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Genome-wide association study of retinopathy in individuals without diabetes.

TitleGenome-wide association study of retinopathy in individuals without diabetes.
Publication TypeJournal Article
Year of Publication2013
AuthorsJensen RA, Sim X, Li X, Cotch M F, M Ikram K, Holliday EG, Eiriksdottir G, Harris TB, Jonasson F, Klein BEK, Launer LJ, Smith A V, Boerwinkle E, Cheung N, Hewitt AW, Liew G, Mitchell P, Wang J J, Attia J, Scott R, Glazer NL, Lumley T, McKnight B, Psaty BM, Taylor K, Hofman A, de Jong PTVM, Rivadeneira F, Uitterlinden AG, Tay W-T, Teo YYing, Seielstad M, Liu J, Cheng C-Y, Saw S-M, Aung T, Ganesh SK, O'Donnell CJ, Nalls MA, Wiggins KL, Kuo JZ, van Duijn CM, Gudnason V, Klein R, Siscovick DS, Rotter JI, E Tai S, Vingerling J, Wong TY
Corporate AuthorsBlue Mountains Eye Study GWAS Team, CKDGen Consortium
JournalPLoS One
Volume8
Issue2
Paginatione54232
Date Published2013
ISSN1932-6203
KeywordsAged, Aged, 80 and over, Female, Genome-Wide Association Study, Genotype, Histone Deacetylases, Humans, Hypertension, Male, Polymorphism, Single Nucleotide, Repressor Proteins, Retinal Diseases
Abstract

BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.

METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.

RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.

CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

DOI10.1371/journal.pone.0054232
Alternate JournalPLoS One
PubMed ID23393555
PubMed Central IDPMC3564946
Grant ListZ01 EY000426-05 / ImNIH / Intramural NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
ZIA EY000403-10 / ImNIH / Intramural NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
Z01 EY000403-06 / ImNIH / Intramural NIH HHS / United States
ZIA EY000426-09 / ImNIH / Intramural NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
ZIA EY000401-09 / ImNIH / Intramural NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
ZIA EY000401-13 / ImNIH / Intramural NIH HHS / United States
UL1RR033176 / RR / NCRR NIH HHS / United States
R01 HL075366 / HL / NHLBI NIH HHS / United States
AG027058 / AG / NIA NIH HHS / United States
AG15928 / AG / NIA NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
Z99 EY999999 / ImNIH / Intramural NIH HHS / United States
N01HC85239 / HC / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
HHSN2682011000010C / / PHS HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
ZIA EY000401-11 / ImNIH / Intramural NIH HHS / United States
ZIA EY000403-13 / ImNIH / Intramural NIH HHS / United States
ZIA EY000426-10 / ImNIH / Intramural NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
N01HC95159 / HC / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
ZIAEY000401 / / PHS HHS / United States
N01HC95169 / HL / NHLBI NIH HHS / United States
ZIA EY000426-13 / ImNIH / Intramural NIH HHS / United States
ZIA AG007380 / ImNIH / Intramural NIH HHS / United States
R56 AG020098 / AG / NIA NIH HHS / United States
ZIA EY000403-14 / ImNIH / Intramural NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
ZIA EY000401 / ImNIH / Intramural NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
UL1 RR024156 / RR / NCRR NIH HHS / United States
ZIA EY000426-08 / ImNIH / Intramural NIH HHS / United States
ZIA EY000401-08 / ImNIH / Intramural NIH HHS / United States
085475/B/08/Z / WT_ / Wellcome Trust / United Kingdom
R01 HL087652 / HL / NHLBI NIH HHS / United States
ZIA EY000403-11 / ImNIH / Intramural NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
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U01HG004402 / HG / NHGRI NIH HHS / United States
ZIA EY000426-11 / ImNIH / Intramural NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HL075366 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
ZIA EY000403-09 / ImNIH / Intramural NIH HHS / United States
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HHSN2682011000012C / / PHS HHS / United States
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Z01 EY000401-06 / ImNIH / Intramural NIH HHS / United States
ZIA EY000426-07 / ImNIH / Intramural NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
RR024156 / RR / NCRR NIH HHS / United States
ZIA EY000426-12 / ImNIH / Intramural NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N02HL64278 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
ZIA EY000426-06 / ImNIH / Intramural NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
N01HC15103 / HC / NHLBI NIH HHS / United States
AG20098 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
ZIA EY000403-15 / ImNIH / Intramural NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
085475/08/Z / WT_ / Wellcome Trust / United Kingdom
N01HC35129 / HC / NHLBI NIH HHS / United States
R01 AG027058 / AG / NIA NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
AG023629 / AG / NIA NIH HHS / United States
ZIA EY000401-14 / ImNIH / Intramural NIH HHS / United States
Z01 EY000401-07 / ImNIH / Intramural NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
ZIA EY000401-10 / ImNIH / Intramural NIH HHS / United States
ZIA EY000403-12 / ImNIH / Intramural NIH HHS / United States
N01 HC095159 / HC / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
HHSN2682011000011C / / PHS HHS / United States