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

Benjamin M. Neale, Jesen Fagerness, Robyn Reynolds, Lucia Sobrin, Margaret Parker, Soumya Raychaudhuri, Perciliz L. Tan, Edwin C. Oh, Joanna E. Merriam, Eric Souied, Paul S. Bernstein, Binxing Li, Jeanne M. Frederick, Kang Zhang, Milam A. Brantley, Aaron Y. Lee, Donald J Zack, Betsy Campochiaro, Peter A Campochiaro, Stephan RipkeR. Theodore Smith, Gaetano R. Barile, Nicholas Katsanis, Rando Allikmets, Mark J. Daly, Johanna M. Seddon

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)7395-7400
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number16
DOIs
StatePublished - Apr 20 2010

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Genome-Wide Association Study
Macular Degeneration
Lipase
HDL Cholesterol
Liver
Genes
Alleles
DNA Copy Number Variations
Tissue Inhibitor of Metalloproteinase-3
Blindness
Serum
Proteins

Keywords

  • Complex disease
  • HDL
  • Lipid pathway
  • Retinal degeneration

ASJC Scopus subject areas

  • General

Cite this

Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). / Neale, Benjamin M.; Fagerness, Jesen; Reynolds, Robyn; Sobrin, Lucia; Parker, Margaret; Raychaudhuri, Soumya; Tan, Perciliz L.; Oh, Edwin C.; Merriam, Joanna E.; Souied, Eric; Bernstein, Paul S.; Li, Binxing; Frederick, Jeanne M.; Zhang, Kang; Brantley, Milam A.; Lee, Aaron Y.; Zack, Donald J; Campochiaro, Betsy; Campochiaro, Peter A; Ripke, Stephan; Smith, R. Theodore; Barile, Gaetano R.; Katsanis, Nicholas; Allikmets, Rando; Daly, Mark J.; Seddon, Johanna M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 16, 20.04.2010, p. 7395-7400.

Research output: Contribution to journalArticle

Neale, BM, Fagerness, J, Reynolds, R, Sobrin, L, Parker, M, Raychaudhuri, S, Tan, PL, Oh, EC, Merriam, JE, Souied, E, Bernstein, PS, Li, B, Frederick, JM, Zhang, K, Brantley, MA, Lee, AY, Zack, DJ, Campochiaro, B, Campochiaro, PA, Ripke, S, Smith, RT, Barile, GR, Katsanis, N, Allikmets, R, Daly, MJ & Seddon, JM 2010, 'Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC)', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 16, pp. 7395-7400. https://doi.org/10.1073/pnas.0912019107
Neale, Benjamin M. ; Fagerness, Jesen ; Reynolds, Robyn ; Sobrin, Lucia ; Parker, Margaret ; Raychaudhuri, Soumya ; Tan, Perciliz L. ; Oh, Edwin C. ; Merriam, Joanna E. ; Souied, Eric ; Bernstein, Paul S. ; Li, Binxing ; Frederick, Jeanne M. ; Zhang, Kang ; Brantley, Milam A. ; Lee, Aaron Y. ; Zack, Donald J ; Campochiaro, Betsy ; Campochiaro, Peter A ; Ripke, Stephan ; Smith, R. Theodore ; Barile, Gaetano R. ; Katsanis, Nicholas ; Allikmets, Rando ; Daly, Mark J. ; Seddon, Johanna M. / Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 16. pp. 7395-7400.
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AU - Neale, Benjamin M.

AU - Fagerness, Jesen

AU - Reynolds, Robyn

AU - Sobrin, Lucia

AU - Parker, Margaret

AU - Raychaudhuri, Soumya

AU - Tan, Perciliz L.

AU - Oh, Edwin C.

AU - Merriam, Joanna E.

AU - Souied, Eric

AU - Bernstein, Paul S.

AU - Li, Binxing

AU - Frederick, Jeanne M.

AU - Zhang, Kang

AU - Brantley, Milam A.

AU - Lee, Aaron Y.

AU - Zack, Donald J

AU - Campochiaro, Betsy

AU - Campochiaro, Peter A

AU - Ripke, Stephan

AU - Smith, R. Theodore

AU - Barile, Gaetano R.

AU - Katsanis, Nicholas

AU - Allikmets, Rando

AU - Daly, Mark J.

AU - Seddon, Johanna M.

PY - 2010/4/20

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N2 - 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.

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