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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
Secondary AuthorsWong 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 ListUL1RR025005 / RR / NCRR NIH HHS / United States
ZIA EY000401-09 / / Intramural NIH HHS / United States
ZIA EY000401-13 / / Intramural NIH HHS / United States
UL1RR033176 / RR / NCRR NIH HHS / United States
AG027058 / AG / NIA NIH HHS / United States
AG15928 / AG / NIA NIH HHS / United States
Z01 EY000426-05 / / Intramural NIH HHS / United States
Z99 EY999999 / / Intramural NIH HHS / United States
N01HC85239 / HC / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN2682011000010C / / PHS HHS / United States
ZIA EY000401-11 / / Intramural NIH HHS / United States
ZIA EY000403-13 / / Intramural NIH HHS / United States
ZIA EY000426-10 / / Intramural NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
N01HC95159 / HC / NHLBI NIH HHS / United States
ZIAEY000401 / / PHS HHS / United States
ZIA EY000426-13 / / Intramural NIH HHS / United States
085475/08/Z / / Wellcome Trust / United Kingdom
HHSN268201100009C / / PHS HHS / United States
ZIA EY000403-14 / / Intramural NIH HHS / United States
ZIA EY000426-08 / / Intramural NIH HHS / United States
ZIA EY000401-08 / / Intramural NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
ZIA EY000403-11 / / Intramural 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
Z01 EY000426-04 / / Intramural NIH HHS / United States
ZIAAG007380 / / PHS HHS / United States
N01HC45133 / HC / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
ZIA EY000426-11 / / Intramural NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
ZIA EY000403-10 / / Intramural NIH HHS / United States
N01HC95169 / HC / NHLBI NIH HHS / United States
HL075366 / HL / NHLBI NIH HHS / United States
N01HC85079 / HC / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
ZIA EY000403-09 / / Intramural NIH HHS / United States
Z01 EY000403-06 / / Intramural NIH HHS / United States
N01HC85086 / HC / NHLBI NIH HHS / United States
ZIA EY000403-08 / / Intramural NIH HHS / United States
HHSN2682011000012C / / PHS HHS / United States
ZIA EY000401-15 / / Intramural NIH HHS / United States
Z01 EY000403-07 / / Intramural NIH HHS / United States
Z01 EY000401-06 / / Intramural NIH HHS / United States
085475/B/08/Z / / Wellcome Trust / United Kingdom
HHSN268201100007C / / PHS HHS / United States
ZIA EY000426-09 / / Intramural NIH HHS / United States
ZIA EY000426-07 / / Intramural NIH HHS / United States
RR024156 / RR / NCRR NIH HHS / United States
ZIA EY000426-12 / / Intramural NIH HHS / United States
N01HC75150 / HC / NHLBI NIH HHS / United States
N02HL64278 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
/ / Wellcome Trust / United Kingdom
N01HC15103 / HC / NHLBI NIH HHS / United States
ZIA EY000426-06 / / Intramural NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
AG20098 / AG / NIA NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
ZIA EY000403-15 / / Intramural NIH HHS / United States
N01HC35129 / HC / NHLBI NIH HHS / United States
AG023629 / AG / NIA NIH HHS / United States
ZIA EY000401-14 / / Intramural NIH HHS / United States
Z01 EY000401-07 / / Intramural NIH HHS / United States
ZIA EY000401-10 / / Intramural NIH HHS / United States
ZIA EY000403-12 / / Intramural NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
HHSN2682011000011C / / PHS HHS / United States