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(Investigative Ophthalmology and Visual Science. 2006;47:5453-5459.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.06-0655
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Expanded Genome Scan in Extended Families with Age-Related Macular Degeneration

Sandra Barral,1 Peter J. Francis,2 Dennis W. Schultz,2 Mitchell B. Schain,2 Chad Haynes,1 Jacek Majewski,1 Jurg Ott,1 Ted Acott,2 Richard G. Weleber,2 and Michael L. Klein2

1From the Laboratory of Statistical Genetics, Rockefeller University, New York, New York; and the 2Macular Degeneration Center, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
PURPOSE. To investigate further the genetic contribution to age-related macular degeneration (AMD), increasing the power of a previous analysis and reproducing the original findings.

METHODS. A large cohort of families with this condition was assembled, and an expanded genome scan was performed with 556 microsatellite markers. In 2003, the results were reported of a genome-wide linkage analysis of 70 of these pedigrees. Members of 51 new families have now been ascertained and many of the original pedigrees expanded. Parametric and nonparametric linkage analyses were performed with a denser map of markers. In addition, analyses were performed with the sample stratified by age at ascertainment and by two major advanced phenotypes for the disease: neovascular AMD (choroidal neovascularization) and geographic atrophy.

RESULTS. The results corroborate the macular degeneration–susceptibility loci consistently reported by the authors and others in genome-wide scans. New loci were identified, including the finding of a two-point HLOD of 3.70 at 6q25.2.

CONCLUSIONS. The results suggest that the use of families enriched in predisposition to AMD has legitimacy. Genetic analyses of a genome-wide scan performed on our large cohort of families add further confirmatory evidence that susceptibility loci lie on 1q, 3p, 9q, and 10q. Furthermore, new loci have been identified, including a locus on 6q.

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world.1 It is now undisputed that both genetic2 and environmental factors3 contribute to its development, though the precise etiology of this condition remains to be elucidated.

Several linkage and association studies have now been published identifying several putative AMD-susceptibility loci.1 To increase the power of such analyses, in which many loci show only tentative linkage, much of the summary genotype data have been pooled in a genome-scan meta-analysis.4

Recently, several independent studies have established a significant association with a common coding variant in the CFH gene within the 1q31 locus.5 6 7 8 9 Other genes so far implicated in the AMD disease process include hemicentin-1 (1q31),10 APOE,11 fibulin-5,12 TLR4,13 ABCA4,14 ACE,15 CX3CR1,16 and PLEKHA1/LOC387715.17

The phenotypic hallmark of AMD is the accumulation of drusen (subretinal yellow deposits) at the macula. Advanced AMD is characterized by poor central vision after the development of (1) choroidal neovascularization (CNV), which leads to hemorrhage and scarring in the retina, also known as wet AMD; or (2) patches of retinal pigment epithelial atrophy, geographic atrophy (GA), also known as advanced dry AMD.1 In our study, affected individuals were identified by the presence of either of these features of advanced AMD or extensive large (>125 µm in minimum diameter) drusen >393,744 µm2 in area. This amount of drusen represented the highest risk category for the development of late AMD (19.2% in 5 years and 55.3% in 10 years) in the Beaver Dam Eye Study.18 Unaffected individuals did not have these features, and those with no drusen >125-µm in minimum diameter and no pigment changes were considered as definitely unaffected (Table 1) .


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  		TABLE 1. Diagnostic Categories and AMD Subgroups

 

   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
In total, 124 families (1669 individuals) were studied. The study was conducted in accordance with the Declaration of Helsinki. Each family included three or more members with AMD. Genotyping errors were checked using the PedCheck19 and RELATIVE software programs (available at ftp://linkage.rockefeller.edu/software/relative/ developed by Harald Göring, Columbia University, New York, NY) as previously described. Allele frequencies at each locus were estimated from the data by allele counting in all genotyped individuals, with the Pedmanager program (available at http://www-genome.wi.mit.edu/ftp/distribution/software/pedmanager/ developed by Mary Pat Daly, Whitehead Institute, Massachusetts Institute of Technology, Cambridge, MA). PCR-based microsatellite marker genotyping of all individuals, both affected and unaffected, was performed by the National Heart, Lung, and Blood Institute’s (NHLBI) mammalian genotyping service, by using a set of 556 microsatellite markers from Marshfield panels 9, 10, 12, and 13 (Marshfield, Clinic, Marshfield, WI), and genetic linkage was analyzed using the Analyze/Linkage and Allegro software packages to produce two-point and multipoint LOD scores.

In consideration of the possible genetic heterogeneity of AMD and consistent with prior analyses, three different genetic analysis models were used: (1) a parametric model assuming a dominant mode of inheritance, with a set of age-dependent penetrances and either a phenocopy rate of 5% and disease allele frequency of 0.005 or a phenocopy rate of 10% and disease allele frequency of 0.01; (2) a parametric model with a dominant mode of inheritance and age-independent penetrances as described by Majewski et al.20 ; (3) a nonparametric approach based on allele-sharing statistics (Table 2) .


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  		TABLE 2. Genetic Models and Statistics Used in the Linkage Analysis

 
These three genetic models were applied to different phenotype diagnostic schemes: (A) the entire collection of individuals; (B) affected and those unaffected individuals classified as definitively unaffected; (C) individuals who are either definitely affected or definitely unaffected; and (D) affected individuals only. Finally, some of the analyses (NuFam; nuclear family) were performed on all the families but with each reduced to a nuclear pedigree. Table 3 summarizes how the different genetic models and diagnostic schemes were combined in the analyses.


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  		TABLE 3. Combinations of Phenotype Diagnostic Schemes and Diagnostic Categories, Dataset Description, Dataset Size, and Genetic Models

 
The same modeled analyses were performed with the families stratified for (1) advanced AMD phenotype: The GA cohort (>50% of the definitely affected members had had GA) included 42 pedigrees comprising 560 individuals and the neovascular AMD (CNV) cohort (>50% of definitely affected ones had neovascular AMD) included 91families comprising 1252 individuals; (2) age at ascertainment: The EARLY group (affected members had a mean age of <75 years) included 32 families comprising 462 individuals, and the LATE group (affected members had a mean age of ≥75 years) included 95 families comprising 1245 individuals (Table 3) .

Chromosomal loci with LOD scores exceeding a threshold of 1.5 in at least one of the analysis methods are reported. Parametric LOD scores that allow for heterogeneity require the estimation of the {alpha} parameter (proportion of families linked to a particular locus). To account for this additional parameter (the statistical test has now more than 1 degree of freedom), the significance cutoff for the LOD score is increased by 0.3.

In the case of the nonparametric statistics, we used the exponential model from the Allegro software package and we reported Sall and Spairs (allele-sharing) statistics, since among our families we had some extended pedigrees.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
The major findings of this expanded genome scan are shown in Tables 4 to 6 . Figure 1 shows graphically the statistical analyses performed on multiple models across loci of interest. The LOD score results from two-point linkage analysis that exceeded an initial genome-wide threshold of 1.5 are summarized in Table 4 , which also includes the various combinations of diagnostic criteria and analytic methods used.


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  		TABLE 4. Summary of Overall Two-Point Linkage Analysis

 

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  		TABLE 6. Corrected Significance Levels for Two-Point and Multipoint LOD Scores Exceeding the Threshold of 2

 

Figure 1
Figure 1
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  		FIGURE 1. Two-point and multipoint LOD score graphs at loci showing the most significant linkage to AMD. Positive linkage signals obtained are plotted for different-modeled analyses of AMD at loci of interest. Markers are ordered in accordance with the Marshfield genetic map and are expressed in Kosambi centimorgans. The graphs are labeled according to the model in which the linkage peak was found in the following order: analysis type (e.g. 2P)-phenotype diagnostic scheme (e.g., A)-subgroup (e.g., E)-genetic model (e.g., 2). The phenotype diagnostic schemes and genetic models used are described in Tables 3 and Table 2 , respectively. When the results of two-point linkage analysis are shown, the data points are not joined by lines, so as to avoid implying that linkage data between the points is known. 2P, two-point; MP, multipoint; NS, nonstratified dataset; GA, geographic atrophy group; CNV, neovascular AMD group; NF, nuclear families.

 
Similarly, the multipoint linkage analysis results obtained from the different genetic models and diagnostic schemes are displayed in Table 5 . Finally, Table 6 highlights those loci where a two-point or multipoint LOD score >2 was observed with estimations of statistical significance when corrected for multiple testing.


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  		TABLE 5. Summary of Multipoint Linkage Analysis

 
The loci identified in our previous analysis have been reproduced. We have also identified new loci not found in our previous genome scan, including a locus on at 6q25.2 (LOD = 3.70) for families whose affected members had a mean age of diagnosis of AMD of ≥75 years (LATE). A maximum two-point HLOD of 3.70 ({alpha} = 1.00) was observed at microsatellite marker GATA165G02 (D6S2436) in the parametric analysis of model 1. The score exceeded the suggested threshold for parametric statistical significance (LOD ≥ 3.3).


   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Our expanded genome-wide scan has identified a new AMD-susceptibility locus at 6q25.2 that was not identified in the original study. Furthermore, loci previously identified have been reproduced.

The novel 6q locus is identified in the ~75% of families in which the mean age of diagnosis of affected individuals was ≥75 years of age and is >37cM from the chromosome 6 locus identified by Schick et al.21 Fine mapping is under way to narrow the interval. It is intriguing to speculate that the "disease" allele at this locus may delay the onset of AMD in individuals who carry a genetic risk of the disease. Alternatively, because more of the affected members of LATE families had advanced AMD than in the EARLY group, perhaps the gene determines progression to this stage of the disease process. In support of this notion, it is of note that at the same microsatellite marker for those in the GA group (families in which >50% of affected individuals had GA) an LOD score of 2.31 was observed. Perhaps, then, the gene also reduces the risk of development of CNV, and therefore individuals progress to the development of GA instead. It will be interesting to examine the relationship between this locus and the CFH gene variants, which are considered to confer significant risk of the development of AMD.

In our previous studies, AMD-susceptibility loci were identified at 1q31 (D1S518, HLOD = 2.07), 3p13 (D3S1304/D3S4545, HLOD = 2.19), 4q32 (D4S2368, HLOD = 2.66),9q33 (D9S930/D9S934, LODzir = 2.01), and 10q26 (D10S1230, HLOD = 3.06). All but the chromosome 4 locus have been corroborated in other investigations.21 22 23 24 25 26 27 28 This adds further validity to the claim that these loci encompass susceptibility genes for AMD, despite the fact that in our study as in others, the empiric threshold for statistical significance is not achieved. A meta-analysis of the data from these studies has provided further evidence favoring the presence of AMD genes at the 1q, 3p, and 10q loci.4

In this current analysis, which includes a substantial number of new families as well as expansion of the original pedigrees and an increased number of microsatellite markers, evidence favoring the existence of a 4q locus is reduced (LOD = 1.16). In the dry AMD phenotype group, we found a parametric LOD score of 2.78 at marker D10S1239. This 10q26 chromosomal region has become one of the most frequently implicated susceptibility loci for AMD,27 20 25 23 and indeed harbors the gene LOC387715.

All other linkage peaks were replicated including the 9q locus where the LOD score was 2.17 for the EARLY subgroup of families stratified by age at ascertainment of affected members. This peak is located near the peak in the nonstratified dataset reported by Majewski et al.20 and near the location of TLR4 (117.5 Mb). A weakly positive signal (LOD = 1.837) was obtained on chromosome 19 at a location encompassing the APOE gene.

Our results suggest that the use of families enriched in predisposition to AMD has legitimacy. Furthermore, concerns about sources of bias such as phenocopy rate may not be as important as thought, as these may not have a significant effect. Of interest, at each locus, we observed that only a small number of families contributed most of the positive LOD score. This finding may be interpreted in several ways; however, it is possible that in a subset of families predisposed to AMD, a single gene contributes most of the disease determination. There is strong evidence that the gene frequently determining risk of AMD at the 1q31 locus is CFH.29 In our genome-wide scan, two families largely contributed (LOD = 1.64 and 1.33, respectively) to the overall nonparametric LOD score at this locus (Sall = 2.52). The first family is the same pedigree in which a segregating mutation in the hemicentin-1 gene (which lies within the same locus) has been identified that may determine AMD development.30

The uncertain mode of AMD inheritance justifies the use of different genetic models used in the study. However, accounting for different analysis schemes, diagnostic categories, andgenetic models tends to increase the type 1 error rate (rate of false-positive results). Whereas a maximum LOD score of at least 3 (point-wise P = 0.0001) is generally considered significant evidence for linkage in a genome-wide scan, Ulgen et al.31 investigated the null distribution of the LOD score maximized over essentially the entire range of the genetic parameter space for a major gene model. They find that the probability associated with an observed maximized LOD score, x, is given by

Formula
where {Phi} is the (cumulative) normal distribution function. When applied to our observed LOD score of 3.71, this leads to a corrected point-wise significance level of 0.0006. Although this value does not quite reach the established genome-widesignificance level of 0.0001, the method proposed by Ulgen et al.,31 correcting for maximizing LOD scores over a very wide range of parameters, is probably too rigorous for our case. We applied the same calculation for the remaining parametric LOD scores reported in Table 6 that exceed a threshold of 2. In the case of the nonparametric LOD scores, we used a Bonferroni correction to derive the corrected probabilities, using the equation

Formula
where {alpha}1 corresponds to the uncorrected significance level, g is the number of tests performed (g = 8), and {alpha}c is the resultant corrected probability. Table 6 summarizes all the corrected probabilities after adjustment for multiple testing.


   Conclusion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Genetic analyses of a genome-wide scan performed on our large cohort of families—genetically enriched for their susceptibility to age-related macular degeneration—add further confirmatory evidence that susceptibility loci lie on 1q, 3p, 9q, and 10q. Furthermore, we have identified new loci, including a locus on 6q.


   Footnotes
 
Supported by National Eye Institute Grant EY12203 (MLK); National Human Genome Research Institute Grant HG00008 (JO); National Center for Research Resources Grant 5M01-RR000334; a career development award (PJF) and an unrestricted grant to Casey Eye Institute from Research to Prevent Blindness; and the Foundation Fighting Blindness (PJF, RGW and DWS); the Macular Vision Research Foundation (DWS); and the Macular Degeneration Center Research Fund, Casey Eye Institute, Oregon Health and Science University.

Submitted for publication June 14, 2006; revised August 7, 2006; accepted October 12, 2006.

Disclosure: S. Barral, None; P.J. Francis, None; D.W. Schultz, None; M.B. Schain, None; C. Haynes, None; J. Majewski, None; J. Ott, None; T. Acott, None; R.G. Weleber, None; M.L. Klein, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Michael L. Klein, Casey Eye Institute, Oregon Health & Science University, 3375 SW Terwilliger Boulevard, Portland, OR 97239-4197; kleinm{at}ohsu.edu.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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