TY - JOUR
T1 - Investigating the modulation of genetic effects on late AMD by age and sex
T2 - Lessons learned and two additional loci
AU - Winkler, Thomas W.
AU - Brandl, Caroline
AU - Grassmann, Felix
AU - Gorski, Mathias
AU - Stark, Klaus
AU - Loss, Julika
AU - Weber, Bernhard H.F.
AU - Heid, Iris M.
AU - for the International Age-related Macular Degeneration Genomics Consortium (IAMDGC)
N1 - Funding: The authors gratefully acknowledge the excellent International Age-related Macular Degeneration Genomics Consortium (IAMDGC), (http://amdgenetics.org/). This analyses are supported by grants from the German Federal Ministry of Education and Research (BMBF 01ER1206, BMBF 01ER1507 to IMH, and BMBF 01GP1308) to JL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2018/3/12
Y1 - 2018/3/12
N2 - Late-stage age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly with a complex etiology. The most important non-modifiable risk factors for onset and progression of late AMD are age and genetic risk factors, however, little is known about the interplay between genetics and age or sex. Here, we conducted a large-scale age- and sex-stratified genome-wide association study (GWAS) using 1000 Genomes imputed genome-wide and ExomeChip data (>12 million variants). The data were established by the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) from 16,144 late AMD cases and 17,832 controls. Our systematic search for interaction effects yielded significantly stronger effects among younger individuals at two known AMD loci (near CFH and ARMS2/HTRA1). Accounting for age and gene-age interaction using a joint test identified two additional AMD loci compared to the previous main effect scan. One of these two is a novel AMD GWAS locus, near the retinal clusterin-like protein (CLUL1) gene, and the other, near the retinaldehyde binding protein 1 (RLBP1), was recently identified in a joint analysis of nuclear and mitochondrial variants. Despite considerable power in our data, neither sex-dependent effects nor effects with opposite directions between younger and older individuals were observed. This is the first genome-wide interaction study to incorporate age, sex and their interaction with genetic effects for late AMD. Results diminish the potential for a role of sex in the etiology of late AMD yet highlight the importance and existence of age-dependent genetic effects.
AB - Late-stage age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly with a complex etiology. The most important non-modifiable risk factors for onset and progression of late AMD are age and genetic risk factors, however, little is known about the interplay between genetics and age or sex. Here, we conducted a large-scale age- and sex-stratified genome-wide association study (GWAS) using 1000 Genomes imputed genome-wide and ExomeChip data (>12 million variants). The data were established by the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) from 16,144 late AMD cases and 17,832 controls. Our systematic search for interaction effects yielded significantly stronger effects among younger individuals at two known AMD loci (near CFH and ARMS2/HTRA1). Accounting for age and gene-age interaction using a joint test identified two additional AMD loci compared to the previous main effect scan. One of these two is a novel AMD GWAS locus, near the retinal clusterin-like protein (CLUL1) gene, and the other, near the retinaldehyde binding protein 1 (RLBP1), was recently identified in a joint analysis of nuclear and mitochondrial variants. Despite considerable power in our data, neither sex-dependent effects nor effects with opposite directions between younger and older individuals were observed. This is the first genome-wide interaction study to incorporate age, sex and their interaction with genetic effects for late AMD. Results diminish the potential for a role of sex in the etiology of late AMD yet highlight the importance and existence of age-dependent genetic effects.
UR - http://www.scopus.com/inward/record.url?scp=85043716404&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0194321
DO - 10.1371/journal.pone.0194321
M3 - Article
C2 - 29529059
AN - SCOPUS:85043716404
SN - 1932-6203
VL - 13
JO - PloS ONE
JF - PloS ONE
IS - 3
M1 - e0194321
ER -