Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration

Rinki Ratnapriya, Xiaowei Zhan, Robert N. Fariss, Kari E. Branham, David Zipprer, Christina F. Chakarova, Yuri V. Sergeev, Maria M. Campos, Mohammad Othman, James S. Friedman, Arvydas Maminishkis, Naushin H. Waseem, Matthew Brooks, Harsha K. Rajasimha, Albert O. Edwards, Andrew Lotery, Barbara E. Klein, Barbara J. Truitt, Bingshan Li, Debra A. SchaumbergDenise J. Morgan, Margaux A. Morrison, Eric Souied, Evangelia E. Tsironi, Felix Grassmann, Gerald A. Fishman, Giuliana Silvestri, Hendrik P N Scholl, Ivana K. Kim, Jacqueline Ramke, Jingsheng Tuo, Joanna E. Merriam, John C. Merriam, Kyu Hyung Park, Lana M. Olson, Lindsay A. Farrer, Matthew P. Johnson, Neal S. Peachey, Mark Lathrop, Robert V. Baron, Robert P. Igo, Ronald Klein, Stephanie A. Hagstrom, Yoichiro Kamatani, Tammy M. Martin, Yingda Jiang, Yvette Conley, Jose Alan Sahel, Donald J. Zack, Chi Chao Chan, Margaret A. Pericak-Vance, Samuel G. Jacobson, Michael B. Gorin, Michael L. Klein, Rando Allikmets, Sudha K. Iyengar, Bernhard H. Weber, Jonathan L. Haines, Thierry Léveillard, Margaret M. Deangelis, Dwight Stambolian, Daniel E. Weeks, Shomi S. Bhattacharya, Emily Y. Chew, John R. Heckenlively, Gonçalo R. Abecasis, Anand Swaroop

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Neurodegenerative diseases affecting the macula constitute amajor cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial lateonset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominantmaculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-richextracellular matrix (ECM). Sangersequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch'smembrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR 5 1.10; P-value 5 3.79 3× 10-5). Thus, it appears that rare and common variants in a single gene-FBN2-can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

Original languageEnglish (US)
Pages (from-to)5827-5837
Number of pages11
JournalHuman Molecular Genetics
Volume23
Issue number21
DOIs
StatePublished - Nov 1 2014

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Macular Degeneration
Extracellular Matrix
Genes
Elastin
Bruch Membrane
Exome
Genetic Heterogeneity
Pedigree
Rare Diseases
Neurodegenerative Diseases
Retina
Fibrillin-2
Glycoproteins
Homeostasis
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Ratnapriya, R., Zhan, X., Fariss, R. N., Branham, K. E., Zipprer, D., Chakarova, C. F., ... Swaroop, A. (2014). Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration. Human Molecular Genetics, 23(21), 5827-5837. https://doi.org/10.1093/hmg/ddu276

Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration. / Ratnapriya, Rinki; Zhan, Xiaowei; Fariss, Robert N.; Branham, Kari E.; Zipprer, David; Chakarova, Christina F.; Sergeev, Yuri V.; Campos, Maria M.; Othman, Mohammad; Friedman, James S.; Maminishkis, Arvydas; Waseem, Naushin H.; Brooks, Matthew; Rajasimha, Harsha K.; Edwards, Albert O.; Lotery, Andrew; Klein, Barbara E.; Truitt, Barbara J.; Li, Bingshan; Schaumberg, Debra A.; Morgan, Denise J.; Morrison, Margaux A.; Souied, Eric; Tsironi, Evangelia E.; Grassmann, Felix; Fishman, Gerald A.; Silvestri, Giuliana; Scholl, Hendrik P N; Kim, Ivana K.; Ramke, Jacqueline; Tuo, Jingsheng; Merriam, Joanna E.; Merriam, John C.; Park, Kyu Hyung; Olson, Lana M.; Farrer, Lindsay A.; Johnson, Matthew P.; Peachey, Neal S.; Lathrop, Mark; Baron, Robert V.; Igo, Robert P.; Klein, Ronald; Hagstrom, Stephanie A.; Kamatani, Yoichiro; Martin, Tammy M.; Jiang, Yingda; Conley, Yvette; Sahel, Jose Alan; Zack, Donald J.; Chan, Chi Chao; Pericak-Vance, Margaret A.; Jacobson, Samuel G.; Gorin, Michael B.; Klein, Michael L.; Allikmets, Rando; Iyengar, Sudha K.; Weber, Bernhard H.; Haines, Jonathan L.; Léveillard, Thierry; Deangelis, Margaret M.; Stambolian, Dwight; Weeks, Daniel E.; Bhattacharya, Shomi S.; Chew, Emily Y.; Heckenlively, John R.; Abecasis, Gonçalo R.; Swaroop, Anand.

In: Human Molecular Genetics, Vol. 23, No. 21, 01.11.2014, p. 5827-5837.

Research output: Contribution to journalArticle

Ratnapriya, R, Zhan, X, Fariss, RN, Branham, KE, Zipprer, D, Chakarova, CF, Sergeev, YV, Campos, MM, Othman, M, Friedman, JS, Maminishkis, A, Waseem, NH, Brooks, M, Rajasimha, HK, Edwards, AO, Lotery, A, Klein, BE, Truitt, BJ, Li, B, Schaumberg, DA, Morgan, DJ, Morrison, MA, Souied, E, Tsironi, EE, Grassmann, F, Fishman, GA, Silvestri, G, Scholl, HPN, Kim, IK, Ramke, J, Tuo, J, Merriam, JE, Merriam, JC, Park, KH, Olson, LM, Farrer, LA, Johnson, MP, Peachey, NS, Lathrop, M, Baron, RV, Igo, RP, Klein, R, Hagstrom, SA, Kamatani, Y, Martin, TM, Jiang, Y, Conley, Y, Sahel, JA, Zack, DJ, Chan, CC, Pericak-Vance, MA, Jacobson, SG, Gorin, MB, Klein, ML, Allikmets, R, Iyengar, SK, Weber, BH, Haines, JL, Léveillard, T, Deangelis, MM, Stambolian, D, Weeks, DE, Bhattacharya, SS, Chew, EY, Heckenlively, JR, Abecasis, GR & Swaroop, A 2014, 'Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration', Human Molecular Genetics, vol. 23, no. 21, pp. 5827-5837. https://doi.org/10.1093/hmg/ddu276
Ratnapriya, Rinki ; Zhan, Xiaowei ; Fariss, Robert N. ; Branham, Kari E. ; Zipprer, David ; Chakarova, Christina F. ; Sergeev, Yuri V. ; Campos, Maria M. ; Othman, Mohammad ; Friedman, James S. ; Maminishkis, Arvydas ; Waseem, Naushin H. ; Brooks, Matthew ; Rajasimha, Harsha K. ; Edwards, Albert O. ; Lotery, Andrew ; Klein, Barbara E. ; Truitt, Barbara J. ; Li, Bingshan ; Schaumberg, Debra A. ; Morgan, Denise J. ; Morrison, Margaux A. ; Souied, Eric ; Tsironi, Evangelia E. ; Grassmann, Felix ; Fishman, Gerald A. ; Silvestri, Giuliana ; Scholl, Hendrik P N ; Kim, Ivana K. ; Ramke, Jacqueline ; Tuo, Jingsheng ; Merriam, Joanna E. ; Merriam, John C. ; Park, Kyu Hyung ; Olson, Lana M. ; Farrer, Lindsay A. ; Johnson, Matthew P. ; Peachey, Neal S. ; Lathrop, Mark ; Baron, Robert V. ; Igo, Robert P. ; Klein, Ronald ; Hagstrom, Stephanie A. ; Kamatani, Yoichiro ; Martin, Tammy M. ; Jiang, Yingda ; Conley, Yvette ; Sahel, Jose Alan ; Zack, Donald J. ; Chan, Chi Chao ; Pericak-Vance, Margaret A. ; Jacobson, Samuel G. ; Gorin, Michael B. ; Klein, Michael L. ; Allikmets, Rando ; Iyengar, Sudha K. ; Weber, Bernhard H. ; Haines, Jonathan L. ; Léveillard, Thierry ; Deangelis, Margaret M. ; Stambolian, Dwight ; Weeks, Daniel E. ; Bhattacharya, Shomi S. ; Chew, Emily Y. ; Heckenlively, John R. ; Abecasis, Gonçalo R. ; Swaroop, Anand. / Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 21. pp. 5827-5837.
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title = "Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration",
abstract = "Neurodegenerative diseases affecting the macula constitute amajor cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial lateonset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominantmaculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-richextracellular matrix (ECM). Sangersequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch'smembrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR 5 1.10; P-value 5 3.79 3× 10-5). Thus, it appears that rare and common variants in a single gene-FBN2-can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.",
author = "Rinki Ratnapriya and Xiaowei Zhan and Fariss, {Robert N.} and Branham, {Kari E.} and David Zipprer and Chakarova, {Christina F.} and Sergeev, {Yuri V.} and Campos, {Maria M.} and Mohammad Othman and Friedman, {James S.} and Arvydas Maminishkis and Waseem, {Naushin H.} and Matthew Brooks and Rajasimha, {Harsha K.} and Edwards, {Albert O.} and Andrew Lotery and Klein, {Barbara E.} and Truitt, {Barbara J.} and Bingshan Li and Schaumberg, {Debra A.} and Morgan, {Denise J.} and Morrison, {Margaux A.} and Eric Souied and Tsironi, {Evangelia E.} and Felix Grassmann and Fishman, {Gerald A.} and Giuliana Silvestri and Scholl, {Hendrik P N} and Kim, {Ivana K.} and Jacqueline Ramke and Jingsheng Tuo and Merriam, {Joanna E.} and Merriam, {John C.} and Park, {Kyu Hyung} and Olson, {Lana M.} and Farrer, {Lindsay A.} and Johnson, {Matthew P.} and Peachey, {Neal S.} and Mark Lathrop and Baron, {Robert V.} and Igo, {Robert P.} and Ronald Klein and Hagstrom, {Stephanie A.} and Yoichiro Kamatani and Martin, {Tammy M.} and Yingda Jiang and Yvette Conley and Sahel, {Jose Alan} and Zack, {Donald J.} and Chan, {Chi Chao} and Pericak-Vance, {Margaret A.} and Jacobson, {Samuel G.} and Gorin, {Michael B.} and Klein, {Michael L.} and Rando Allikmets and Iyengar, {Sudha K.} and Weber, {Bernhard H.} and Haines, {Jonathan L.} and Thierry L{\'e}veillard and Deangelis, {Margaret M.} and Dwight Stambolian and Weeks, {Daniel E.} and Bhattacharya, {Shomi S.} and Chew, {Emily Y.} and Heckenlively, {John R.} and Abecasis, {Gon{\cc}alo R.} and Anand Swaroop",
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T1 - Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration

AU - Ratnapriya, Rinki

AU - Zhan, Xiaowei

AU - Fariss, Robert N.

AU - Branham, Kari E.

AU - Zipprer, David

AU - Chakarova, Christina F.

AU - Sergeev, Yuri V.

AU - Campos, Maria M.

AU - Othman, Mohammad

AU - Friedman, James S.

AU - Maminishkis, Arvydas

AU - Waseem, Naushin H.

AU - Brooks, Matthew

AU - Rajasimha, Harsha K.

AU - Edwards, Albert O.

AU - Lotery, Andrew

AU - Klein, Barbara E.

AU - Truitt, Barbara J.

AU - Li, Bingshan

AU - Schaumberg, Debra A.

AU - Morgan, Denise J.

AU - Morrison, Margaux A.

AU - Souied, Eric

AU - Tsironi, Evangelia E.

AU - Grassmann, Felix

AU - Fishman, Gerald A.

AU - Silvestri, Giuliana

AU - Scholl, Hendrik P N

AU - Kim, Ivana K.

AU - Ramke, Jacqueline

AU - Tuo, Jingsheng

AU - Merriam, Joanna E.

AU - Merriam, John C.

AU - Park, Kyu Hyung

AU - Olson, Lana M.

AU - Farrer, Lindsay A.

AU - Johnson, Matthew P.

AU - Peachey, Neal S.

AU - Lathrop, Mark

AU - Baron, Robert V.

AU - Igo, Robert P.

AU - Klein, Ronald

AU - Hagstrom, Stephanie A.

AU - Kamatani, Yoichiro

AU - Martin, Tammy M.

AU - Jiang, Yingda

AU - Conley, Yvette

AU - Sahel, Jose Alan

AU - Zack, Donald J.

AU - Chan, Chi Chao

AU - Pericak-Vance, Margaret A.

AU - Jacobson, Samuel G.

AU - Gorin, Michael B.

AU - Klein, Michael L.

AU - Allikmets, Rando

AU - Iyengar, Sudha K.

AU - Weber, Bernhard H.

AU - Haines, Jonathan L.

AU - Léveillard, Thierry

AU - Deangelis, Margaret M.

AU - Stambolian, Dwight

AU - Weeks, Daniel E.

AU - Bhattacharya, Shomi S.

AU - Chew, Emily Y.

AU - Heckenlively, John R.

AU - Abecasis, Gonçalo R.

AU - Swaroop, Anand

PY - 2014/11/1

Y1 - 2014/11/1

N2 - Neurodegenerative diseases affecting the macula constitute amajor cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial lateonset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominantmaculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-richextracellular matrix (ECM). Sangersequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch'smembrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR 5 1.10; P-value 5 3.79 3× 10-5). Thus, it appears that rare and common variants in a single gene-FBN2-can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

AB - Neurodegenerative diseases affecting the macula constitute amajor cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial lateonset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominantmaculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-richextracellular matrix (ECM). Sangersequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch'smembrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR 5 1.10; P-value 5 3.79 3× 10-5). Thus, it appears that rare and common variants in a single gene-FBN2-can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

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