are comparable enough that exchanging SNPs enables valid primary replication.

    “SNPs with *P* < 10−3 from our GWAS discovery sample (*n* = 720 SNPs excluding previously associated regions) were exchanged with the MPM study group, which enabled us to use the two scans as primary replication efforts, and enhanced the power of each study.”
4 of 4

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 [18]

  • 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).”

    From Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration (2011) · cites this paper as [15]

  • 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”

    From Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration (2011) · cites this paper as [15]

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.

  • Odds ratio falls outside its reported confidence interval

    Minor

    For rs11755724, the reported meta-analysis odds ratio is 0.87, but its stated 95% confidence interval is 0.88-0.92. A confidence interval for that odds ratio should contain the estimate.

1 of 1

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Authors
Neale, B. M., Fagerness, J., Reynolds, R., Sobrin, L., Parker, M., Raychaudhuri, S., Tan, P. L., Oh, E. C., Merriam, J. E., Souied, E., Bernstein, P. S., Li, B., Frederick, J. M., Zhang, K., Brantley, M. A., Lee, A. Y., Zack, D. J., Campochiaro, B., Campochiaro, P., Ripke, S., Smith, R. T., Barile, G. R., Katsanis, N., Allikmets, R., Daly, M. J., & Seddon, J. M.
Affiliations
  • Broad Institute (US)
  • Tufts University (US)
  • Massachusetts Eye and Ear Infirmary (US)
  • Johns Hopkins University (US)
  • Columbia University (US)
  • Hôpital Intercommunal de Créteil (FR)
  • University of Utah (US)
  • Washington University in St. Louis (US)
  • Duke University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2010-04-12
Volume
107
Issue
16
Pages
7395-7400
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0912019107
PMC
PMC2867697
OpenAlex
W2133561122
Semantic Scholar
0a74263a532d129fa975e4c182d94d8a637b7c33
Cited by
442
References
53
Citations by year
2026: 11 · 2025: 12 · 2024: 22 · 2023: 15 · 2022: 16 · 2021: 20 · 2020: 21 · 2019: 23 · 2018: 25 · 2017: 21 · 2016: 29 · 2015: 33 · 2014: 34 · 2013: 47 · 2012: 51
FWCI
55.83
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
Funders
  • National Institutes of Health (5k12ey016335-17, 6u54rr020278-06)
  • National Heart, Lung, and Blood Institute (R01HL087676)
  • National Eye Institute (K12 EY16335, R01EY013435, R01 EY13435, K12-EY016335, R01 EY 11309, R01-EY11600, R01EY009769, R01EY011309, R24EY017404, R01EY011600)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR055688)
  • National Center for Research Resources (U54-RR020278)
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, hepatic lipase, HDL cholesterol, TIMP-3, copy number variation, genetic susceptibility, neovascular age-related macular degeneration, dry age-related macular degeneration, pleiotropy, ABCA1
MeSH terms
Delta-5 Fatty Acid Desaturase, Alleles, Gene Expression Regulation, Genotype, Humans, Lipase, Lipids, Cholesterol, HDL, Macular Degeneration, Risk, Case-Control Studies, Tissue Inhibitor of Metalloproteinase-3, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, 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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