Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration

Iyengar, Sudha K.; Song, Danhong; Klein, Barbara E.K.; Klein, Ronald; Schick, James H.; Humphrey, Jennifer; Millard, Christopher; Liptak, Rachel; Russo, Karlie; Jun, Gyungah; Lee, Kristine E.; Fijal, Bonnie; Elston, Robert C.

doi:10.1086/380912

Cited by 173Retinal Diseases and TreatmentsGenetic Associations and EpidemiologyRetinal Development and Disorders

Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration

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Iyengar, Sudha K., Song, Danhong, Klein, Barbara E.K., Klein, Ronald, Schick, James H., Humphrey, Jennifer, Millard, Christopher, Liptak, Rachel +5 more·2004·The American Journal of Human Genetics

DOI 10.1086/380912PMC PMC1181910

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Abstract

To examine the genetic basis of age-related macular degeneration (ARMD), a degenerative disease of the retinal pigment epithelium and neurosensory retina, we conducted a genomewide scan in 34 extended families (297 individuals, 349 sib pairs) ascertained through index cases with neovascular disease or geographic atrophy. Family and medical history was obtained from index cases and family members. Fundus photographs were taken of all participating family members, and these were graded for severity by use of a quantitative scale. Model-free linkage analysis was performed, and tests of heterogeneity and epistasis were conducted. We have evidence of a major locus on chromosome 15q (GATA50C03 multipoint P=1.98x10-7; empirical P< or =1.0x10-5; single-point P=3.6x10-7). This locus was present as a weak linkage signal in our previous genome scan for ARMD, in the Beaver Dam Eye Study sample (D15S659, multipoint P=.047), but is otherwise novel. In this genome scan, we observed a total of 13 regions on 11 chromosomes (1q31, 2p21, 4p16, 5q34, 9p24, 9q31, 10q26, 12q13, 12q23, 15q21, 16p12, 18p11, and 20q13), with a nominal multipoint significance level of P< or =.01 or LOD > or =1.18. Family-by-family analysis of the data, performed using model-free linkage methods, suggests that there is evidence of heterogeneity in these families. For example, a single family (family 460) individually shows linkage evidence at 8 loci, at the level of P<.0001. We conducted tests for heterogeneity, which suggest that ARMD susceptibility loci on chromosomes 9p24, 10q26, and 15q21 are not present in all families. We tested for mutations in linked families and examined SNPs in two candidate genes, hemicentin-1 and EFEMP1, in subsamples (145 and 189 sib pairs, respectively) of the data. Mutations were not observed in any of the 11 exons of EFEMP1 nor in exon 104 of hemicentin-1. The SNP analysis for hemicentin-1 on 1q31 suggests that variants within or in very close proximity to this gene cause ARMD pathogenesis. In summary, we have evidence for a major ARMD locus on 15q21, which, coupled with numerous other loci segregating in these families, suggests complex oligogenic patterns of inheritance for ARMD.

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These linkage studies provided more modest evidence for linkage on many other chromosomes, including a region on chromosome 22 near TIMP3.
“In addition, these studies provided more modest evidence for linkage on many other chromosomes (2, 77, 104, 137, 160), including a region on chromosome 22 near TIMP3, the gene mutated in Sorsby fundus dystrophy (158) (Figure 4).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [77]
Analysis of a cohort of AMD patients with the human ortholog of MDM1 on chromosome 12q did not reveal an association between MDM1 and AMD.
“Analysis of a cohort of AMD patients with the human ortholog of MDM1 on chromosome 12q did not reveal an association between MDM1 and AMD”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Iyengar et al., 2004
The location of MDM1 on chromosome 12q has previously been reported to be an AMD susceptibility locus.
“though this location has previously been reported to be an AMD susceptibility locus”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Iyengar et al., 2004
Several genome-wide linkage scans for AMD have found suggestive linkage on chromosome 1q.
“Several genome-wide linkage scans for AMD including ours (unpublished data) have found suggestive linkage on chromosome 1q [9–15].”
From CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD (2005) · cites this paper as [15]

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Background
Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts
Gehrs, K. M., Anderson, D. H., Johnson, L. V., & Hageman, G. S. (2006) · Annals of Medicine · doi:10.1080/07853890600946724 · Cited by 633 · see citing works
Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration
Maller, J., George, S., Purcell, S., Fagerness, J., Altshuler, D., Daly, M. J., & Seddon, J. M. (2006) · Nature Genetics · doi:10.1038/ng1873 · Cited by 599 · see citing works
Susceptibility genes for age-related maculopathy on chromosome 10q26
Jakobsdottir, J., Conley, Y. P., Weeks, D. E., Mah, T. S., Ferrell, R. E., & Gorin, M. B. (2005) · The American Journal of Human Genetics · doi:10.1086/444437 · Cited by 470 · see citing works
“…sib pairs have identified a number of potential susceptibility loci (Klein et al. 1998; Weeks et al. 2000; Majewski et al. 2003; Schick et al. 2003; Seddon et al. 2003; Abecasis et al. 2004; Iyengar et al. 2004; Kenealy et al. 2004; Schmidt et al. 2004; Weeks et al. 2004; Santangelo et al. 2005).”
Background
Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration
Zareparsi, S., Branham, K. E. H., Li, M., Shah, S., Klein, R. J., Ott, J., Hoh, J., Abecasis, G. R., & Swaroop, A. (2005) · The American Journal of Human Genetics · doi:10.1086/431426 · Cited by 371 · see citing works
“However, this change does not appear to play a significant role in AMD (Abecasis et al. 2004; Hayashi et al. 2004; Iyengar et al. 2004).”
BackgroundResultInfluentialSelf-citation
Complement Factor H Polymorphism, Complement Activators, and Risk of Age-Related Macular Degeneration
Despriet, D. D. G., Klaver, C. C. W., Witteman, J. C. M., Bergen, A. A. B., Kardys, I., de Maat, M. P. M., Boekhoorn, S. S., Vingerling, J. R., Hofman, A., Oostra, B. A., et al. (2006) · JAMA · doi:10.1001/jama.296.3.301 · Cited by 348 · see citing works
“Erythrocyte sedimentation rate, median (IQR), mm/h 10 (6-16) 10 (6-17) 10 (6-18)”
Cigarette Smoking Strongly Modifies the Association of LOC387715 and Age-Related Macular Degeneration
Schmidt, S., Hauser, M. A., Scott, W. K., Postel, E. A., Agarwal, A., Gallins, P., Wong, F., Chen, Y. S., Spencer, K., Schnetz-Boutaud, N., et al. (2006) · The American Journal of Human Genetics · doi:10.1086/503822 · Cited by 335 · see citing works
The Genetics of Age-Related Macular Degeneration: A Review of Progress to Date
Haddad, S., Chen, C. A., Santangelo, S. L., & Seddon, J. M. (2006) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2006.05.001 · Cited by 299 · see citing works
Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration
Swaroop, A., Chew, E. Y., Bowes Rickman, C., & Abecasis, G. R. (2009) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.9.081307.164350 · Cited by 270 · see citing works
“In addition, these studies provided more modest evidence for linkage on many other chromosomes (2, 77, 104, 137, 160), including a region on chromosome 22 near TIMP3, the gene mutated in Sorsby fundus dystrophy (158) (Figure 4).”
The complement system in age-related macular degeneration
Armento, A., Ueffing, M., & Clark, S. J. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03796-9 · Cited by 258 · see citing works
Meta-analysis of genome scans of age-related macular degeneration
Fisher, S. A., Abecasis, G. R., Yashar, B. M., Zareparsi, S., Swaroop, A., Iyengar, S. K., Klein, B. E. K., Klein, R., Lee, K. E., Majewski, J., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi230 · Cited by 239 · see citing works
“The most significant result (chromosome 10q) was identified as a putative locus by several of the independent studies (25,27,29,32) but did not attain a genomewide level of significance in any of these studies.”
Background
CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD
Magnusson, K. P., Duan, S., Sigurdsson, H., Petursson, H., Yang, Z., Zhao, Y., Bernstein, P. S., Ge, J., Jonasson, F., Stefansson, E., et al. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0030005 · Cited by 226 · see citing works
Systematic review and meta-analysis of the association between complementary factor H Y402H polymorphisms and age-related macular degeneration
Thakkinstian, A., Han, P., McEvoy, M., Smith, W. T., Hoh, J. J., Magnússon, K. P., Zhang, K., & Attia, J. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl220 · Cited by 224 · see citing works
The complement system in age-related macular degeneration: A review of rare genetic variants and implications for personalized treatment
Geerlings, M. J., de Jong, E. K., & den Hollander, A. I. (2016) · Molecular Immunology · doi:10.1016/j.molimm.2016.11.016 · Cited by 202 · see citing works
“In search for genomic regions implicated in AMD, genetic linkge analyses were done in large family-based studies (Abecasis t al., 2004; Iyengar et al., 2004; Majewski et al., 2003; Seddon t al., 2003; Weeks et al., 2004).”
Background
Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions
Weeks, D. E., Conley, Y. P., Tsai, H.-J., Mah, T. S., Schmidt, S., Postel, E. A., Agarwal, A., Haines, J. L., Pericak-Vance, M. A., Rosenfeld, P. J., et al. (2004) · The American Journal of Human Genetics · doi:10.1086/422476 · Cited by 195 · see citing works
“In addition to being implicated by our studies, the 1q25–31 region has been implicated by five other studies (Klein et al. 1998; Majewski et al. 2003; Seddon et al. 2003; Abecasis et al. 2004; Iyengar et al. 2004).”
BackgroundMethodResultInfluential
Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration
Zareparsi, S., Buraczynska, M., Branham, K. E. H., Shah, S., Eng, D., Li, M., Pawar, H., Yashar, B. M., Moroi, S. E., Lichter, P. R., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi154 · Cited by 190 · see citing works
“A quick evaluation of genetic data had revealed a possible AMD susceptibility locus at 9q32–33 in three independent studies (20,22,23).”
Background
Functional Candidate Genes in Age-Related Macular Degeneration: Significant Association withVEGF,VLDLR, andLRP6
Haines, J. L., Schnetz-Boutaud, N., Schmidt, S., Scott, W. K., Agarwal, A., Postel, E. A., Olson, L., Kenealy, S. J., Hauser, M., Gilbert, J. R., et al. (2006) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.05-0116 · Cited by 189 · see citing works
Age‐related macular degeneration—clinical review and genetics update
Ratnapriya, R., & Chew, E. Y. (2013) · Clinical Genetics · doi:10.1111/cge.12206 · Cited by 179 · see citing works
Genetic Modulation of Senescent Phenotypes in Homo sapiens
Martin, G. M. (2005) · Cell · doi:10.1016/j.cell.2005.01.031 · Cited by 171 · see citing works
“…presbycusis (Fischel-Ghodsian, 2000; Dai et al., 2004), the preliminary evidence for a major locus for susceptibility to age-related macular degeneration (Iyengar et al., 2004), and the ongoing linkage analysis to detect major genes that modulate susceptibility to osteoporosis (Shen et al., 2004).”
Background
Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD)
Ramkumar, H. L., Zhang, J., & Chan, C.-C. (2010) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2010.02.002 · Cited by 163 · see citing works
“Analysis of a cohort of AMD patients with the human ortholog of MDM1 on chromosome 12q did not reveal an association between MDM1 and AMD, though this location has previously been reported to be an AMD susceptibility locus (Chang et al., 2008; Iyengar et al., 2004; Fisher et al., 2005).”
Background
Complement factor H in AMD: Bridging genetic associations and pathobiology
Toomey, C. B., Johnson, L. V., & Rickman, C. B. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.09.001 · Cited by 160 · see citing works
“…to chromosome 1q25–31 in a large pedigree with an apparent autosomal dominant inheritance for “dry” AMD (Klein et al., 1998), which was then supported by a number of other linkage studies (Abecasis et al., 2004; Iyengar et al., 2004; Majewski et al., 2003; Seddon et al., 2003; Weeks et al., 2004).”
Result
Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy
Conley, Y. P., Thalamuthu, A., Jakobsdottir, J., Weeks, D. E., Mah, T., Ferrell, R. E., & Gorin, M. B. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi204 · Cited by 158 · see citing works
CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses
Conley, Y. P., Jakobsdottir, J., Mah, T., Weeks, D. E., Klein, R., Kuller, L., Ferrell, R. E., & Gorin, M. B. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl396 · Cited by 157 · see citing works
An update on the genetics of age-related macular degeneration
Scholl, H. P. N., Fleckenstein, M., Issa, P. C., Keilhauer, C. N., Holz, F. G., & Weber, B. H. F. (2007) · PubMed Central · doi:10.5283/epub.35844 · Cited by 156 · see citing works
Risk Alleles in CFH and ARMS2 Are Independently Associated with Systemic Complement Activation in Age-related Macular Degeneration
Smailhodzic, D., Klaver, C. C. W., Klevering, B. J., Boon, C. J. F., Groenewoud, J. M. M., Kirchhof, B., Daha, M. R., den Hollander, A. I., & Hoyng, C. B. (2011) · Ophthalmology · doi:10.1016/j.ophtha.2011.07.056 · Cited by 147 · see citing works
CURRENT KNOWLEDGE AND TRENDS IN AGE-RELATED MACULAR DEGENERATION
Vélez-Montoya, R., Oliver, S. C. N., Olson, J. L., Fine, S. L., Quiroz-Mercado, H., & Mandava, N. (2013) · Retina · doi:10.1097/iae.0000000000000036 · Cited by 137 · see citing works
ARMS2 Is a Constituent of the Extracellular Matrix Providing a Link between Familial and Sporadic Age-Related Macular Degenerations
Körtvely, E., Hauck, S. M., Duetsch, G., Gloeckner, C. J., Kremmer, E., Priglinger, C., Deeg, C. A., & Ueffing, M. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.09-3850 · Cited by 134 · see citing works
Mechanism of Inflammation in Age-Related Macular Degeneration
Parmeggiani, F., Romano, M., Costagliola, C., Semeraro, F., Incorvaia, C., D’Angelo, S., Perri, P., Palma, P. D., Nadai, K. D., & Sebastiani, A. (2012) · Mediators of Inflammation · doi:10.1155/2012/546786 · Cited by 135 · see citing works
Age-related macular degeneration and changes in the extracellular matrix
Romaniuk, W. (2014) · Medical Science Monitor · doi:10.12659/msm.889887 · Cited by 116 · see citing works
“ARMS2 shows functional interaction with the protein network of the ECM; many of these proteins are present in the development of maculopathy [90,91,195,198,199].”
Background
Epistatic Module Detection for Case-Control Studies: A Bayesian Model with a Gibbs Sampling Strategy
Tang, W., Wu, X., Jiang, R., & Li, Y. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000464 · Cited by 109 · see citing works
“Iyengar et al [34] have also identified linkage signal for a marker in the nearby locus 15q21.”
Background
Neovascular Age-Related Macular Degeneration Risk Based on CFH, LOC387715/HTRA1, and Smoking
Hughes, A. E., Orr, N., Patterson, C. C., Esfandiary, H., Hogg, R. E., McConnell, V. P. M., Silvestri, G., & Chakravarthy, U. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040355 · Cited by 110 · see citing works
Review of Genetics in Age Related Macular Degeneration
Montezuma, S. R., Sobrin, L., & Seddon, J. M. (2007) · Seminars in Ophthalmology · doi:10.1080/08820530701745140 · Cited by 108 · see citing works
The Epidemiology of Age-Related Macular Degeneration
Seddon, J. M., & Chen, C. A. (2004) · International Ophthalmology Clinics · doi:10.1097/00004397-200404440-00004 · Cited by 106 · see citing works
Genetic insights into age-related macular degeneration: Controversies addressing risk, causality, and therapeutics
Gorin, M. B. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.04.004 · Cited by 105 · see citing works
Genetic factors of age-related macular degeneration
Tuo, J., Bojanowski, C. M., & Chan, C. (2004) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2004.02.001 · Cited by 100 · see citing works
“…locus Marker Maximum lod References 1q25–31 D1S240/D1S412 3.20 Klein et al. (1998),Majewski et al. (2003),Seddon et al. (2003),Weeks et al. (2001),Iyengar et al. (2004) 2q31/2q32 D2S1391/D2S1384 2.32/2.03aa Seddon et al. (2003) 3p13 D12S1300/D12S1763 2.19b Majewski et al. (2003),Schick et al.…”
BackgroundInfluential
The molecular genetic basis of age-related macular degeneration: an overview
Katta, S., Kaur, I., & Chakrabarti, S. (2009) · Journal of Genetics · doi:10.1007/s12041-009-0064-4 · Cited by 96 · see citing works
Vitamin D: Implications for ocular disease and therapeutic potential
Reins, R. Y., & McDermott, A. M. (2015) · Experimental Eye Research · doi:10.1016/j.exer.2015.02.019 · Cited by 100 · see citing works
Localization of Age-Related Macular Degeneration-Associated ARMS2 in Cytosol, Not Mitochondria
Wang, G., Spencer, K. L., Court, B. L., Olson, L. M., Scott, W. K., Haines, J. L., & Pericak‐Vance, M. A. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.08-3240 · Cited by 96 · see citing works
Genetics of age-related macular degeneration: current concepts, future directions
DeAngelis, M. M., Silveira, A. C., Carr, E. A., & Kim, I. K. (2011) · Seminars in Ophthalmology · doi:10.3109/08820538.2011.577129 · Cited by 94 · see citing works
Toll-like receptor polymorphisms and age-related macular degeneration
Edwards, A. O., Chen, D., Fridley, B. L., James, K. M., Wu, Y., Abecasis, G., Swaroop, A., Othman, M., Branham, K., Iyengar, S. K., et al. (2008) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.07-1378 · Cited by 84 · see citing works
“The study sample comprised the 34 probands with advanced AMD, the average family size was 12 persons, and the average AMD score for affected individuals was 13.(25) In summary, the Dallas case–control cohort was used for the initial discovery studies and the Michigan case–control and FARMS family-based cohorts were us…”
Method
HTRA1 Variants in Exudative Age-Related Macular Degeneration and Interactions with Smoking and CFH
Tam, P. O. S., Ng, T. K., Liu, D. T. L., Chan, W. M., Chiang, S. W. Y., Chen, L. J., DeWan, A. T., Hoh, J. J., Lam, D. S. C., & Pang, C. P. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-1520 · Cited by 84 · see citing works
“No disease-causing allele was identified.(21) In 2005, a genome-wide association study revealed the single-nucleotide polymorphism (SNP) Tyr402His in the complement factor H (CFH) gene on 1q32 as an AMD-related variant, but no association was found between CFH Tyr402His and AMD in Chinese and Japanese populations.”
Background
Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration
Morrison, M. A., Silveira, A. C., Huynh, N., Jun, G., Smith, S. E., Zacharaki, F., Satō, H., Loomis, S. J., Andreoli, M. T., Adams, S. M., et al. (2011) · Human Genomics · doi:10.1186/1479-7364-5-6-538 · Cited by 83 · see citing works
“These particular genes were chosen because they are in regions of the genome previously reported by linkage studies to harbour AMD susceptibility loci.(36,48) CYP27A1 is located on chromosome 2q33-qter and spans approximately 34 kilobases (kb).”
BackgroundResult
Genetics of Immunological and Inflammatory Components in Age-related Macular Degeneration
Tuo, J., Grob, S., Zhang, K., & Chan, C. (2012) · Ocular Immunology and Inflammation · doi:10.3109/09273948.2011.628432 · Cited by 80 · see citing works
TheLOC387715Polymorphism and Age-Related Macular Degeneration: Replication in Three Case–Control Samples
Ross, R. J., Bojanowski, C. M., Wang, J. J., Chew, E. Y., Rochtchina, E., Ferris, F. L., Mitchell, P., Chan, C.-C., & Tuo, J. (2007) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.06-0999 · Cited by 75 · see citing works
Analysis of the Y402H Variant of the Complement Factor H Gene in Age-Related Macular Degeneration
Baird, P. N., Islam, A. F. M., Richardson, A. J., Cain, M. S., Hunt, N. C., & Guymer, R. H. (2006) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.05-1285 · Cited by 73 · see citing works
Progress in defining the molecular biology of age related macular degeneration
Lotery, A. J., & Trump, D. (2007) · Human Genetics · doi:10.1007/s00439-007-0406-3 · Cited by 70 · see citing works
“Despite the diYculties in pursuing linkage analysis in AMD several studies found evidence of a susceptibility locus at Chromosome 1q32 (Abecasis et al. 2004; Iyengar et al. 2004; Klein et al. 1998; Majewski et al. 2003; Seddon et al. 2003b; Weeks et al. 2001).”
Background
Suppression of Drusen Formation by Compstatin, a Peptide Inhibitor of Complement C3 activation, on Cynomolgus Monkey with Early-Onset Macular Degeneration
Chi, Z., Yoshida, T., Lambris, J. D., & Iwata, T. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-5635-4_9 · Cited by 64 · see citing works
“With the help of the haplotype marker project (HapMap Project), genome wide scanning has identified at least 13 loci linked to AMD on different chromosomes (Iyengar et al. 2004; Schick et al. 2003; Majewski et al. 2003).”
The HtrA1 promoter polymorphism, smoking, and age-related macular degeneration in multiple case-control samples
Tuo, J., Ross, R. J., Reed, G. F., Yan, Q., Wang, J. J., Bojanowski, C. M., Chew, E. Y., Feng, X., Olsen, T. W., Ferris, F. L., et al. (2008) · Ophthalmology · doi:10.1016/j.ophtha.2008.05.021 · Cited by 63 · see citing works
Convergence of linkage, gene expression and association data demonstrates the influence of the RAR-related orphan receptor alpha (RORA) gene on neovascular AMD: A systems biology based approach
Silveira, A. C., Morrison, M. A., Ji, F., Xu, H., Reinecke, J. B., Adams, S. M., Arneberg, T. M., Janssian, M., Lee, J., Yuan, Y., et al. (2009) · Vision Research · doi:10.1016/j.visres.2009.09.016 · Cited by 64 · see citing works
“Additionally, because other loci do exist which have yet to be elucidated (Abecasis et al., 2004; Fisher et al., 2005; Iyengar et al., 2004; Jun et al., 2005; Kenealy et al., 2004; Majewski et al., 2003; Schick et al., 2003; Schmidt et al., 2004; Seddon, Santangelo, Book, Chong, & Cote, 2003), it is clear that the per…”
Ocular Albinism and Hypopigmentation Defects in Slc24a5—I— Mice
Vogel, P., Read, R. W., Vance, R. B., Platt, K. A., Troughton, K., & Rice, D. S. (2008) · Veterinary Pathology · doi:10.1354/vp.45-2-264 · Cited by 63 · see citing works
Age-related macular degeneration: a perspective on genetic studies
Patel, N., Adewoyin, T., & Chong, V. N. (2007) · Eye · doi:10.1038/sj.eye.6702844 · Cited by 62 · see citing works
Analysis of the indel at the ARMS2 3′UTR in age-related macular degeneration
Wang, G., Spencer, K. L., Scott, W. K., Whitehead, P. G., Court, B. L., Ayala-Haedo, J., Mayo, P., Schwartz, S. G., Kovach, J. L., Gallins, P. J., et al. (2010) · Human Genetics · doi:10.1007/s00439-010-0805-8 · Cited by 61 · see citing works
“Loci at chromosomes 1q32 and 10q26 have been repeatedly and consistently linked to the disease in multiple studies (Majewski et al. 2003; Seddon et al. 2003; Weeks et al. 2004; Kenealy et al. 2004; Iyengar et al. 2004) and represent the strongest genetic eVects in AMD.”
Ordered subset linkage analysis supports a susceptibility locus for age-related macular degeneration on chromosome 16p12
Schmidt, S., Scott, W. K., Postel, E. A., Agarwal, A., Hauser, E. R., De La Paz, M. A., Gilbert, J. R., Weeks, D. E., Gorin, M. B., Haines, J. L., et al. (2004) · BMC Genetics · doi:10.1186/1471-2156-5-18 · Cited by 60 · see citing works
“These families were screened for the first time and were not included in previously published genome screens for AMD [32-37].”
Background
Genome-wide association identifies SKIV2L and MYRIP as protective factors for age-related macular degeneration
Kopplin, L. J., Igo, R. P., Wang, Y., Sivakumaran, T. A., Hagstrom, S. A., Peachey, N. S., Francis, P. J., Klein, M. L., SanGiovanni, J. P., Chew, E. Y., et al. (2010) · Genes and Immunity · doi:10.1038/gene.2010.39 · Cited by 61 · see citing works
Genetic analysis of typical wet-type age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese population
Goto, A., Akahori, M., Okamoto, H., MINAMI, M., Terauchi, N., Haruhata, Y., Obazawa, M., Noda, T., Honda, M., Mizota, A., et al. (2009) · Journal of ocular biology, diseases, and informatics · doi:10.1007/s12177-009-9047-1 · Cited by 61 · see citing works
Was the Human Genome Project Worth the Effort?
Daiger, S. P. (2005) · Science · doi:10.1126/science.1111655 · Cited by 59 · see citing works
Evidence for association between multiple complement pathway genes and AMD
Dinu, V., Miller, P. L., & Zhao, H. (2007) · Genetic Epidemiology · doi:10.1002/gepi.20204 · Cited by 58 · see citing works
“The region on chromosome 9q where C5 is located, however, has previously been linked to AMD by at least three other studies [Abecasis et al., 2004; Iyengar et al., 2004; Majewski et al., 2003].”
Background
Risk Alleles in CFH and ARMS2 and the Long-term Natural History of Age-Related Macular Degeneration
Klein, R., Myers, C. E., Meuer, S. M., Gangnon, R. E., Sivakumaran, T. A., Iyengar, S. K., Lee, K. E., & Klein, B. E. K. (2012) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2013.713 · Cited by 58 · see citing works
“F OLLOWING THE OBSERVAtions of the associations of specific single-nucleotide polymorphisms (SNPs) in the complement factor H region (CFH, rs1061170) and in the age-related maculopathy susceptibility 2 region (ARMS2, rs10490924) with late agerelated macular degeneration (AMD), there has been a growing number of studie…”
Complement factor H and hemicentin-1 in age-related macular degeneration and renal phenotypes
Thompson, C. L., Klein, R., Klein, R., Xu, Z., Capriotti, J., Joshi, T., Leontiev, D. V., Lee, K. E., Elston, R. C., & Iyengar, S. K. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm164 · Cited by 56 · see citing works
Genetics of age-related macular degeneration
Ting, A., Lee, T. K. M., & MacDonald, I. M. (2009) · Current Opinion in Ophthalmology · doi:10.1097/icu.0b013e32832f8016 · Cited by 56 · see citing works
A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration
Sivakumaran, T. A., Igo, R. P., Kidd, J. M., Itsara, A., Kopplin, L. J., Chen, W., Hagstrom, S. A., Peachey, N. S., Francis, P. J., Klein, M. L., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025598 · Cited by 53 · see citing works
“Several genetic and environmental risk factors influence disease susceptibility [2,3].”
BackgroundMethod
Complete Transcriptome Profiling of Normal and Age-Related Macular Degeneration Eye Tissues Reveals Dysregulation of Anti-Sense Transcription
Kim, E. J., Grant, G. R., Bowman, A. S., Haider, N., Gudiseva, H. V., & Chavali, V. R. M. (2018) · Scientific Reports · doi:10.1038/s41598-018-21104-7 · Cited by 50 · see citing works
Complement System and Potential Therapeutics in Age-Related Macular Degeneration
Park, Y. G., Park, Y. S., & Kim, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136851 · Cited by 50 · see citing works
“The next strong risk locus identified through genome-wide association studies (GWASs) was reported a year later on 10q26 chromosomes [18], which turned out to be associated with age-related maculopathy susceptibility 2 (ARMS2), and high-temperature requirement A serine peptidase 1 (HTRA1) genes [19].”
Background
Genetic variants in three genes and smoking show strong associations with susceptibility to exudative age-related macular degeneration in a Chinese population
Chu, J., Zhou, C., Lü, N., Zhang, X., & Dong, F.-T. (2008) · Chinese Medical Journal · doi:10.1097/00029330-200812020-00011 · Cited by 46 · see citing works
Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration
Hammadi, S., Tzoumas, N., Ferrara, M., Meschede, I. P., Lo, K., Harris, C., Lako, M., & Steel, D. H. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082870 · Cited by 44 · see citing works
“Y402H) conferring an approximately two-fold higher risk of developing late-stage AMD per allele [76] and a common haplotype affecting the age-related maculopathy susceptibility 2 (ARMS2) and HtrA serine peptidase 1 (HTRA1) gene loci [77].”
Background
Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence
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HEMICENTIN-1 (FIBULIN-6) and the 1q31 AMD Locus in the Context of Complex Disease: Review and Perspective
Schultz, D. W., Weleber, R. G., Lawrence, G., Barral, S., Majewski, J., Acott, T. S., & Klein, M. L. (2005) · Ophthalmic Genetics · doi:10.1080/13816810590968023 · Cited by 44 · see citing works
Genotype–Phenotype Correlations for Exudative Age-Related Macular Degeneration Associated with Homozygous HTRA1 and CFH Genotypes
Leveziel, N., Zerbib, J., Richard, F., Querques, G., Morineau, G., Frémeaux‐Bacchi, V., COSCAS, G. J., Soubrane, G., Benlian, P., & Souied, E. H. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-1540 · Cited by 43 · see citing works
Unraveling A Complex Genetic Disease: Age-related Macular Degeneration
Chamberlain, M., Baird, P. N., Dirani, M., & Guymer, R. H. (2006) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2006.08.003 · Cited by 42 · see citing works
Toward a better understanding of ADHD: LPHN3 gene variants and the susceptibility to develop ADHD
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“This is in contrast to a multifactorial threshold model (Elston and Yelverton 1975; Stricker et al. 1995; Iyengar et al. 2004), which incorporates an infinite number of genes with small and equal effects, plus the presence of an environmental trigger.”
Result
Gene Ontology and KEGG Enrichment Analyses of Genes Related to Age-Related Macular Degeneration
Zhang, J., Xing, Z., Ma, M., Wang, N., Cai, Y., Chen, L., & Xu, X. (2014) · BioMed Research International · doi:10.1155/2014/450386 · Cited by 41 · see citing works
Expression of the diabetes risk gene wolframin (WFS1) in the human retina
Schmidt‐Kastner, R., Kreczmański, P., Preising, M. N., Diederen, R. M. H., Schmitz, C., Reis, D., Blanks, J. C., & Dorey, C. K. (2009) · Experimental Eye Research · doi:10.1016/j.exer.2009.05.007 · Cited by 39 · see citing works
“A survey of linkage studies for AMD revealed one study with linkage to 4p16 at marker D4S3360 (Iyengar et al., 2004).”
Background
Molecular Genetic Mechanisms in Age-Related Macular Degeneration
Shughoury, A., Sevgi, D. D., & Ciulla, T. A. (2022) · Genes · doi:10.3390/genes13071233 · Cited by 39 · see citing works
Associations between the Complement System and Choroidal Neovascularization in Wet Age-Related Macular Degeneration
Jensen, E. G., Jakobsen, T. S., Thiel, S., Askou, A. L., & Corydon, T. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249752 · Cited by 39 · see citing works
Case-control genetic association study of fibulin-6 (FBLN6orHMCN1) variants in age-related macular degeneration (AMD)
Fisher, S. A., Rivera, A., Fritsche, L. G., Keilhauer, C. N., Lichtner, P., Meitinger, T., Rudolph, G., & Weber, B. H. F. (2007) · Human Mutation · doi:10.1002/humu.20464 · Cited by 38 · see citing works
“Gln5346Arg mutation was not detected and no other functional associated variants have been reported in these families [Iyengar et al., 2004].”
BackgroundInfluential
The Application of Genetic Risk Scores in Age-Related Macular Degeneration: A Review
Bailey, J. N. C., Hoffman, J., Sardell, R. J., Scott, W. K., Pericak‐Vance, M. A., & Haines, J. L. (2016) · Journal of Clinical Medicine · doi:10.3390/jcm5030031 · Cited by 36 · see citing works
Prospective Study of Common Variants in the Retinoic Acid Receptor–Related Orphan Receptor α Gene and Risk of Neovascular Age-Related Macular Degeneration
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“It is also located within a linkage peak identified previously by 2 independent studies.(18,19) In an initial study, we identified common variants (rs4335725, rs12900948, and 2 haplotypes) within intron 1 of RORA that were associated with AMD in 2 independent, cross-sectional, clinic-based study populations.”
Genetic Factors Associated with Age-Related Macular Degeneration
Leveziel, N., Tilleul, J., Puche, N., Zerbib, J., Lalloum, F., Querques, G., & Souied, E. H. (2011) · Ophthalmologica · doi:10.1159/000328981 · Cited by 32 · see citing works
Novel Retinal and Cone Photoreceptor Transcripts Revealed by Human Macular Expression Profiling
Hornan, D., Peirson, S. N., Hardcastle, A. J., Molday, R. S., Cheetham, M. E., & Webster, A. R. (2007) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-0355 · Cited by 31 · see citing works
Reduction of Sample Heterogeneity through Use of Population Substructure: An Example from a Population of African American Families with Sarcoidosis
Thompson, C. L., Rybicki, B. A., Iannuzzi, M. C., Elston, R. C., Iyengar, S. K., & Gray‐McGuire, C. (2006) · The American Journal of Human Genetics · doi:10.1086/507847 · Cited by 31 · see citing works
“Because multiple analyses of the same data can result in increased type I error, we performed a test of interaction between subpopulation membership and allele sharing to confirm the difference in results from the full and stratified samples.(42) To do this, we fitted two regression models: (1) a reduced model, in whi…”
Method
Age-related retinal degeneration (arrd2) in a novel mouse model due to a nonsense mutation in the Mdm1 gene
Chang, B., Mandal, M. N. A., Chavali, V. R. M., Hawes, N. L., Khan, N. W., Hurd, R. E., Smith, R. S., Davisson, M. L., Kopplin, L., Klein, B. E. K., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn295 · Cited by 30 · see citing works
“Subjects were recruited through the Retina Clinic at the University of Wisconsin, Madison and evaluated as previously described (17).”
BackgroundMethod
Adaptive Two-Stage Analysis of Genetic Association in Case-Control Designs
Zheng, G., Song, K. S., & Elston, R. C. (2007) · Human Heredity · doi:10.1159/000099830 · Cited by 30 · see citing works
Genetic Variations Strongly Influence Phenotypic Outcome in the Mouse Retina
Jelcick, A. S., Yuan, Y., Leehy, B. D., Cox, L. C., Silveira, A. C., Qiu, F., Schenk, S., Sachs, A. J., Morrison, M. A., Nystuen, A., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021858 · Cited by 31 · see citing works
Genetic and Functional Dissection of ARMS2 in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy
Cheng, Y., Huang, L., Li, X., Zhou, P., Zeng, W., & Zhang, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053665 · Cited by 29 · see citing works
“These early studies lead to genomewide linkage analyses using microsatellite markers to search for chromosomal regions associated with affected individuals [19,20,21,22,23,24,25,26,27].”
Background
Single nucleotide polymorphism-based genome-wide linkage analysis in Japanese atopic dermatitis families
Enomoto, H., Noguchi, E., Iijima, S., Takahashi, T., Hayakawa, K., Ito, M., Kano, T., Aoki, T., Suzuki, Y., Koga, M., et al. (2007) · BMC Dermatology · doi:10.1186/1471-5945-7-5 · Cited by 29 · see citing works
“However, linkage of 15q21 to several other inflammatory diseases including osteoarthritis [8] and macular degeneration [27], has been reported.”
Background
Genome-Wide Analyses Demonstrate Novel Loci That Predispose to Drusen Formation
Jun, G., Klein, R., Klein, R., Fox, K. A., Millard, C., Capriotti, J., Russo, K., Lee, K. E., Elston, R. C., & Iyengar, S. K. (2005) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.04-1360 · Cited by 29 · see citing works
Genetic Association of Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy
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“The CFH gene is located on chromosome 1q31, a locus previously identified by linkage analyses.(9,10) Of note, a small sample of 96 patients and 50 control subjects were included in this GWAS.”
Background
Pharmacogenetics of Antiangiogenic and Antineovascular Therapies of Age-Related Macular Degeneration
Agosta, E., Lazzeri, S., Orlandi, P., Figus, M., Fioravanti, A., Desidero, T. D., Sartini, M. S., Nardi, M., Danesi, R., & Bocci, G. (2012) · Pharmacogenomics · doi:10.2217/pgs.12.77 · Cited by 27 · see citing works
Ongoing controversies and recent insights of the ARMS2-HTRA1 locus in age-related macular degeneration
May, A., Su, F., Dinh, B., Ehlen, R., Tran, C., Adivikolanu, H., & Shaw, P. X. (2021) · Experimental Eye Research · doi:10.1016/j.exer.2021.108605 · Cited by 29 · see citing works
Heterogeneity of the genetic risk in age-related macular disease
Assink, J. J. M., Klaver, C. C. W., Houwing‐Duistermaat, J. J., Wolfs, R. C. W., van Duijn, C. M., Albert Hofman, D., & de Jong, P. T. V. M. (2005) · Ophthalmology · doi:10.1016/j.ophtha.2004.10.035 · Cited by 27 · see citing works
Incorporating prior knowledge to facilitate discoveries in a genome-wide association study on age-related macular degeneration
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“For example, complement factor H (CFH, GeneID 3075) gene within 1q32 was reported to be related to AMD, both from genome-wide linkage analyses [10-15] (all published before Klein et al.”
BackgroundResultInfluential
Epidemiology of Age-Related Macular Degeneration
Seddon, J. M., & Chen, C. A. (2006) · Elsevier eBooks · doi:10.1016/b978-0-323-02598-0.50064-1 · Cited by 26 · see citing works
Genomic and Phenomic Research in the 21st Century
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“This study, along with two others published simultaneously in Science[7, 8], was able to map a common variant in CFH that was associated with AMD, which validated previous findings first discovered by family-based linkage analyses [9–12].”
Result
Resequencing of pooled DNA for detecting disease associations with rare variants
Wang, T., Lin, C., Rohan, T. E., & Ye, K. Q. (2010) · Genetic Epidemiology · doi:10.1002/gepi.20502 · Cited by 24 · see citing works
The Impact of the Human Genome Project on Complex Disease
Bailey, J. N. C., Pericak‐Vance, M. A., & Haines, J. L. (2014) · Genes · doi:10.3390/genes5030518 · Cited by 23 · see citing works
“These four studies simultaneously reported the role of variation in a chromosome 1 region that had previously been highlighted in AMD linkage studies [14,15,22]; identifying this major genetic determinant of AMD, something that even a year earlier was thought not to exist, was a major”
Background
Genetics of Age-related Macular Degeneration
DeAngelis, M. M., & Ji, F. (2008) · Elsevier eBooks · doi:10.1016/b978-1-4160-0016-7.50146-6 · Cited by 23 · see citing works

Expanded genome scan in extended families with age-related macular degeneration
Barral, S., Francis, P. J., Schultz, D. W., Schain, M. B., Haynes, C. L., Majewski, J., Ott, J., Acott, T. S., Weleber, R. G., & Klein, M. (2007) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2006.12.018 · Cited by 2 · see citing works
Am. J. Hum. Genet. 74:482–494, 2004 Age-Related Macular Degeneration: A High-Resolution Genome Scan for Susceptibility Loci in a Population Enriched for Late-Stage Disease
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Age-related macular degeneration–a genome scan in extended families
Majewski, J., Schultz, D. W., Weleber, R. G., Schain, M. B., Edwards, A. O., Matise, T. C., Acott, T. S., Ott, J., & Klein, M. L. (2003) · The American Journal of Human Genetics · doi:10.1086/377701 · Cited by 201 · see citing works
Age-Related Macular Degeneration: A High-Resolution Genome Scan for Susceptibility Loci in a Population Enriched for Late-Stage Disease
Abecasis, G. R., Yashar, B. M., Zhao, Y., Ghiasvand, N. M., Zareparsi, S., Branham, K. E. H., Reddick, A. C., Trager, E. H., Yoshida, S., Bahling, J., et al. (2004) · The American Journal of Human Genetics · doi:10.1086/382786 · Cited by 182 · see citing works
A full genome scan for age-related maculopathy
Weeks, D. E. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.9.1329 · Cited by 137 · see citing works

Authors: Iyengar, S. K., Song, D., Klein, B. E. K., Klein, R., Schick, J. H., Humphrey, J., Millard, C., Liptak, R., Russo, K., Jun, G., Lee, K. E., Fijal, B., & Elston, R. C.
Affiliations: Case Western Reserve University (US)
University of Wisconsin–Madison (US)
Corresponding author: Iyengar, Sudha K.
ORCID: Iyengar, Sudha K.
Jun, Gyungah
Lee, Kristine E.
Elston, Robert C.
Venue: The American Journal of Human Genetics
Publisher: Elsevier BV
Published: 2004-01
Volume: 74
Issue: 1
Pages: 20-39
ISSN: 0002-9297 (ISSN-L)
DOI: 10.1086/380912
PMC: PMC1181910
OpenAlex: W1968744211
Cited by: 173
References: 73
Citations by year: 2025: 3 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 7 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 1 · 2014: 4 · 2013: 10 · 2012: 9
FWCI: 25.21
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3487 d)
Locations: The American Journal of Human Genetics (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Public Health Service
National Heart, Lung, and Blood Institute (HL07567, T32HL007567)
National Eye Institute (U10 EY06594, U10EY006594, EY10605, R01EY010605)
National Institute of General Medical Sciences (GM-28356, R37GM028356, R01GM028356)
National Center for Research Resources (RR-03655, P41RR003655)
Topics: Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Keywords: age-related macular degeneration, genetic susceptibility, chromosome 15q, oligogenic inheritance, family heterogeneity, epistasis, neovascular disease, geographic atrophy, EFEMP1, extended family, Beaver Dam Eye Study, retinal pigment epithelium degeneration, candidate genes, single nucleotide polymorphisms
MeSH terms: Aged, Aging, Chromosome Mapping, Female, Genetic Markers, Humans, Lod Score, Macular Degeneration, Male, Middle Aged, Phenotype, Genome, Human, Genetic Predisposition to Disease, Siblings

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Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration

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