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Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.

TitleInsights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.
Publication TypeJournal Article
Year of Publication2013
AuthorsHolliday EG, Smith AV, Cornes BK, Buitendijk GHS, Jensen RA, Sim X, Aspelund T, Aung T, Baird PN, Boerwinkle E, Cheng CYu, van Duijn CM, Eiriksdottir G, Gudnason V, Harris T, Hewitt AW, Inouye M, Jonasson F, Klein BEK, Launer L, Li X, Liew G, Lumley T, McElduff P, McKnight B, Mitchell P, Psaty BM, Rochtchina E, Rotter JI, Scott RJ, Tay W, Taylor K, Teo YYing, Uitterlinden AG, Viswanathan A, Xie S, Vingerling JR, Klaver CCW, E Tai S, Siscovick D, Klein R, Cotch M F, Wong TY, Attia J
Secondary AuthorsWang J J
Corporate AuthorsWellcome Trust Case Control Consortium 2
JournalPLoS One
Volume8
Issue1
Paginatione53830
Date Published2013
ISSN1932-6203
KeywordsApolipoproteins E, Complement Factor H, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Kruppel-Like Transcription Factors, Macular Degeneration, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Proteins, Risk Factors, Zinc Finger Protein Gli3
Abstract

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

DOI10.1371/journal.pone.0053830
Alternate JournalPLoS One
PubMed ID23326517
PubMed Central IDPMC3543264
Grant ListUL1RR025005 / RR / NCRR NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
ZIA EY000401-09 / / Intramural NIH HHS / United States
ZIA EY000401-13 / / Intramural NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
Z01 EY000426-05 / / Intramural NIH HHS / United States
Z99 EY999999 / / Intramural NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
N01-HC-85085 / HC / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
ZIA EY000401-11 / / Intramural NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
ZIA EY000426-10 / / Intramural NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
N01-HC-85081 / HC / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
ZIAEY000401 / / PHS HHS / United States
ZIA EY000426-13 / / Intramural NIH HHS / United States
AG-15928 / AG / NIA NIH HHS / United States
ZIA EY000426-08 / / Intramural NIH HHS / United States
ZIA EY000401-08 / / Intramural NIH HHS / United States
085475/B/08/Z / WT_ / Wellcome Trust / United Kingdom
R01 HL087652 / HL / NHLBI NIH HHS / United States
AG-20098 / AG / NIA NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
ZIA EY000401-12 / / Intramural NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
Z01 EY000426-04 / / Intramural NIH HHS / United States
ZIAAG007380 / / PHS HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
AG-027058 / AG / NIA NIH HHS / United States
ZIA EY000426-11 / / Intramural NIH HHS / United States
N01-HC-85082 / HC / NHLBI NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
N01-HC-85083 / HC / NHLBI NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-85080 / HC / NHLBI NIH HHS / United States
ZIA EY000401-15 / / Intramural NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
Z01 EY000401-06 / / Intramural NIH HHS / United States
ZIA EY000426-09 / / Intramural NIH HHS / United States
ZIA EY000426-07 / / Intramural NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
ZIA EY000426-12 / / Intramural NIH HHS / United States
N01-AG-12100 / AG / NIA NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
N01-HC-45133 / HC / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
ZIA EY000426-06 / / Intramural NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
N01-HC-85239 / HC / NHLBI NIH HHS / United States
AG-023629 / AG / NIA NIH HHS / United States
085475/08/Z / WT_ / Wellcome Trust / United Kingdom
R01 HL087641 / HL / NHLBI NIH HHS / United States
ZIA EY000401-14 / / Intramural NIH HHS / United States
Z01 EY000401-07 / / Intramural NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
N01-HC-85084 / HC / NHLBI NIH HHS / United States
ZIA EY000401-10 / / Intramural NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States