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1.  A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants 
Fritsche, Lars G. | Igl, Wilmar | Cooke Bailey, Jessica N. | Grassmann, Felix | Sengupta, Sebanti | Bragg-Gresham, Jennifer L. | Burdon, Kathryn P. | Hebbring, Scott J. | Wen, Cindy | Gorski, Mathias | Kim, Ivana K. | Cho, David | Zack, Donald | Souied, Eric | Scholl, Hendrik P. N. | Bala, Elisa | Lee, Kristine E. | Hunter, David J. | Sardell, Rebecca J. | Mitchell, Paul | Merriam, Joanna E. | Cipriani, Valentina | Hoffman, Joshua D. | Schick, Tina | Lechanteur, Yara T. E. | Guymer, Robyn H. | Johnson, Matthew P. | Jiang, Yingda | Stanton, Chloe M. | Buitendijk, Gabriëlle H. S. | Zhan, Xiaowei | Kwong, Alan M. | Boleda, Alexis | Brooks, Matthew | Gieser, Linn | Ratnapriya, Rinki | Branham, Kari E. | Foerster, Johanna R. | Heckenlively, John R. | Othman, Mohammad I. | Vote, Brendan J. | Liang, Helena Hai | Souzeau, Emmanuelle | McAllister, Ian L. | Isaacs, Timothy | Hall, Janette | Lake, Stewart | Mackey, David A. | Constable, Ian J. | Craig, Jamie E. | Kitchner, Terrie E. | Yang, Zhenglin | Su, Zhiguang | Luo, Hongrong | Chen, Daniel | Ouyang, Hong | Flagg, Ken | Lin, Danni | Mao, Guanping | Ferreyra, Henry | Stark, Klaus | von Strachwitz, Claudia N. | Wolf, Armin | Brandl, Caroline | Rudolph, Guenther | Olden, Matthias | Morrison, Margaux A. | Morgan, Denise J. | Schu, Matthew | Ahn, Jeeyun | Silvestri, Giuliana | Tsironi, Evangelia E. | Park, Kyu Hyung | Farrer, Lindsay A. | Orlin, Anton | Brucker, Alexander | Li, Mingyao | Curcio, Christine | Mohand-Saïd, Saddek | Sahel, José-Alain | Audo, Isabelle | Benchaboune, Mustapha | Cree, Angela J. | Rennie, Christina A. | Goverdhan, Srinivas V. | Grunin, Michelle | Hagbi-Levi, Shira | Campochiaro, Peter | Katsanis, Nicholas | Holz, Frank G. | Blond, Frédéric | Blanché, Hélène | Deleuze, Jean-François | Igo, Robert P. | Truitt, Barbara | Peachey, Neal S. | Meuer, Stacy M. | Myers, Chelsea E. | Moore, Emily L. | Klein, Ronald | Hauser, Michael A. | Postel, Eric A. | Courtenay, Monique D. | Schwartz, Stephen G. | Kovach, Jaclyn L. | Scott, William K. | Liew, Gerald | Tƒan, Ava G. | Gopinath, Bamini | Merriam, John C. | Smith, R. Theodore | Khan, Jane C. | Shahid, Humma | Moore, Anthony T. | McGrath, J. Allie | Laux, Reneé | Brantley, Milam A. | Agarwal, Anita | Ersoy, Lebriz | Caramoy, Albert | Langmann, Thomas | Saksens, Nicole T. M. | de Jong, Eiko K. | Hoyng, Carel B. | Cain, Melinda S. | Richardson, Andrea J. | Martin, Tammy M. | Blangero, John | Weeks, Daniel E. | Dhillon, Bal | van Duijn, Cornelia M. | Doheny, Kimberly F. | Romm, Jane | Klaver, Caroline C. W. | Hayward, Caroline | Gorin, Michael B. | Klein, Michael L. | Baird, Paul N. | den Hollander, Anneke I. | Fauser, Sascha | Yates, John R. W. | Allikmets, Rando | Wang, Jie Jin | Schaumberg, Debra A. | Klein, Barbara E. K. | Hagstrom, Stephanie A. | Chowers, Itay | Lotery, Andrew J. | Léveillard, Thierry | Zhang, Kang | Brilliant, Murray H. | Hewitt, Alex W. | Swaroop, Anand | Chew, Emily Y. | Pericak-Vance, Margaret A. | DeAngelis, Margaret | Stambolian, Dwight | Haines, Jonathan L. | Iyengar, Sudha K. | Weber, Bernhard H. F. | Abecasis, Gonçalo R. | Heid, Iris M.
Nature genetics  2015;48(2):134-143.
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. Here, we report on a study of >12 million variants including 163,714 directly genotyped, most rare, protein-altering variant. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5×10–8) distributed across 34 loci. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 4.1×10–10). Very rare coding variants (frequency < 0.1%) in CFH, CFI, and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
PMCID: PMC4745342  PMID: 26691988
2.  No Clinically Significant Association Between CFH and ARMS2 Genotypes and Response to Nutritional Supplements 
Ophthalmology  2014;121(11):2173-2180.
To determine whether genotypes at two major loci associated with late age-related macular degeneration (AMD), complement factor H (CFH) and Age-Related Maculopathy Susceptibility 2 (ARMS2), influenced the relative benefits of Age-Related Eye Disease Study (AREDS) supplements.
Unplanned retrospective evaluation of a prospective, randomized, placebo-controlled clinical trial of vitamins and minerals for the treatment of AMD.
AREDS participants (mean age of 69 years) who were at risk for developing late AMD and who were randomized to the 4 arms of the AREDS supplements.
Analyses were performed using the Cox proportional hazards model to predict progression to late AMD (neovascular or central geographic atrophy). Statistical models, adjusted for age, gender, smoking status and baseline AMD severity, were used to examine the influence of genotypes on the response to therapy with 4 randomly assigned arms of AREDS supplement components: placebo, antioxidants (vitamins C, E, beta-carotene), zinc with copper, or the combination.
Main Outcome Measures
The influence of the genotype on the relative treatment response to the randomized components of the AREDS supplement, measured as progression to late AMD.
Of the 1237 genotyped AREDS participants of Caucasian ethnicity, 385 (31.1%) developed late AMD during the mean follow-up period of 6.6 years. As previously demonstrated, both CFH genotype (p=0.005), ARMS2 (<0.0001) and supplement were each individually associated with progression to late AMD. An interaction analysis found no evidence that the relative benefits of AREDS supplementation varied by genotype. Analysis of (1) CFH rs1061170 and rs1410996 combined with ARMS2 rs10490924, with the 4 randomly assigned arms of AREDS supplement and (2) analysis of the combination of CFH rs412852 and rs3766405 with ARMS2 c.372_815del443ins54 with the AREDS components resulted in no interaction (p=0.06 and p=0.45, respectively, before multiplicity adjustment).
AREDS supplements reduced the rate of AMD progression across all genotype groups. Furthermore, the genotypes at the CFH and ARMS2 loci did not statistically significantly alter the benefits of AREDS supplements. Genetic testing remains a valuable research tool, but analysis of AREDS study data suggests it provides no benefits in managing nutritional supplementation for patients at risk of late AMD.
PMCID: PMC4253656  PMID: 24974817
3.  Age-Related Macular Degeneration: Genetics and Biology Coming Together 
Genetic and genomic studies have enhanced our understanding of complex neurodegenerative diseases that exert a devastating impact on individuals and society. One such disease, age-related macular degeneration (AMD), is a major cause of progressive and debilitating visual impairment. Since the pioneering discovery in 2005 of complement factor H (CFH) as a major AMD susceptibility gene, extensive investigations have confirmed 19 additional genetic risk loci, and more are anticipated. In addition to common variants identified by now-conventional genome-wide association studies, targeted genomic sequencing and exome-chip analyses are uncovering rare variant alleles of high impact. Here, we provide a critical review of the ongoing genetic studies and of common and rare risk variants at a total of 20 susceptibility loci, which together explain 40–60% of the disease heritability but provide limited power for diagnostic testing of disease risk. Identification of these susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment.
PMCID: PMC4217162  PMID: 24773320
complex disease; genetic susceptibility; neurodegeneration; retina; blindness
4.  Assessment of the contribution of CFH and chromosome 10q26 AMD susceptibility loci in a Russian population isolate 
A strong association has been confirmed between age‐related macular degeneration (AMD) and variants at two independent loci including Tyr402His in the complement factor H (CFH) on 1q32 and Ser69Ala at LOC387715, a hypothetical gene on chromosome 10q26. The contribution of both loci to AMD was investigated in an isolated north‐west Russian population.
Together with a PLEKHA1 variant at 10q26, the CFH Tyr402His and LOC387715 Ser69Ala polymorphisms were genotyped in 155 patients with AMD and 151 age‐matched controls. χ2 and Mantel–Haenszel (M–H) score tests were used to test for association. Sex‐adjusted ORs were calculated.
The frequency of the Tyr402His C allele was significantly higher in patients with AMD compared with controls (pM–H = 0.0035). The increased risk observed in patients homozygous for the C allele (ORHOM = 2.71, 95% CI 1.25 to 5.90) in this indigenous Russian population was considerably lower than that observed in previous western Caucasian populations. A significant increase in the frequency of the LOC387715 variant was observed in patients with late‐stage AMD compared with controls (pM–H = 0.007), with a homozygous OR of 3.47 (95% CI 1.01 to 11.9), although this association was not seen with early‐stage AMD.
The CFH gene contributes to AMD in this Russian population, although the risk conferred is considerably lower in this population than that found in other Western populations. A contribution of LOC387715 to disease in this population is also likely to be of weak effect.
PMCID: PMC1954757  PMID: 17050575
5.  Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype 
Background Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case–control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.
Methods To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, ‘Y402H’) with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene–smoking interaction; and 16 published studies from non-European ancestry.
Results In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10–2.45; P = 1.1 x 10−161]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.
Conclusion The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.
PMCID: PMC3304526  PMID: 22253316
Age-related macular degeneration (AMD); Complement factor H gene; meta-ananlysis
6.  Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies 
Human mutation  2011;32(12):1407-1416.
Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status, has been reported. We present a pooled analysis (n=21,160) demonstrating associations between late AMD and APOε4 (OR=0.72 per haplotype; CI: 0.65–0.74; P=4.41×10−11) and APOε2 (OR=1.83 for homozygote carriers; CI: 1.04–3.23; P=0.04), following adjustment for age-group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR=1.54; CI: 1.38–1.72; P=2.8×10−15) and atrophic (OR=1.38; CI: 1.18–1.61; P=3.37×10−5) AMD but not early AMD (OR=0.94; CI: 0.86–1.03; P=0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyondε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.
PMCID: PMC3217135  PMID: 21882290
age-related macular degeneration; AMD; apolipoprotein E; APOE; case-control association study
7.  Variations in Apolipoprotein E Frequency With Age in a Pooled Analysis of a Large Group of Older People 
American Journal of Epidemiology  2011;173(12):1357-1364.
Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ε4 isoform with increasing age (χ2 for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ε3 isoform (χ2 for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ε4 homozygotes; the frequency of ε4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ε3/ε4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.
PMCID: PMC3145394  PMID: 21498624
aged; apolipoprotein E2; apolipoprotein E3; apolipoprotein E4; apolipoproteins E; longevity; meta-analysis; multicenter study
8.  Modelling the Genetic Risk in Age-Related Macular Degeneration 
PLoS ONE  2012;7(5):e37979.
Late-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69–2.05) than patients aged 75 and above (1.45, 95% CI: 1.36–1.54). Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11–1131.96) for individuals in the highest category (GRS 3.44–5.18, 0.5% of the general population) compared to subjects with the most common genetic background (GRS −0.05–1.70, 40.2% of general population). The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available.
PMCID: PMC3364197  PMID: 22666427
9.  Risk- and non-risk-associated variants at the 10q26 AMD locus influence ARMS2 mRNA expression but exclude pathogenic effects due to protein deficiency 
Human Molecular Genetics  2011;20(7):1387-1399.
Fifteen variants in 10q26 are in strong linkage disequilibrium and are associated with an increased risk for age-related macular degeneration (AMD), a frequent cause of blindness in developed countries. These variants tag a single-risk haplotype encompassing the genes ARMS2 (age-related maculopathy susceptibility 2) and part of HTRA1 (HtrA serine peptidase 1). To define the true AMD susceptibility gene in 10q26, several studies have focused on the influence of risk alleles on the expression of ARMS2 and/or HTRA1, but the results have been inconsistent. By heterologous expression of genomic ARMS2 variants, we now show that ARMS2 mRNA levels transcribed from the risk haplotype are significantly reduced compared with non-risk mRNA isoforms. Analyzing variant ARMS2 constructs, this effect could specifically be assigned to the known insertion/deletion polymorphism (c.(*)372_815del443ins54) in the 3′-untranslated region of ARMS2. Reporter gene assays with HTRA1 promoter sequences demonstrated the presence of a Müller glia-specific cis-regulatory region further upstream of the transcription start site. However, AMD risk alleles had little or no effect on HTRA1 promoter activity in the retina. Analysis of a large series of human post-mortem retina/retinal pigment epithelial samples heterozygous for the risk haplotype confirmed the in vitro/ex vivo results and demonstrated that the risk haplotype affects ARMS2 but not HTRA1 mRNA expression. Furthermore, we provide in vivo evidence that a common non-risk-associated non-synonymous variant (rs2736911) also leads to decreased ARMS2 transcript levels. Consequently, our data suggest that pathogenic effects due to ARMS2 protein deficiency are unlikely to account for AMD pathology.
PMCID: PMC3049360  PMID: 21252205
10.  Multicenter cohort association study of SLC2A1 single nucleotide polymorphisms and age-related macular degeneration 
Molecular Vision  2012;18:657-674.
Age-related macular degeneration (AMD) is a major cause of blindness in older adults and has a genetically complex background. This study examines the potential association between single nucleotide polymorphisms (SNPs) in the glucose transporter 1 (SLC2A1) gene and AMD. SLC2A1 regulates the bioavailability of glucose in the retinal pigment epithelium (RPE), which might influence oxidative stress–mediated AMD pathology.
Twenty-two SNPs spanning the SLC2A1 gene were genotyped in 375 cases and 199 controls from an initial discovery cohort (the Amsterdam-Rotterdam-Netherlands study). Replication testing was performed in The Rotterdam Study (the Netherlands) and study populations from Würzburg (Germany), the Age Related Eye Disease Study (AREDS; United States), Columbia University (United States), and Iowa University (United States). Subsequently, a meta-analysis of SNP association was performed.
In the discovery cohort, significant genotypic association between three SNPs (rs3754219, rs4660687, and rs841853) and AMD was found. Replication in five large independent (Caucasian) cohorts (4,860 cases and 4,004 controls) did not yield consistent association results. The genotype frequencies for these SNPs were significantly different for the controls and/or cases among the six individual populations. Meta-analysis revealed significant heterogeneity of effect between the studies.
No overall association between SLC2A1 SNPs and AMD was demonstrated. Since the genotype frequencies for the three SLC2A1 SNPs were significantly different for the controls and/or cases between the six cohorts, this study corroborates previous evidence that population dependent genetic risk heterogeneity in AMD exists.
PMCID: PMC3324365  PMID: 22509097
11.  CFH, C3 and ARMS2 Are Significant Risk Loci for Susceptibility but Not for Disease Progression of Geographic Atrophy Due to AMD 
PLoS ONE  2009;4(10):e7418.
Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown.
Methodology/Principal Findings
Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6×10−9, 3.2×10−3, and P = 2.6×10−12, respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm2/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13).
This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression.
PMCID: PMC2756620  PMID: 19823576
12.  Correction: Systemic Complement Activation in Age-Related Macular Degeneration 
PLoS ONE  2008;3(7):10.1371/annotation/511a1029-bc43-4510-a4ca-c1db31810acc.
PMCID: PMC2656691
13.  Correction: Systemic Complement Activation in Age-Related Macular Degeneration 
PLoS ONE  2008;3(7):10.1371/annotation/32b9bc31-ed6d-4d31-9ce0-480407017bad.
PMCID: PMC2651648
14.  Systemic Complement Activation in Age-Related Macular Degeneration 
PLoS ONE  2008;3(7):e2593.
Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.
This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility.
PMCID: PMC2440421  PMID: 18596911

Results 1-14 (14)