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National Eye Institute Workshop to Identify Gaps, Needs, and Opportunities in Ophthalmic Genetics

June 4-5, 2009

Diseases, Biological Systems, Approaches and Methodologies

White Papers

Prior to the workshop, short white papers were prepared summarizing the progress in various fields of disease research, biological systems, approaches, and methodologies. These white papers represent the opinions of their authors, but not necessarily the views of the NEI. All white papers were distributed to participants in advance of the meeting.


Congenital Strabismus

Elizabeth Engle


Strabismus and secondary amblyopia is a leading cause of visual impairment in those under 60 years of age. For the sake of genetic analysis it is helpful to divide strabismus into incomitant and comitant forms. Individuals with incomitant (complex or paralytic) strabismus have an ocular misalignment of greater magnitude in one direction. Incomitant strabismus includes the various forms of Duane syndrome, horizontal gaze palsy, and CFEOM (congenital fibrosis of the extraocular muscles), each of which is relatively rare and can be inherited as a Mendelian trait. Individuals with comitant strabismus have a similar magnitude of deviation in all gaze positions. Comitant strabismus includes various forms of eso-, exo-, hyper- and hypodeviations. Although it is much more common and does cluster in families, comitant strabismus appears to segregate as a complex trait (as was noted by Hippocrates).

Genetics of incomitant strabismus: Heritability has been established by identification of Mendelian inheritance in families. Gene identification has been through family-based linkage analysis and sequencing of positional candidate genes. This has resulted in the publication of the phenotypic features and genetic etiology of multiple syndromes, now referred to as the congenital cranial dysinnervation disorders (CCDDs). A subset is nonsyndromic. Genetics suggest that these disorders can result from errors in the development of ocular motor neurons and, in particular, in the appropriate guidance and/or targeting of axons to extraocular muscles.

Genetics of comitant strabismus: The incidence of nonsyndromic comitant strabismus is estimated to be between 1-5%, and varies for specific types of strabismus and between different races. In addition, over 270 entries in OMIM are associated with comitant strabismus, most of which is syndromic. Population, twin, and family studies support inheritance of nonsyndromic comitant strabismus as a complex trait with an odds ratio for concordant sibs of ~3 and of a first-degree relative of 3 to 5. Families are usually concordant for either esotropia or exotropia; families with both may reflect the presence of two relatively common variants or a common underlying genetic susceptibility. Low birth weight, maternal smoking in pregnancy, and advanced maternal age have each been identified as contributing risk factors in some but not all studies. Several family-based linkage analyses are reviewed below. No GWAS studies reported.

Consensus on phenotyping: (a) Incomitant strabismus: Phenotyping has been based primarily on phenotype-genotype studies following gene identification. There may be ascertainment bias. (b) Comitant strabismus: In most cases it is clear if someone is affected, and the Olmsted, Baltimore, and MEPED studies were in close agreement as to phenotypic definitions. GWAS studies may benefit from consensus on diagnostic cutoffs, data collection, and patient population. If strabismus is a quantitative trait it may be indicated to enroll patients at risk.

Genetic resources for strabismus: Researcher-based cohorts, population-based cohorts, EyeGENE.

Major strabismus genetics studies

Incomitant strabismus: Multiple publications of linkage and gene identification for incomitant strabismus genes. These are family-based linkage using STRP or SNP-based methods followed by position-based candidate gene sequencing.

1. Elizabeth Engle PI. NEI support for the identification of CCDD genes includes: Molecular Basis of Congenital Strabismus, 5R01EY012498-09; Genetic and anatomic basis of the fibrosis syndromes, 5R01EY013583-08; and Genetic Etiologies of Horizontal Strabismus, 5R01EY015298-05 - Current enrollment of 997 CCDD pedigrees from ascertainment world-wide. Phenotyping typically performed prospectively by collaborating clinician and, as necessary, in a targeted fashion following gene identification. Mutations identified in 153 probands, or 15% of ascertained cohort. Phenotyping parameters: incomitant strabismus or ptosis.
2. Ascertainment of incomitant strabismus by investigators in the Middle East, Japan, Europe, Australia, and the USA.

Comitant strabismus: Four manuscripts of linkage studies published from three populations. There are two family-based STRP genome-wide screens using 400 markers and one family-based linkage to previously reported locus.

1. Jeremy Nathans, PI (USA). Dr. Nathan's 2003 PNAS paper reported ascertainment of 209 pedigrees with nonsyndromic strabismus from the USA (most in mid-Atlantic region), from which 7 of the first 150 families were chosen for STRP genome-wide linkage analysis by CIDR. Phenotypes were based on telephone interviews and, in some cases, retrospective chart review and did not necessarily distinguish eso- and exotropia. They reported linkage of 1 pedigree to 7p22.1 (STBMS1) as a recessive trait with incomplete penetrance and high carrier frequency. Funded by NEI and HHMI.
2. Toshihiko Matsuo, PI (Japan). Dr. Matsuo's 2003 Acta Med. Okayama and 2009 IOVS papers report a combined ascertainment of 55 Japanese pedigrees with 2 or more affected members (average number of affected per family was 2.2 with range of 2-7) and family-based genome-wide STRP analysis of all families. Phenotyping based on exam of all probands and all available relatives, history, and medical record review. Data was analyzed in collaboration with Dr. Jurg Ott under various assumptions. The 2009 paper reports linkage to 4q28.3 under a dominant model (HLOD 3.62, NPL 2.68) and to two loci at 7q31.2 under a recessive model (HLOD 4.4 and 3.93); they did not identify linkage to STBMS1.
3. Aine Rice, PI (UK). Dr. Rice's 2009 IOVS paper reported linkage analysis to the STMBS1 locus using STR markers in 12 British pedigrees with primary nonsyndromic comitant strabismus. Phenotyping was done by exam whenever possible. One pedigree mapped to the locus with a lod score of >3 assuming autosomal dominant inheritance with reduced penetrance.
4. Elizabeth Engle, PI (USA). Dr. Engle is currently collaborating with Dr. Hunter and the Ophthalmology Dept at Children's Hospital Boston to ascertain and enroll families and individuals with comitant strabismus or associated risk factors. The last several years were focused on developing the infrastructure for accurate, high-throughput enrollment and phenotyping, and developing the database program for phenotype and genotype entry and sample management. This is complete and enrollment is underway.

Known Genes

Locus Inherit. Linkage Gene Mutation Protein Ref
CFEOM1 AD 12q12 KIF21A missense Kinesin 1
CFEOM2 ar 11q13.3 PHOX2A LOF Transc. factor 2
CFEOM3 AD 16qter       3
CFEOM4 (3B) AD t(2:13)(q37.3;q12.11)       4
Turkel ar 21q22       5
DURS1 spor 8q13 (CPA6) cytogen   6 7
DURS2 AD 2q31-q32.1 CHN1 missense Cell signaling RacGAP 8
DRRS AD 20q13.13-q13.2 SALL4 haploinsuf Transc. factor 9
BSAS/ABDS ar 7p15.3 HOXA1 LOF Transc. factor 10
HGPPS ar 11q23-q25 ROBO3 LOF Axon guide receptor 11
STBMS1 ar/AD 7p22.1       12 13
  ar 7q31.2       14
  AD 4q28.3       14

Next Steps

Short-term goals to advance the field:
1. Continue ascertainment of new syndromes & identification of genes
2. GWAS and CNV analysis of Duane syndrome

1. Continue family-based linkage studies
2. Initial GWAS(s) to determine if existing cohorts can identify common variants that explain a sizable fraction of strabismus heritability.
3. Establish consortia for standardized large-scale enrollment and phenotyping of patients with all common forms of strabismus, anisometropia, hypermetropia > 3 D, and amblyopia
4. Standardized and/or centralized data entry and biospecimen banking
5. Establish ophthalmic consortia for statistical genetic analysis of GWAS data

Long-term goals to advance the field:
1. Functional studies of molecular etiologies with eventual translation to treatment

1. Linkage, GWAS meta-analysis, replication, identification of causal variants
2. Functional studies of variants / associated genes to understand molecular etiologies
3. Improved treatment and outcome prediction through accurate genetic characterization in advance of intervention

Communal strabismus research resources that would represent a good investment for NEI:
1. Consortium of clinicians and investigators for standardized identification, characterization of phenotype, and collection of genetic material.
2. Centralized sample banking and storage


1: Donahue SP. Clinical practice. Pediatric strabismus. N Engl J Med. 2007 Mar 8;356(10): 1040-7.
2: Engle EC. Genetic basis of congenital strabismus. Arch Ophthalmol. 2007 Feb;125(2):189-95.


  1. Yamada, K. et al. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet 35, 318-321 (2003).
  2. Nakano, M. et al. Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet 29, 315-320. (2001).
  3. Doherty, E.J. et al. CFEOM3: a new extraocular congenital fibrosis syndrome that maps to 16q24.2-q24.3. Invest Ophthalmol Vis Sci 40, 1687-94 (1999).
  4. Aubourg, P. et al. Assignment of a new congenital fibrosis of extraocular muscles type 3 (CFEOM3) locus, FEOM4, based on a balanced translocation t(2;13) (q37.3;q12.11) and identification of candidate genes. J Med Genet 42, 253-9 (2005).
  5. Tukel, T. et al. A new syndrome, congenital extraocular muscle fibrosis with ulnar hand anomalies, maps to chromosome 21qter. J Med Genet 42, 408-15 (2005).
  6. Calabrese, G. et al. Narrowing the Duane syndrome critical region at chromosome 8q13 down to 40 kb. Eur J Hum Genet 8, 319-24 (2000).
  7. Pizzuti, A. et al. A peptidase gene in chromosome 8q is disrupted by a balanced translocation in a duane syndrome patient. Invest Ophthalmol Vis Sci 43, 3609-12 (2002).
  8. Miyake, N. et al. Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome. Science 321, 839-43 (2008).
  9. Al-Baradie, R. et al. Duane Radial Ray Syndrome (Okihiro Syndrome) Maps to 20q13 and Results from Mutations in SALL4, a New Member of the SAL Family. Am J Hum Genet 71, 1195-9 (2002).
  10. Tischfield, M.A. et al. Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet 37, 1035-7 (2005).
  11. Jen, J.C. et al. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 304, 1509-13 (2004).
  12. Parikh, V. et al. A strabismus susceptibility locus on chromosome 7p. Proc Natl Acad Sci U S A 100, 12283-8 (2003).
  13. Rice, A. et al. Replication of the recessive STBMS1 locus but with dominant inheritance. Investigative Ophthalmology and Visual Science (2009).
  14. Shaaban, S. et al. Chromosomes 4q28.3 and 7q31.2 as new susceptibility loci for comitant strabismus. Investigative Ophthalmology and Visual Science 50, 654-61 (2009).

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Retinal Degenerations

Michael Gorin


Historically, the major advances in the molecular genetics of retinal degenerations have been based on a combination of family-based linkage studies and candidate gene screening. These approaches have been used in combination and independently of each other. The greatest success has been for autosomal dominant and X-linked conditions, though recessive conditions have been successfully studied using homozygosity mapping and inbred populations with strong founder effects. In a number of instances (e.g. Bardet Biedl Syndrome), multiple disease-causing genes have been found by using initial mapping and gene screening in conjunction with subsequent candidate gene analyses based on genes that were suspected based on biological pathway analyses. A summary of the current status of the molecular genetics of retinal degenerations can be found at RetNet.

Large-scale mutation screening efforts for specific genes such as ABCA4 have been undertaken by several groups but never in a coordinated manner. For most forms of retinal degenerations, there remains a significant number of patients for whom mutations in the known disease-causing genes have not been found and this is the result of a combination of genetic heterogeneity as well as the limitation of current mutation screening methods. There currently remains a place for family-based linkage analysis and candidate gene testing for retinal degenerations, but funding for such studies has virtually disappeared from NIH or private foundations. In part this is due to a shift in priorities of these groups towards translational research and new therapies, as well as greater emphasis on genome-wide association studies and sequencing to find disease-causing genes. The advantages and disadvantages of these alternative approaches are beyond the scope of this summary.

There are several groups that provide either research or CLIA- approved molecular diagnostic testing for a number of retinal degenerations (LCA, Bardet Biedl, autosomal dominant RP, X-linked RP, cone dystrophies (autosomal recessive and X-linked), achromatopsias, CSNB, albinism, Stargardt disease (including AD Stargardt-like dystrophy, Bietti crystalline dystrophy).(see The mutation detection rate of these screening programs is not known, nor are there standards for phenotyping prior to the submission of samples. All of these testing groups rely on the referring clinician to have a suspected diagnosis. In cases of RP, it is unclear if most referring physicians take an adequate family history or examine family members to clearly establish an inheritance pattern.

There is no central clearing house for the collection of mutations that have been found by research or clinical testing. If such a central system were established, it would probably be necessary to also identify samples for which no mutation is found and to be able to distinguish when an individual has been tested multiple times or at different laboratories. A standard forensic DNA genotyping of each tested person (or comparable set of genetic markers) would solve this issue, but would raise significant legal and ethical issues (and raise testing costs). However having a unique genetic tag for each individual would be a means of ensuring anonymity of the person while still allowing the system to know if the person has undergone multiple testing.

There is also no clear consensus as to what is sufficient to define a disease-causing mutation. Some laboratories such as the Carver Laboratory, have a methodology for describing if a variant is definitely disease-causing, probably disease-causing, possibly disease-causing, or not disease-causing. A central database of variants could greatly facilitate these efforts. This issue becomes even more critical as the newer sequencing technologies makes it feasible to sequence not only the entire coding regions of genes and splice sites but also introns and promoters that may harbor functionally active variants. The explosion of genetic variants that can be readily identified makes their interpretation all the more important and challenging, especially when compared to some of the current technologies that test only for known disease-causing variants and avoid this issue but also miss out on discovering new disease-causing mutations.

Known Genes

Last updated April 26, 2009

A. Number of Genes and Loci by Disease Category (One Disease per Gene/Locus)
Disease Category Total # of Genes and Loci No. of Identified Genes
Bardet-Biedl syndrome, autosomal recessive 12 12
Chorioretinal atrophy or degeneration, autosomal dominant 1 1
Cone or cone-rod dystrophy, autosomal dominant 7 5
Cone or cone-rod dystrophy, autosomal recessive 5 3
Cone or cone-rod dystrophy, X-linked 2 0
Congenital stationary night blindness, autosomal dominant 1 1
Congenital stationary night blindness, autosomal recessive 5 5
Congenital stationary night blindness, X-linked 2 2
Leber congenital amaurosis, autosomal recessive 9 8
Macular degeneration, autosomal dominant 12 6
Macular degeneration, autosomal recessive 2 2
Ocular-retinal developmental disease, autosomal dominant 1 1
Optic atrophy, autosomal dominant 3 1
Optic atrophy, autosomal recessive 2 1
Optic atrophy, X-linked 1 0
Retinitis pigmentosa, autosomal dominant 16 15
Retinitis pigmentosa, autosomal recessive 20 16
Retinitis pigmentosa, X-linked 6 2
Syndromic/systemic diseases with retinopathy, autosomal dominant 8 6
Syndromic/systemic diseases with retinopathy, autosomal recessive 29 22
Syndromic/systemic diseases with retinopathy, X-linked 2 1
Usher syndrome, autosomal recessive 11 9
Other retinopathy, autosomal dominant 9 4
Other retinopathy, autosomal recessive 14 12
Other retinopathy, mitochondrial 7 7
Other retinopathy, X-linked 9 7
TOTALS 196 149
Prevalence of Retinitis Pigmentosa and Estimated Percentages of Retinitis Pigmentosa Types
Category Type % of Total*
Nonsyndromic RP Autosomal dominant RP 20
Autosomal recessive RP 13
X-linked RP 8
Isolated or unknown RP 20
Leber congenital amaurosis 4
Subtotal 65
Syndromic and systemic RP Usher syndrome 10
Bardet-Biedl syndrome 5
Other 10
Subtotal 25
Other or unknown types of RP 10
  Total 100

Abbreviation: RP, retinitis pigmentosa.
*The total prevalence is 1 case per 3100 persons (range, 1 case per 3000 persons to 1 case per 7000 persons), or 32.2 cases per 100 000 persons. Arch Ophthalmol. 2007 February; 125(2): 151-158.

Nonsyndromic, nonsystemic RP encompasses 65% of all cases, or about 65 000 people in the United States. Of the total number of nonsyndromic, nonsystemic cases, roughly 30% are adRP, 20% are autosomal recessive RP, 15% are X-linked RP, and 5% are early-onset forms of RP that are typically diagnosed as recessive LCA. The remaining cases, at least 30%, are isolated or simplex cases. The simplex cases are likely to include many individuals with recessive mutations, but dominant-acting de novo mutations are also found in these individuals.

Leber congenital amaurosis (LCA) is a group of severe autosomal recessive retinal dystrophies defined by the onset of blindness at birth and absent electroretinographic signals. LCA is the most common cause of infant blindness in schools for the blind with approximately 200,000 humans affected worldwide. In total, 14 genes are associated with LCA and mutations in these retinal genes account for approximately 60% of patients. Koenekoop R, et al. Genetics, phenotypes, mechanisms and treatments for Leber congenital amaurosis: a paradigm shift. Expert Review of Ophthalmology; Aug2008, Vol. 3 Issue 4, p397-415

Next Steps

Areas for future investigation:

Modifier genes for retinal degenerations and their complications Genetics of macular edema, central serous chorioretinopathy, macular telangectasia, others. Mechanisms of photoreceptor death including cone cell death in rod dystrophies.

Potential Communal Resources to be developed:


Mutations in Known Genes Account for 58% of Autosomal Dominant Retinitis Pigmentosa (adRP)
Stephen P. Daiger, Lori S. Sullivan, Anisa I. Gire, David G. Birch, John R. Heckenlively, and Sara J. Bowne
R.E. Anderson et al. (eds.), Recent Advances in Retinal Degeneration Springer 2008 pp203-9

Genetic Analysis of Indian Families with Autosomal Recessive Retinitis Pigmentosa by Homozygosity Screening
Hardeep Pal Singh1, Subhadra Jalali2, Raja Narayanan2, Chitra Kannabiran1*
IOVS Papers in Press. Published on April 1, 2009 as Manuscript iovs.09-3479

Perspective on Genes and Mutations Causing Retinitis Pigmentosa
Stephen P. Daiger, Ph.D., Sara J. Bowne, Ph.D., and Lori S. Sullivan, Ph.D.
Arch Ophthalmol. 2007 February; 125(2): 151-158

GeneReviews -- NCBI Bookshelf
Bardet-Biedl Syndrome
Cohen Syndrome
Leber Congenital Amaurosis
Retinitis Pigmentosa
Usher Syndrome



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Age-related Macular Degeneration (AMD)

Anand Swaroop


AMD is a common multifactorial neurodegenerative disease that is a major cause of visual impairment in the elderly, accounting for approximately half of all blindness in the US. Clinical phenotypes of AMD are rather broad, ranging from the presence of drusen in early stages to focal loss of photoreceptors and RPE and neovascularization in the advanced disease. While several phenotype classifications have been proposed, the disease grading system proposed by AREDS is now used in many genetic studies.

Aging is the strongest risk factor for AMD. Environmental factors, such as smoking, diet, and probably others, can modify the risk. Genetic contribution to AMD susceptibility was first documented in early 1990s by multiple studies reporting familial aggregation, higher risk in first degree relatives of affected individuals and concordance in twins. Initial genetic studies used linkage analysis using large families and subsequently sibs or relative pairs. Despite complications associated with phenotypic variations, late age of diagnosis, and phenocopy effects, Klein and colleagues were the first to map, in 1998, an AMD locus to human chromosome 1q25-31 in a large apparently autosomal dominant family with dry form of disease. Within few years, several groups (headed by Gorin, Klein, Pericak-Vance, Seddon, Swaroop, Weber) used small families (affected sib- or relative- pairs) to map potential susceptibility loci in independent cohorts. These studies, together with a meta-analysis, identified two major loci at 1q31 and 10q26 and evidence for additional loci at several other chromosomes. Linkage studies, however, suggested only broad chromosomal regions but formed the basis for future identification of associated gene variants.

Based on a priori knowledge of AMD pathobiology and/or phenotypic similarity with early-onset macular diseases, multiple candidate genes were selected for association studies. However, the findings from these investigations have not been definitive, probably because of small sample sizes, narrow definition of the gene, and/or limited number of SNPs used.

More recent genetic studies have focused on association studies targeted to either specific candidate regions or whole genome .

Major Studies

Genetic studies of AMD had a major success in 2005 when three groups (headed by Hoh, Haines/Pericak-Vance and Edwards) using different approaches identified strong association of a key variant Y402H in Complement Factor H (CFH) with disease. The involvement of complement pathway in AMD pathogenesis was consistent with the hypothesis of Hageman and colleagues based on the analysis of drusen and significantly advanced the research in this field. Quickly thereafter, several groups all over the world replicated CFH association to AMD; however, more recent studies including those from Abecasis/Swaroop, Chakravorty/Hughes, Daly/Seddon, Haines/Pericak-Vance, Iyengar, and other investigators demonstrate the involvement of multiple variants in over 100 kb CFH region (primarily in the non-coding region and in nearby CFH-like genes), suggesting that changes in expression and/or activity of CFH likely contribute to AMD pathogenesis. Genetic variants in a number of other complement genes have since been associated with AMD. Discovery of CFH association with AMD represents a key milestone in genetics of complex disease research and success of human genome project.

Another major milestone in AMD genetics was the discovery of strong association of variants by groups led by Gorin/Weeks, Weber and others in a region at chromosome 10q26 including PLEKHA1, an uncharacterized gene LOC387715 (now called ARMS2) and HTRA1 (or PRSS11). While two groups (headed by Hoh and Zhang) provided evidence for the involvement of HTRA1, more recent studies by several groups (particularly Swaroop/Abecasis and Weber) have provided strong support for variants in the ARMS2 gene. ARMS2 variants can account for the association signal at 10q26 and significantly affect its expression (Weber, Edwards). It is however possible that ARMS2 variants also alter the nearby HTRA1 promoter activity.

Several AMD genomewide association studies (GWAS) have been initiated during the last couple of years. AMD-GWAS of almost 3500 case-controls in a discovery cohort was completed recently (directed by Swaroop, with Abecasis, Stambolian and Edwards as co-investigators) and the data has been submitted to dbGAP. Replication of top SNPs was performed in over 10,000 samples from five groups. Another GWAS has been completed by Seddon/Daly group with replications from three other groups. The two GWAS manuscripts are currently under review.

A number of other groups around the world have initiated GWAS in independent cohorts. What is becoming clear is that the association signals from new loci are relatively weak and require large sample size. While the current GWAS has identified at least two new genes (and pathways), a satisfactory conclusion of AMD genetic studies will require GWAS in very large samples and meta-analysis. Another recent medical resequencing study (directed by Abecasis and Swaroop) has been initiated with support from NHGRI, with a goal to resequence thousands of case-controls in the region of major loci to identify causal variants.

All major discovery studies have been performed in Caucasian samples and, to my knowledge, were supported by NEI.

Known Genes

Genetic studies have led to tremendous progress during the last 4 years in elucidating the pathways associated with AMD pathogenesis. The discovery of CFH led to the identification of variants in several complement pathway genes that are associated with AMD susceptibility; while association with C2/CFB, C3, and CFI is confirmed by replication studies, a few others require further validation. A number of other immune response genes have also been associated with AMD risk; however, subsequent studies have not validated such associations. In addition to immune modulation, some evidence exists for association of genes with a role in extracellular matrix; their contribution, if any, to AMD will require further investigations. Pathways involved in stress response and mitochondrial function have also been implicated, but additional studies are needed to delineate their role in AMD.

Despite extensive studies, the precise role of AMD-associated variants in CFH and ARMS2 in disease pathogenesis is as yet unclear.

Next Steps

We have been fortunate to have excellent new treatments for the neovascular subtype of AMD based on inhibition of angiogenesis. These treatments have provided new hope to patients with choroidal neovascularization. It must however be emphasized that AMD phenotype is not dictated by a single gene variant or even with a few. It is highly likely that aging associated changes compound the impact of inherited AMD-associated variants and that environmental factors further modify this to give the clinical spectrum of AMD phenotypes. Treatments involving one gene or pathway are unlikely to have a major impact on early and/or dry AMD. Our long-term focus should be on intervention in early stages of AMD and eventually in presymptomatic individuals based on genetic risk diagnosis. Discovery of new treatment and intervention paradigms must therefore involve a comprehensive understanding of important genes and pathways and multiple approaches using different strategies and model systems.

Short-term goals: (i) Completion of genetic analysis - this should include meta-analysis of GWAS and replication of top signals for advanced AMD, resequencing of associated regions to determine causal and/or protective alleles, and GWAS of ethnic groups other than Caucasians to identify pathways and causality, (ii) Genetic analysis of retinal aging and early AMD, (iii) Impact of genetic variants on cell function.

Long-term: (i) A prospective long-term study to evaluate the effect of genotypes (using top associated SNPs for CFH, ARMS2/HTRA1, C2/CFB, C3, CFI, and others from GWAS) on disease progression and treatments in defined population cohort(s), (ii) Development of model systems (such as appropriate cell culture, C. elegans and/or Drosophila) for faster screening of drug targets and compounds, and of animal models (mouse, swine and primates) with multiple causal/associated alleles for evaluating treatments, (iii) Novel approaches for pathway analysis, and to investigate gene-gene and gene-environment interactions. At this stage, it appears we have at least three or four pathways associated with AMD. This however requires careful exploration using genetic and biochemical methods.

NEI should establish 8-10 Centers of Excellence for Genetic Analysis of Ocular Diseases. Each center should follow similar phenotyping criteria for standardized phenotyping of patient population using specific parameters and latest equipment and methodology for each disease. Each Center should establish comprehensive electronic databases for phenotype and genetic information.


Swaroop A, Chew EY, Bowes Rickman C, Abecasis GR: Unraveling a multifactorial late-onset disease: From genetic susceptibility to disease mechanisms for age-related macular degeneration. Annu. Rev. Genomics Hum. Genet. 2009. 10:1.1-1.25 doi: 10.1146/annurev.genom.9.081307.164350

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Janey Wiggs and Lou Pasquale


Glaucoma is the third most prevalent cause of visual impairment and blindness among white Americans and is the leading cause of blindness among black Americans. All forms of glaucoma have in common optic nerve degeneration characterized by typical visual field defects and are usually associated with elevated intraocular pressure (IOP). In most instances, the elevation of IOP results from impaired drainage of aqueous humor (produced by the ciliary body) through the trabecular meshwork outflow pathways. Glaucoma causes irreversible blindness that can only be prevented by therapeutic intervention at early stages of the disease. A family history of glaucoma has long been recognized as a major risk factor, suggesting that specific gene defects contribute to the pathogenesis of the disorder. Glaucoma may be inherited as mendelian-dominant or mendelian-recessive traits (usually early-onset forms of the disease), or may exhibit a heritable susceptibility consistent with complex trait inheritance.

Genetics of early-onset (mendelian) glaucoma: Typically, early-onset forms of glaucoma are inherited as mendelian-dominant or mendelian-recessive traits, including early-onset open-angle glaucoma; congenital glaucoma; development glaucomas, including Rieger syndrome, glaucoma associated with nail-patella syndrome, and nanophthalmos; and glaucoma associated with pigment dispersion syndrome. At least one gene has been identified for each of these forms of glaucoma (with the exception of pigment dispersion syndrome) through family-based linkage analysis and sequencing of positional candidate genes. Genes responsible for early-onset forms of glaucoma are primarily associated with high intraocular pressure phenotypes and accordingly lead to a disruption of the aqueous humor outflow pathways.

Genetics of late-onset (complex) glaucoma: Adult-onset forms of glaucoma, including primary open angle glaucoma (POAG), low-tension glaucoma, and glaucoma associated with pseudoexfoliation, are inherited as complex traits. POAG is the most common form of glaucoma and a history affected first-degree relatives is a major risk factor (sibling risk of 7 to 10 times that of the general population). The high concordance of POAG between monozygotic twins [90%] is also consistent with a significant genetic predisposition. Parametric linkage approaches using large pedigrees affected by POAG have lead to the identification of 14 major glaucoma loci (GLC1A-N), and genes that contribute to rare mendelian forms of POAG have been identified in 3 of these regions. Microsatellite-based genome-wide scans using nonparametric methods have also been completed for Caucasian POAG patients (Wiggs et al. 2000), African-Caribbean patients in Barbados (Nemesure et al. 2003), and African-American patients with diabetes and elevated IOP (Rotimi et al. 2006). These scans, using between 373 to 445 microsatellite repeat markers, identified 10 genomic regions that may harbor POAG susceptibility genes. Pseudoexfoliation syndrome is also inherited as a complex trait, and one gene, LOXL1, has been significantly associated with the disease. The high frequency of the at risk genotype in unaffected individuals indicates that additional genetic and/or environmental factors also contribute to this disease. Normal tension or low tension glaucoma (glaucomatous optic nerve degeneration without elevated intraocular pressure) is heritable and a familial form of NTG is caused by variants in OPTN.

Phenotype consensus: Glaucoma is a heterogeneous collection of disorders that all have in common a characteristic degeneration of the optic nerve that is usually associated with an elevation of the intraocular pressure. For the GENEVA GLAUGEN and NEIGHBOR studies a harmonized case/control definition has been developed that uses reproducible visual field defects characteristic of glaucoma-associated optic nerve disease as the centerpiece.

Genetic resources for glaucoma: Population-based studies, clinic-based studies, eyeGENE.

Major Studies

Early onset glaucoma:
On going studies in early onset glaucoma include: whole genome linkage approaches to identify new genes; genotype-phenotype correlations to develop diagnostic/prognostic panels and to define modifier genes; defining molecular events responsible for early onset disease.

Late onset glaucoma:
Current studies are directed toward the identification of genetic risk factors for POAG. Low-density genome-wide family linkage studies have revealed several broad chromosomal regions likely to contain POAG susceptibility genes but genetic variants showing significant association with POAG have not yet been found. To identify genetic variants that are biologically relevant to this genetically complex disease, large-scale whole genome association (WGA) studies are needed.

Ongoing studies:
Admixture Mapping of Glaucoma Genes in African Americans (R01EY019126-01) Hauser PI, Duke University Medical Center, funded by NEI. US African American clinic based population and Ghana clinic based population.

GENEVA (GLAUGEN): Genes and Environment Initiative in Glaucoma (1U01HG004728-01); Pasquale PI, Wiggs co-PI; Nurses Health Study, Physicians Health Study, Mass Eye and Ear Clinic; 1200 cases, 1200 controls, phenotype harmonized with NEIGHBOR; funded by NHGRI.

NEIGHBOR: The NEIGHBOR Consortium Glaucoma GWAS (1X01HG005259-01); Wiggs PI, Hauser co-PI; University of Pittsburgh, Johns Hopkins, University of West Virginia, University of Miami, Duke, University of Michigan, Stanford, University of California San Diego; 2400 cases, 2400 controls, phenotype harmonized with GENEVA GLAUGEN, funded by NEI.

OHTS study, PI Fingert, 2000 samples (200-300) POAG; CCT on all
Beaver Dam, PI B. Klein, 5000 samples, approximately 10% POAG

Known Genes

Table. Chromosomal Locations of genes Associated With Glaucoma

Chromosome Location Condition Locus (Gene) Inheritance Pattern
1q23 Early-and adult-onset POAG GLC1A (MYOC) Early-onset: AD
Adult-onset; complex
1p36 Congenital glaucoma GLC3B AR
2p21 Congenital glaucoma GLC3A (CYP1B1) AR
2cen-2q13 Adult-onset POAG GLC1B AD
3q21-24 Adult-onset POAG GLC1C AD
4q25 Rieger syndrome RIEG1 (PITX2) AD
5q22 Adult-onset POAG GLC1G (WDR36) AD; complex
6p25 Indodysgenesis IRID1 (FOXC1) AD
7q35 Adult-onset POAG GLC1F AD
7q35-q36 Pigment dispersion syndrome GPDS1 AD
8q23 Adult-onset POAG GLC1D AD
9q22 Early-onset POAG GLC1J AD
9q34 Glaucoma associated with nail-patella syndrome (LMX1B) AD
10p15-p14 Adult-onset POAG; Low tension glaucoma GLC1E (OPTN) AD
11p Nanophthalmos NNO1 AD
11p13 Aniridia AN2 (PAX6) AD
11q12 Nanophthalmos VMD2 AD
11q23 Nanophthalmos MFRP AR
13q14 Rieger syndrome RIEG2 AD
14q11 Adult-onset POAG Locus pending Complex
15q11-q13 Adult-onset POAG GLC1I Complex
20p12 Early-onset POAG GLC1K AD
Abbreviations: AD, autosomal dominant; AR: autosomal recessive; POAG: primary open-angle glaucoma.

Wiggs JL, 2007.

Next Steps

Short-term goals to advance the field:
1. GWAS for POAG sufficiently powered to identify multiple genes of moderate effect, also to enable support for gene-gene and gene-environment interactions.
2. GWAS for pseudoexfoliation syndrome sufficiently powered to identify secondary genetic and/or environmental risk factors.
3. Support gene identification for mendelian forms of glaucoma including pigment dispersion syndrome (relatively common and without known genes currently). Disease causing genes and products can identify biological pathways that may also be relevant for common forms of glaucoma.
4. Genotype/phenotype studies for genes known to cause early-onset glaucoma. Will make gene-based medicine possible for these types of glaucoma, including novel methods of diagnosis and therapy.

Long-term goals:
1. Application of gene variants/haplotypes associated with disease for screening/diagnosis/prognosis in advance of intervention.
2. Identification of modifiable risk factors: environmental exposures, gene/environment interactions and translation to clinical practice
3. Functional analysis of genetic factors leading to a better understanding of the molecular pathways involved in ganglion cell death: develop novel therapies and diagnostic methodologies (i.e. real-time in vivo imaging of ganglion cell death)
4. Animal models for evaluation novel therapeutics

Communal glaucoma research resources NEI:
1. Genotype/phenotype database
2. Support for novel sequencing approaches: diagnostic as well as new gene discovery


Wiggs JL, Genetic Etiologies of Glaucoma Arch Ophthalmol. 2007;125(1):30-37.

Kwon YH, Fingert JH, Kuehn MH, Alward WL, Primary open-angle glaucoma. N Engl J Med. 2009 Mar 12;360(11):1113-24.

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Terri Young


Myopia is the most studied refractive error due to the high prevalence and the increased risk of associated blinding complications. Research pursuits include why and how myopia develops, and whether treatments can be developed to prevent this refractive error, or prevent progression to high amounts. A fundamental question is whether myopic development is a result of predetermined genetic or environmental factors such as excessive near work or limited outdoor activity and time. Both appear to play a role in human myopia development.

The refractive state is determined by the relative contributions of the optical components, primarily corneal curvature, anterior-chamber depth, and lens thickness - all of which determine the location of the focal plane, and the axial length (primarily the vitreous chamber depth) - which determine whether the retina is located at the focal plane. Separately, these may be assessed as quantitative traits intimately related to the clinical phenotype of myopia. Multiple reports have examined familial aggregation and heritability of spherical refractive error and its contributing ocular components.

Axial length is the largest contributor to the determination of refractive error. Several studies have reported an inverse relationship of axial length to refraction (the longer the eye, the more myopic the refractive error). Axial length of a myopic adult population may show a bimodal distribution with a second peak of increased axial length relating to high myopia (< -6.00 D at 24 mm, > -6.00 D at 30 mm) when plotted as a distribution curve. This suggests that myopia of -6.00 D or greater represents a deviation from the normal distribution of axial length and is not physiologic.

Estimates of heritability for axial length range from 40% to 94%. Overall axial length includes anterior-chamber depth, and studies have shown that increased anterior-chamber depth has an inverse relationship as well to refractive error. The heritability reports for anterior-chamber depth range from 70% to 94%. The steeper the corneal curvature, the more likely the resulting refractive error is myopic - eyes with hyperopia are more likely to have flatter corneal curvature readings by keratometry. Heritability estimates for corneal curvature range from 60% to 92%. Increased lens thickness correlates with increased myopia. A di- and monozygotic twin study reported 90-93% heritability for lens thickness.

Multiple familial aggregation studies report a positive correlation between parental myopia and myopia in their children, indicating a hereditary factor in myopia susceptibility. Children with a family history of myopia had on average less hyperopia, deeper anterior chambers, and longer vitreous chambers even before becoming myopic. Yap and colleagues noted a prevalence of myopia in 7-year-old children of 7.3% when neither parent was myopic, 26.2% when one parent was myopic, and 45% when both parents were myopic. This implies a strong role for genetics in myopia.

Multiple familial studies support a high hereditary basis for myopia, especially higher degrees. Naiglin et al performed segregation analysis on 32 French multiplex families with high myopia, and determined an autosomal-dominant (AD) mode of inheritance. The λs for myopia (the increase in risk to siblings of a person with a disease compared to the population prevalence) has been estimated to be approximately 4.9-19.8 for sibs for high myopia (-6.00 spherical D or greater), and approximately 1.5-3 for low or common myopia (approximately -1.00 to -3.00 spherical D), suggesting a definite genetic basis for high myopia, and a strong genetic basis for low myopia. A high degree of familial aggregation of refraction, particularly myopia, was reported in the population-based Beaver Dam Eye Study after accounting for the effects of age, sex, and education. Segregation analysis suggested involvement of multiple genes, rather than a single major gene.

Twin studies provide the most compelling evidence that inheritance plays a significant role in myopia. Multiple studies note an increased concordance of refractive error as well as refractive components (axial length, corneal curvature, lens power) in monozygotic twins compared to dizygotic twins. Sorsby et al noted a correlation coefficient for myopia of 0 for control pairs, 0.5 for dizygotic twins, and almost 1.0 for monozygotic twins in a study of 78 pairs of monozygotic twins and 40 pairs of dizygotic twins. Twin studies estimate a notable high heritability value for myopia (the proportion of the total phenotypic variance that is attributed to genetic variance) of between 0.5 and 0.96. Phenotypes for assessing refractive error genetics as it relates to myopia or hyperopia include therefore: sphere, spherical equivalent, and axial length. Other ocular biometric parameters of study are corneal curvature- either in base curve or diopters, anterior chamber depth, and lens thickness.

Major genetics resources available to the research community would be OMIM, and any Center for Inherited Disease Research genotyping projects that establish data in the public database dbGAP with such phenotypes collected as part of a genome-side association study. I am aware of two NIH/NEI dbGAP Studies: The Age-Related Eye Disease Study (AREDS) - PIs-Emily Chew and Dick Ferris: and the International Twin Study of Refractive Error and Glaucoma Endophenotypes- PI- Terri Young.

Major Studies in Myopia

A. With GWAS Data
1. Paul Baird- PI. The Genes in Myopia Twin Study. Melbourne Australia.
Recent publication: Adult-onset myopia: the Genes in Myopia (GEM) twin study. Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3324-7. This large cohort study of Caucasian twins is the first to provide evidence for a genetic component in adult-onset myopia. The study found a significantly higher monozygotic intrapair correlation compared with that in dizygotic twins for spherical equivalent in twins with adult-onset myopia.

2. Ming-Guang He -PI. The Guangzhou Twin Eye Study. Guangzhou China.
Recent publication: Shared genetic determinant of axial length, anterior chamber depth, and angle opening distance: the Guangzhou Twin Eye Study. Invest Ophthalmol Vis Sci. 2008 Nov;49(11):4790-4. This study estimated the genetic and environmental contributions to axial length, anterior chamber depth, and angle opening distance in twins recruited from the Guangzhou Twin Registry. The data suggests that shared genes are responsible for the significant phenotypic correlations for these parameters.

3. Dwight Stambolian- PI. Myopia Family Study. U.S.-based Caucasian (Amish and Ashzenazi Jewish) and African American cohorts. Recent publication: Genome wide linkage scans for ocular refraction and meta-analysis of four populations in the Myopia Family Study. Invest Ophthalmol Vis Sci. 2009 Jan 17.
This article summarizes the results of a genome wide linkage analysis of Caucasian and Old Order Amish populations, and performs a meta-analysis combining these results with the group's previous linkage data in African American and Ashkenazi Jewish populations. The data show suggestive evidence of linkage of ocular refraction to 12q24 and 4q21 in Caucasian families, and to 5qter in Amish families. The meta-analysis confirms suggestive evidence of linkage to 4q21-22 adjacent to the previously-reported MYP9 and MYP11 loci.

4. Terri Young-PI. International Myopia Consortium (Primarily European and US-based Caucasian high-grade myopia families) recent publication: An international collaborative family-based whole genome linkage scan for high-grade myopia. Invest Ophthalmol Vis Sci. 2009 Mar 25. This is the largest linkage scan to date for familial high-grade myopia was recently published, using data from 254 families (primarily Caucasian) from five independent sites. This study demonstrated linkage replication of the MYP1, MYP3, MYP6, MYP11, MYP12, and MYP14 loci, and identified a novel locus at chromosome 9q34.11.

5. Claire Simpson- PI. The 1958 British Birth Cohort (Primarily Caucasian population-based study)

6. Jeremy Guggenheim- PI. Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (a UK population-based prospective birth cohort)

7. Jan-Tjeerd de Faber- PI. Rotterdam Eye Study, Rotterdam,The Netherlands

8. There are four studies of Asian ethnicities in Singapore where GWAS data is available: The Singapore Malay Eye Study (SiMES) (population based) - PI- Tien Yin Wong, the Singapore Prospective Cohort Study (SP2) (population based) - PI- Eyshong Tai, the Singapore Cohort Study of Risk Factors for Myopia (SCORM) (population-based) - PI- Seang Mei Saw), and the Strabismus, Amblyopia, and Refractive Error in Singapore Children (STARS) study (family based)- PI- Seang Mei Saw.

9. The Blue Mountains Eye Study (population-based study in Australia) is currently undergoing GWA genotyping at the Genome Institute of Singapore - PI- Paul Mitchell- Sydney, Australia.

10. Framingham Eye Study- will soon undergo GWA genotyping

11. The KORA study - PI- Thomas Meitinger- I do not know the details of this study

B. Without GWAS Data
There are also well-characterized, large NIH-funded studies which have not undergone GWA genotyping, but could serve as excellent replicate groups for targeted candidate gene screening. Some need funds for blood/cheek tissue collection to establish a DNA repository

1. Jane Gwiazda -PI. Corrective Myopia Evaluation Treatment Trial. Multicenter- US study. Multi=ethnic, but primarily Caucasian schoolchildren cohort of approx 480 followed longitudinally for 9-10 years. No DNA collected, but interested in participating in genetic studies.

2. Barbara Klein- PI. Beaver Dam Eye Study. Wisconsin.

3. Don Mutti- PI. CLEERE study. Ohio State, Ohio

C. Myopia Genetics in Mouse Models

1. Frank Schaeffel -PI. Tubingen, Germany.
Recent publication: Relative axial myopia in Egr-1 (ZENK) knockout mice. Invest Ophthalmol Vis Sci. 2007 Jan;48:11-17. This group produced knockout mice for the immediate early gene transcription factor ZENK (Egr-1), which is thought to act as an ocular axial growth inhibitory signal. ZENK mice had longer eyes and a myopic shift compared to heterozygous and wild-type mice with identical genetic background, providing strong evidence that ZENK may be a key genetic determinant of myopia development and eye growth.

2. Zhou X- PI, China.
Recent publication : Invest Ophthalmol Vis Sci. 2008 Dec;49(12):5208-14. The development of the refractive status and ocular growth in C57BL/6 mice. This study provides a helpful record of refraction, corneal curvature, axial components, and the correlations between refraction and ocular growth during emmetropization in mice. Refraction was most myopic at day 25, then changed in the hyperopic direction to reach a peak at 47 days.

Known Genes

High myopia also occurs as a feature of several ocular or systemic disease syndromes in which the causative disease gene is known. Candidate gene association and gene sequencing studies have led to the identification of a number of non-syndromic (primarily high-grade) myopia susceptibility genes as outlined below. These findings await replication in independent cohorts.

Han et al recently demonstrated an association of several PAX6 variants with susceptibility to high myopia in southern Han Chinese. (1) Both PAX 6 and SOX2, considered "master control genes" in eye development and growth, have been suggested to play a role in myopia pathogenesis, possibly due to genetic variation in an upstream promoter or regulator. However Simpson et al investigated the association of common myopia with PAX6 and SOX2 in a large population study cohort, and found no significant association. (2)

The membrane-type frizzled-related protein (MFRP) gene, hypothesized to play a role in axial length regulation, has shown similarly contradictory results in different studies. Most recently, Metlapally et al showed reported no association between 16 MFRP SNPs and non-syndromic high myopia. (3)

The myocilin myopia susceptibility gene (MYOC) was identified in a Chinese cohort using the family-based transmission disequilibrium test (TDT) approach; the gene has previously been associated with juvenile-onset glaucoma and early-onset and high myopia. (4) Vatavuk et al also noted an association between high myopia and a common variant in the myocilin gene in 19 individuals in Korcula Island, Croatia. (5) However these results must be interpreted with caution, as the study was relatively under-powered and had limited SNP coverage.

Hall et al recently reported an association between common myopia and polymorphisms in three genes coding for matrix metalloproteinases (MMP-1, MMP-3, MMP-9), enzymes that degrade matrix proteins and modulate scleral extensibility. (6) In their population of Caucasian English individuals, risk of myopia increased progressively with dose of polymorphic alleles in these three genes.

The uromodulin-like 1 (UMODL1) gene, previously prioritized during a whole genome case-control association analysis in Japanese high-myopia patients, has also been identified as a potential candidate gene. Nishizaki et al identified 1 significant SNP within the frequent recombinant region of UMODL1 on chromosome 21q22.3, confirming the gene's candidacy as a disease susceptibility gene. (7)

Andrew et al confirmed evidence for linkage to chromosome 3q26 (MYP8) and identified three loci centered on MFN1, upstream from alternate-splicing SOX20T and PSARL. (8) The fact that MFN1 and PSARL both influence mitochondrial regulatory processes in the retina is somewhat surprising, and may suggest a novel mitochondrial-related pathogenetic pathway for common myopia.

Metlapally et al reported an association between TEX28 copy number variations and the MYP1 X-linked myopia phenotypes, and also revealed that a range of copies (one to five) can produce the same phenotype. (9)

The collagen-related genes have consistently been cited as potential myopia candidates. A case control study of mixed ethnicities showed an association between myopia and 2 SNPs in the collagen 2 alpha 1 gene (COL2A1), which maps to chromosome 12q13.11, a locus not associated with myopia to date. (10) Sequence analysis of three individuals with familial Stickler syndrome type I revealed another COL2A1 mutation accounting for the STL1 phenotype, which includes myopia, congenital vitreous anomaly, and orofacial, articular, and auditory manifestations. (11) A third study, a retrospective notes-review of patients with a type II collagenopathy chondrodysplasia, revealed that over 85% are myopic, thus confirming that myopia can result from defects in type II collagen. (12)

Another candidate gene is the collagen type 1 alpha 1 gene (COL1A1), an extracellular matrix gene expressed in the scleral wall which maps within the MYP5 locus for high myopia (chromosome 17q22-q23.3), and which previously has been suggested to play a role in experimental myopia. A case-control study of a Japanese cohort showed an association of high myopia with 2 SNPs for this gene, providing the first evidence for COL1A1 as a candidate gene for high myopia. (13) However, a follow-up study revealed no association, suggesting that the genetic risk associated with this gene, if any, is weaker than originally thought. (14)

Similarly, Pertile et al found no association between the transforming growth beta-induced factor (TGIF) gene and refraction or ocular biometric measures, indicating that TGIF is unlikely to play a major role in these values. (15) In addition, Wang et al reported no association of high myopia with TGIF in individuals living in southeast China. (16) These reports suggest that future studies should focus on investigating other genes in the MYP2 linkage region or in other linkage regions, rather than TGIF. In addition, Wang et al found no association between high myopia and SNPs in the previously reported candidate genes Lumican, TGFB1, and hepatocyte growth factor (HGF) genes. (16)

As demonstrated by the above studies, the results for many of the candidate myopia genes are promising and may have biological plausibility, but most are not conclusive. Functional SNP effects have not been implicated for all of these candidate genes, and it is unclear how ethnic differences play a role in the degree of associative significance.

Next Steps

Short term:
1. To support performing a meta-analysis of refractive error, myopia and hyperopia on combined GWAS results. The basic plan would be to use similar quality control measures in all datasets, then impute each set of GWAS genotypes to the HapMap (since different platforms may have been used for the typing), then analyze refractive error (defined in the same way, perhaps as average spherical equivalent) separately in each dataset, and then use a meta-analysis technique to combine the p-values across all datasets. We could define some subsets of each dataset (for example cases/controls for myopia and hyperopia or individuals for whom biometric eye measurements are available) for separate analyses and meta-analyses. New methods were proposed at the recent American Society of Human Genetics meeting that perform a meta-analysis that combines the p values at each locus while weighting the results from each study based on whether that locus was genotyped or imputed in that dataset. It is possible to consider this method in place of (or in addition to) the originally proposed method.

Funding support could help in terms of establishing standards and thresholds for research groups interested in participating, such as:

a) Standardization criteria/checks used to check for errors in the genotyping data.

b) Standardization of how refractive error is measured, and obtaining other data, such as education level. Also critical to obtain other pertinent eye measures on these people (such as biometric measurements). Need to determine number of people needed for adequate power.

c) Standardization of analysis methods - initial suggestion is to analyze refractive error as a quantitative trait with PLINK using a linear model including age, gender and education level as covariates and an additive genetic model to test for association with each SNP (normalizing refractive error as needed). If there are enough myopes and hyperopes in the datasets we could also do a meta-analysis of these qualitative traits, after deciding how to define each trait. This also applies to any other refraction-related traits that we all may decide are of interest for the meta-analysis.

Consider funding support to draw in ethnically different groups for separate and combined meta-analysis as well, i.e. ethnic Asians in Singapore and China with GWAS data.

2. Funding support for smaller studies with well-characterized cohorts to obtain tissue for DNA extraction in order to allow participation in GWAS studies either as contributors to a combined dataset, or for utilization in replicate candidate gene screening studies. These smaller cohorts are also ideal for use in future clinical trials.

1. Development of mouse models of myopia based on known candidate gene associations
2. Bio-marker profile development of individuals likely to have the more severe ocular morbidity issues of myopia- such as retinal detachments, premature cataracts.
3. Clinical trials?
4. Increased funding levels or CIDR- established high-throughput sequencing access


Young TL, Metlapally R, Shay AE. Complex trait genetics of refractive error. Arch Ophthalmol 2007;125:38-48.

Vitale S, Ellwein L, Cotch MF, et al. Prevalence of refractive error in the United States, 1999-2004. Arch Ophthalmol. 2008 Aug;126(8):1111-9.
The nationally representative 1999-2004 National Health and Nutrition Examination Survey (NHANES) documents age-standardized prevalences of hyperopia, myopia, and astigmatism in the United States: 3.6%, 33.1%, and 36.2%, respectively. Myopia was more prevalent in women than in men among 20- to 39-year-old participants, and in non-Hispanic whites than in non-Hispanic blacks or Mexican Americans; persons 60 years or older were less likely to have myopia and more likely to have hyperopia and/or astigmatism than younger persons. This data is invaluable for any epidemiological or public health evaluation of myopia in the United States.

Young TL. Molecular genetics of human myopia: An update. Optom Vis Sci. 2009 Jan;86(1):E8-E22.

Candidate Gene Section References:

1. Han W, Leung KH, Fung WY, et al. Association of PAX6 polymorphisms with high myopia in Han Chinese nuclear families. Invest Ophthalmol Vis Sci. 2009 Jan;50(1):47-56.
This study demonstrates the association of several PAX6 variants with susceptibility to high myopia in southern Han Chinese, thereby suggesting that polymorphisms in the PAX6 locus may play a significant role in high myopia in this population.

2. Simpson CL, Hysi P, Bhattacharya SS, et al. The Roles of PAX6 and SOX2 in Myopia: lessons from the 1958 British Birth Cohort. Invest Ophthalmol Vis Sci. 2007 Oct;48(10):4421-5.
PAX6 and SOX2 are genes with fundamental roles in ocular growth and development, and The authors investigate the potential association of PAX6 and SOX2 with common myopia in members of the nationally representative 1958 British Birth Cohort. They find no significant association between any of the SNPs or haplotypes and refractive error, thus countering the candidacy of these genes based upon prior linkage studies and their roles in ocular development.

3. Metlapally R, Li YJ, Tran-Viet KN, et al. Common MFRP sequence variants are not associated with moderate to high hyperopia, isolated microphthalmia, and high myopia. Mol Vis. 2008 Mar 4;14:387-93.
The membrane-type frizzled-related protein (MFRP) gene has been hypothesized to play a role in axial length regulation. This study of non-syndromic high-myopia families shows no association between 16 MFRP SNPs and moderate to high hyperopia, microphthalmia/anophthalmia, or high myopia. Family based association analysis also did not reveal any association between the 17 SNPs genotyped in the larger family data set for any refractive error type. Thus the findings indicate that the MFRP gene may not play a role in regulating ocular axial length in these phenotypes.

4. Tang WC, Yip SP, Lo KK, et al. Linkage and association of myocilin (MYOC) polymorphisms with high myopia in a Chinese population. Mol Vis. 2007 Apr 4;13:534-44.
This family-based gene association study shows linkage and association between myocilin (MYOC) polymorphisms and high myopia in Hong Kong Chinese, with the SNP rs235858 at the 3' flanking region showing the highest degree of confidence for association, followed by the SNP rs2421853. This is the first evidence of positive results for these SNPs, and represents a potential future direction for candidate gene studies.

5. Vatavuk Z, Skunca Herman J, Bencic G, et al. Common variant in myocilin gene is associated with high myopia in isolated population of Korcula Island, Croatia. Croat Med J. 2009 Feb;50(1):17-22.
This study confirmed an association between high myopia and a common variant in the myocilin gene in 19 individuals in Korcula Island, Croatia. The results must be interpreted with caution, as the study was relatively under-powered and had limited SNP coverage.

6. Hall NF, Gale CR, Ye S, Martyn CN. Myopia and polymorphisms in genes for matrix metalloproteinases. Invest Ophthalmol Vis Sci. 2009 Mar 11. [Epub ahead of print]
Hall et al reports an association between common myopia and polymorphisms in three genes coding for matrix metalloproteinases (MMP-1, MMP-3, MMP-9), enzymes that degrade matrix proteins and modulate scleral extensibility. In their population of Caucasian English individuals, risk of myopia increased progressively with dose of polymorphic alleles in these three genes.

7. Nishizaki R, Ota M, Inoko H, et al. New susceptibility locus for high myopia is linked to the uromodulin-like 1 (UMODL1) gene region on chromosome 21q22.3. Eye. 2008 Jun 6. [Epub ahead of print]
This study investigates the position of the uromodulin-like 1 gene (UMODL1), prioritized during the authors' previous whole genome case-control association analysis in Japanese high-myopia patients. They identify 1 significant SNP (rs2839471) within the frequent recombinant region within UMODL1 on chromosome 21q22.3, and suggest that this region may play a role in susceptibility to high myopia.

8. Andrew T, Maniatis N, Carbonaro F, et al. Identification and replication of three novel myopia common susceptibility gene loci on chromosome 3q26 using linkage and linkage disequilibrium mapping. PLoS Genet. 2008 Oct;4(10):e1000220.
This is the first evidence of involvement of mitochondrial regulatory processes in myopia development. The authors confirmed evidence for linkage to chromosome 3q26 and conducted fine-scale association mapping. They identify three loci with putative common functional variants centered on MFN1, upstream from alternate-splicing SOX2OT and PSARL, and replicate these results in an independent sample. Since MFN1 and PSARL both influence mitochondrial regulatory processes in the retina, these findings are surprising and may suggest a novel perspective of the molecular genetic basis of common myopia.

9. Metlapally R, Michaelides M, Bulusu A, et al. Evaluation of the X-Linked High Grade Myopia Locus (MYP1) with Cone Dysfunction and Color Vision Deficiencies. Invest Ophthalmol Vis Sci. 2008 Dec 20. [Epub ahead of print]
This study establishes the association between TEX28 copy number variations (CNVs) and the MYP1 X-linked myopia phenotypes. It also reveals that a range of copies (one to five), not only three copies as previously thought, can produce the same phenotype.

10. Mutti DO, Cooper ME, O'Brien S, et al. Candidate gene and locus analysis of myopia. Molecular Vision. 2007 Jun;13:1012-1019.

11. Olavarrieta L, Morales-Angulo C, del Castillo I, et al. Stickler and branchio-oto-renal syndromes in a patient with mutations in EYA1 and COL2A1 genes. Clin Genet. 2008 Mar;73(3):262-7.
Sequence analysis of three individuals with familial Stickler syndrome type I reveals a novel COL2A1 mutation (c.1468_1475delinsT) that accounts for the STL1 phenotype. This phenotype includes myopia, congenital vitreous anomaly, and orofacial, articular, and auditory manifestations.

12. Meredith SP, Richards AJ, Bearcroft P, et al. Significant ocular findings are a feature of heritable bone dysplasias resulting from defects in type II collagen. Br J Ophthalmol. 2007 Sep;91(9):1148-51.
A retrospective notes review of patients with a type II collagenopathy chondrodysplasia reveals that the majority (10 out of 12) are myopic, in addition to having a high incidence of retinal detachment, retinal tears, lens opacities, and lens subluxation. This study confirms that ophthalmic abnormalities, including myopia, result from defects in type II collagen.

13. Inamori Y, Ota M, Inoko H, et al. The COL1A1 gene and high myopia susceptibility in Japanese. Hum Genet. 2007 Sep;122(2):151-7.
This study identifies an association between high myopia and two SNPs in collagen type Iota alpha Iota (COL1A1), thus providing the first evidence for COL1A1 as a gene associated with high myopia. COL1A1 is a particularly promising candidate gene due to its role in encoding the extracellular matrix component collagen, its location in MYP5 on chromosome 17q22-q23.3, and its previously suggested role in experimental myopia.

14. Nakanishi H, Yamada R, Gotoh N, et al. Absence of Association between COL1A1 Polymorphisms and High Myopia in the Japanese Population. Invest Ophthalmol Vis Sci. 2009 Feb;50(2):544-50.
This study is a follow-up to the Inamori et al. study in September 2007, which identified COL1A1 as a candidate gene for high myopia in a Japanese population. Using a tagging single nucleotide polymorphism (tSNP) approach, this study reveals no association between high myopia and the two SNPs identified in the Inamori et al. paper, suggesting that the genetic risk associated with this gene, if any, is weaker than originally reported.

15. Pertile KK, Schache M, Islam FM, et al. Assessment of TGIF as a candidate gene for myopia. Invest Ophthalmol Vis Sci. 2008;49(1):49-54.
This is the first study to evaluate the association of the transforming growth beta-induced factor (TGIF) gene with high myopia. The data revealed no significant association for either ocular biometric measures or refraction in a Caucasian population, indicating that TGIF is unlikely to play a major role.

16. Wang P, Li S, Xiao X, et al. High myopia is not associated with the SNPs in the TGIF, Lumican, TGFB1, and HGF genes. Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1546-51.
This study investigates the previously reported association between four SNPs in the TGIF, Lumican, TGFB1 and HGF genes and high myopia in Chinese individuals living in southeast China. The study genotypes these SNPs by restriction fragment length polymorphism (RFLP) analysis, and finds no association between high myopia and these SNPs, providing a contrary view to the previous reports.

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