A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration

Theru A. Sivakumaran, Robert P. Igo, Jeffrey M. Kidd, Andy Itsara, Laura J. Kopplin, Wei Chen, Stephanie A. Hagstrom, Neal S. Peachey, Peter J. Francis, Michael Klein, Emily Y. Chew, Vedam L. Ramprasad, Wan Ting Tay, Paul Mitchell, Mark Seielstad, Dwight E. Stambolian, Albert O. Edwards, Kristine E. Lee, Dmitry V. Leontiev, Gyungah JunYang Wang, Liping Tian, Feiyou Qiu, Alice K. Henning, Thomas LaFramboise, Parveen Sen, Manoharan Aarthi, Ronnie George, Rajiv Raman, Manmath Kumar Das, Lingam Vijaya, Govindasamy Kumaramanickavel, Tien Y. Wong, Anand Swaroop, Goncalo R. Abecasis, Ronald Klein, Barbara E K Klein, Deborah A. Nickerson, Evan E. Eichler, Sudha K. Iyengar

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N= 293) and AMD cases (White N= 4210 Indian= 134; Malay= 140) and controls (White N= 3229; Indian= 117; Malay= 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p= 8.31×10 -109); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10 -9) and by 15.57-fold (P= 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.

Original languageEnglish (US)
Article numbere25598
JournalPLoS One
Volume6
Issue number10
DOIs
StatePublished - Oct 12 2011

Fingerprint

Macular Degeneration
Haplotypes
haplotypes
Complement Factor H
Polymorphism
Regression analysis
Single Nucleotide Polymorphism
DNA Copy Number Variations
extended families
macular degeneration
polymorphism
complement
regression analysis
Regression Analysis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Sivakumaran, T. A., Igo, R. P., Kidd, J. M., Itsara, A., Kopplin, L. J., Chen, W., ... Iyengar, S. K. (2011). A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration. PLoS One, 6(10), [e25598]. https://doi.org/10.1371/journal.pone.0025598

A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration. / Sivakumaran, Theru A.; Igo, Robert P.; Kidd, Jeffrey M.; Itsara, Andy; Kopplin, Laura J.; Chen, Wei; Hagstrom, Stephanie A.; Peachey, Neal S.; Francis, Peter J.; Klein, Michael; Chew, Emily Y.; Ramprasad, Vedam L.; Tay, Wan Ting; Mitchell, Paul; Seielstad, Mark; Stambolian, Dwight E.; Edwards, Albert O.; Lee, Kristine E.; Leontiev, Dmitry V.; Jun, Gyungah; Wang, Yang; Tian, Liping; Qiu, Feiyou; Henning, Alice K.; LaFramboise, Thomas; Sen, Parveen; Aarthi, Manoharan; George, Ronnie; Raman, Rajiv; Das, Manmath Kumar; Vijaya, Lingam; Kumaramanickavel, Govindasamy; Wong, Tien Y.; Swaroop, Anand; Abecasis, Goncalo R.; Klein, Ronald; Klein, Barbara E K; Nickerson, Deborah A.; Eichler, Evan E.; Iyengar, Sudha K.

In: PLoS One, Vol. 6, No. 10, e25598, 12.10.2011.

Research output: Contribution to journalArticle

Sivakumaran, TA, Igo, RP, Kidd, JM, Itsara, A, Kopplin, LJ, Chen, W, Hagstrom, SA, Peachey, NS, Francis, PJ, Klein, M, Chew, EY, Ramprasad, VL, Tay, WT, Mitchell, P, Seielstad, M, Stambolian, DE, Edwards, AO, Lee, KE, Leontiev, DV, Jun, G, Wang, Y, Tian, L, Qiu, F, Henning, AK, LaFramboise, T, Sen, P, Aarthi, M, George, R, Raman, R, Das, MK, Vijaya, L, Kumaramanickavel, G, Wong, TY, Swaroop, A, Abecasis, GR, Klein, R, Klein, BEK, Nickerson, DA, Eichler, EE & Iyengar, SK 2011, 'A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration', PLoS One, vol. 6, no. 10, e25598. https://doi.org/10.1371/journal.pone.0025598
Sivakumaran TA, Igo RP, Kidd JM, Itsara A, Kopplin LJ, Chen W et al. A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration. PLoS One. 2011 Oct 12;6(10). e25598. https://doi.org/10.1371/journal.pone.0025598
Sivakumaran, Theru A. ; Igo, Robert P. ; Kidd, Jeffrey M. ; Itsara, Andy ; Kopplin, Laura J. ; Chen, Wei ; Hagstrom, Stephanie A. ; Peachey, Neal S. ; Francis, Peter J. ; Klein, Michael ; Chew, Emily Y. ; Ramprasad, Vedam L. ; Tay, Wan Ting ; Mitchell, Paul ; Seielstad, Mark ; Stambolian, Dwight E. ; Edwards, Albert O. ; Lee, Kristine E. ; Leontiev, Dmitry V. ; Jun, Gyungah ; Wang, Yang ; Tian, Liping ; Qiu, Feiyou ; Henning, Alice K. ; LaFramboise, Thomas ; Sen, Parveen ; Aarthi, Manoharan ; George, Ronnie ; Raman, Rajiv ; Das, Manmath Kumar ; Vijaya, Lingam ; Kumaramanickavel, Govindasamy ; Wong, Tien Y. ; Swaroop, Anand ; Abecasis, Goncalo R. ; Klein, Ronald ; Klein, Barbara E K ; Nickerson, Deborah A. ; Eichler, Evan E. ; Iyengar, Sudha K. / A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration. In: PLoS One. 2011 ; Vol. 6, No. 10.
@article{a40e781de8de4fc6994d6a406ffdf8ad,
title = "A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration",
abstract = "Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N= 293) and AMD cases (White N= 4210 Indian= 134; Malay= 140) and controls (White N= 3229; Indian= 117; Malay= 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95{\%} CI = [2.51, 3.01]; p= 8.31×10 -109); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10 -9) and by 15.57-fold (P= 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89{\%} similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.",
author = "Sivakumaran, {Theru A.} and Igo, {Robert P.} and Kidd, {Jeffrey M.} and Andy Itsara and Kopplin, {Laura J.} and Wei Chen and Hagstrom, {Stephanie A.} and Peachey, {Neal S.} and Francis, {Peter J.} and Michael Klein and Chew, {Emily Y.} and Ramprasad, {Vedam L.} and Tay, {Wan Ting} and Paul Mitchell and Mark Seielstad and Stambolian, {Dwight E.} and Edwards, {Albert O.} and Lee, {Kristine E.} and Leontiev, {Dmitry V.} and Gyungah Jun and Yang Wang and Liping Tian and Feiyou Qiu and Henning, {Alice K.} and Thomas LaFramboise and Parveen Sen and Manoharan Aarthi and Ronnie George and Rajiv Raman and Das, {Manmath Kumar} and Lingam Vijaya and Govindasamy Kumaramanickavel and Wong, {Tien Y.} and Anand Swaroop and Abecasis, {Goncalo R.} and Ronald Klein and Klein, {Barbara E K} and Nickerson, {Deborah A.} and Eichler, {Evan E.} and Iyengar, {Sudha K.}",
year = "2011",
month = "10",
day = "12",
doi = "10.1371/journal.pone.0025598",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration

AU - Sivakumaran, Theru A.

AU - Igo, Robert P.

AU - Kidd, Jeffrey M.

AU - Itsara, Andy

AU - Kopplin, Laura J.

AU - Chen, Wei

AU - Hagstrom, Stephanie A.

AU - Peachey, Neal S.

AU - Francis, Peter J.

AU - Klein, Michael

AU - Chew, Emily Y.

AU - Ramprasad, Vedam L.

AU - Tay, Wan Ting

AU - Mitchell, Paul

AU - Seielstad, Mark

AU - Stambolian, Dwight E.

AU - Edwards, Albert O.

AU - Lee, Kristine E.

AU - Leontiev, Dmitry V.

AU - Jun, Gyungah

AU - Wang, Yang

AU - Tian, Liping

AU - Qiu, Feiyou

AU - Henning, Alice K.

AU - LaFramboise, Thomas

AU - Sen, Parveen

AU - Aarthi, Manoharan

AU - George, Ronnie

AU - Raman, Rajiv

AU - Das, Manmath Kumar

AU - Vijaya, Lingam

AU - Kumaramanickavel, Govindasamy

AU - Wong, Tien Y.

AU - Swaroop, Anand

AU - Abecasis, Goncalo R.

AU - Klein, Ronald

AU - Klein, Barbara E K

AU - Nickerson, Deborah A.

AU - Eichler, Evan E.

AU - Iyengar, Sudha K.

PY - 2011/10/12

Y1 - 2011/10/12

N2 - Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N= 293) and AMD cases (White N= 4210 Indian= 134; Malay= 140) and controls (White N= 3229; Indian= 117; Malay= 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p= 8.31×10 -109); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10 -9) and by 15.57-fold (P= 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.

AB - Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N= 293) and AMD cases (White N= 4210 Indian= 134; Malay= 140) and controls (White N= 3229; Indian= 117; Malay= 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p= 8.31×10 -109); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10 -9) and by 15.57-fold (P= 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.

UR - http://www.scopus.com/inward/record.url?scp=80053938930&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053938930&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0025598

DO - 10.1371/journal.pone.0025598

M3 - Article

C2 - 22022419

AN - SCOPUS:80053938930

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e25598

ER -