A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Neurological basis for eye movements of the blind.

When normal subjects fix their eyes upon a stationary target, their gaze is not perfectly still, due to small movements that prevent visual fading. Visual loss is known to cause greater instability of gaze, but reported comparisons with normal subjects using reliable measurement techniques are few. We measured binocular gaze using the magnetic search coil technique during attempted fixation (monocular or binocular viewing) of 4 individuals with childhood-onset of monocular visual loss, 2 individuals with late-onset monocular visual loss due to age-related macular degeneration, 2 individuals with bilateral visual loss, and 20 healthy control subjects. We also measured saccades to visual or somatosensory cues. We tested the hypothesis that gaze instability following visual impairment is caused by loss of inputs that normally optimize the performance of the neural network (integrator), which ensures both monocular and conjugate gaze stability. During binocular viewing, patients with early-onset monocular loss of vision showed greater instability of vertical gaze in the eye with visual loss and, to a lesser extent, in the normal eye, compared with control subjects. These vertical eye drifts were much more disjunctive than upward saccades. In individuals with late monocular visual loss, gaze stability was more similar to control subjects. Bilateral visual loss caused eye drifts that were larger than following monocular visual loss or in control subjects. Accurate saccades could be made to somatosensory cues by an individual with acquired blindness, but voluntary saccades were absent in an individual with congenital blindness. We conclude that the neural gaze-stabilizing network, which contains neurons with both binocular and monocular discharge preferences, is under adaptive visual control. Whereas monocular visual loss causes disjunctive gaze instability, binocular blindness causes both disjunctive and conjugate gaze instability (drifts and nystagmus). Inputs that bypass this neural network, such as projections to motoneurons for upward saccades, remain conjugate.

Mutation screen of beta-crystallin genes in 274 patients with age-related macular degeneration.

PURPOSE: The crystallin family of proteins comprise the main structural proteins of the vertebrate lens and have been classified into alpha-, beta-, and gamma- families. Several of the beta-crystallin proteins have been detected in the retina where they are each localized to different compartments of rod and cone photoreceptors. Functionally, beta-crystallins have been implicated in the protection of the retina from intense light exposure. Two members of the beta-crystallins, CRYBB1 and CRYBB2, have been identified in drusen preparations isolated from the retina of donor eyes of patients with age-related macular degeneration (AMD), the leading cause of blindness in the elderly population of developed countries. We therefore investigated CRYBB1 and CRYBB2 as candidate genes for AMD in 274 unrelated patients. RESULTS: A mutation screen of the entire coding region of the CRYBB1gene uncovered eight sequence variations, including three missense changes, two intronic changes and three isocoding changes. A mutation screen of the entire coding region of the CRYBB2 gene uncovered three sequence variations, one isocoding change and two intronic changes. CONCLUSIONS: Although variant alleles of the CRYBB1 and CRYBB2 genes were found, none are considered pathogenic.

Two patients with spinocerebellar ataxia type 7 presenting with profound binocular visual loss yet minimal ophthalmoscopic findings.

Two patients with genetically confirmed spinocerebellar ataxia type 7 (SCA7) presented with progressive visual loss. Examination disclosed substantial visual acuity loss, central scotomas, and marked dyschromatopsia. Ophthalmoscopic abnormalities were subtle, with only mild retinal artery attenuation and minimal foveal region pigmentary abnormalities. Both patients had slow saccades and partially limited ductions, although neither reported diplopia. One patient had obvious extremity and gait ataxia, but the other had only an unsteady tandem gait. Results of electroretinography (ERG) were abnormal in both patients. These cases illustrate that SCA7 may present with profound visual loss yet minimal ophthalmoscopic findings and sometimes minimal ataxia. The clues to diagnosis are the abnormal color vision, retinal artery attenuation, abnormal eye movements, and a family history of similar manifestations, which may have gone undiagnosed. Full-field or multifocal ERG will always disclose photoreceptor dysfunction. Genetic testing is now available to confirm the diagnosis.

Branch retinal artery occlusion associated with compound heterozygous genotype for methylenetetrahydrofolate reductase.

We present a case in which mfERG and OCT helped to make a diagnosis of an old BRAO in the setting of compound heterozygous MTHFR genotype. A 44-year-old woman presented for evaluation of a 10 month history of persistently cloudy vision OS. She had been worked up previously for MS versus BRAO, and she was on coumadin, folate, and multivitamin at the time of presentation. The patient has a fraternal twin sister who was diagnosed with MS. Dilated fundus examination OS showed subtle inferior optic atrophy with slight narrowing of the inferotemporal retinal artery, and HVF test revealed a superonasal depression OS. mfERG also showed superonasal depression OS. Retinal origin of the chief complaint was further confirmed by OCT, which showed thinning of the NFL in the corresponding region of the retina OS. Coagulopathy evaluation revealed C677T/A1298C compound heterozygous genotype for MTHFR, and plasma homocysteine level after 6 months of folate and multivitamin supplementation was 10 microM (reference range 4-10 microM). The patient was diagnosed with BRAO and maintained on coumadin therapy.

Bilateral macular lesions in a 10-year-old girl.

PURPOSE: To report a previously undescribed macular dystrophy. DESIGN: Single descriptive case report. METHODS: Presentation of clinical findings, including ophthalmoscopy, fluorescein angiography, full-field and multifocal electroretinography (ERG), optical coherence tomography (OCT), and visual fields. RESULTS: A 10 year-old Caucasian girl had peculiar reddish blotchy macular lesions bilaterally, associated with decreased visual acuity, and no family history of similar lesions. Fluorescein angiography was inconclusive and showed mottled hyperfluorescence in the macula. The full-field electroretinogram was normal, but multifocal ERG revealed diminished waveforms centrally. CONCLUSION: This is possibly a new macular dystrophy, the nature of which remains to be determined.

Mutation screen of the cone-specific gene, CLUL1, in 376 patients with age-related macular degeneration.

Clusterin is a secreted glycoprotein expressed ubiquitously in many tissues that appears to function as a molecular chaperone capable of protecting stressed proteins. It is upregulated in many different forms of neurodegeneration and is thought to represent a defense response against neuronal damage. Clusterin has been found to be a common protein identified in drusen preparations isolated from the retina of donor eyes of patients with age-related macular degeneration (AMD), the leading cause of blindness in the elderly population of developed countries. A retina-specific clusterin-like protein (CLUL1) showing nearly 25% identity to clusterin at the protein level was recently cloned and shown to be expressed specifically in cone photoreceptor cells. For these reasons, we investigated CLUL1 as a candidate gene for AMD. A mutation screen of the entire coding region of the CLUL1 gene in 376 unrelated patients with AMD uncovered three sequence variations, one isocoding change and two intronic changes. One intronic change appears significantly less frequent in patients with the more severe forms of AMD than in control subjects, suggesting that this variant may reduce the risk for AMD or may be linked to a nearby variant that may reduce AMD risk. Variant alleles of the CLUL1 gene were found; however, none are considered pathogenic. None of the variants identified are predicted to create or destroy splice donor or acceptor sites based on splice-site prediction software.

Causes of incident visual field loss in a general elderly population: the Rotterdam study.

OBJECTIVE: To determine the incidence and causes of visual field loss (VFL) in a general elderly population. METHODS: Central visual fields of both eyes were examined with suprathreshold perimetry in 3761 persons aged 55 years or older and free of VFL at baseline from the population-based Rotterdam Study. Goldmann perimetry was performed to confirm suprathreshold VFL. Causes of incident VFL (iVFL) were assessed based on all available ophthalmologic and neurological examination data and medical records. RESULTS: After a mean follow-up time of 6.3 years, 175 persons developed VFL. The overall incidence rate of iVFL was 7.4 per 1000 person-years, increasing to 21.1 per 1000 person-years in those aged 80 years and older. Glaucoma was the leading cause of iVFL in all age categories. The overall incidence of glaucomatous VFL was 2.0 per 1000 person-years. CONCLUSIONS: The incidence of all VFL increased 5-fold between 55 years and 80 years of age or older. After glaucoma, stroke was the second most common cause of iVFL in persons younger than 75 years, followed by age-related macular degeneration and retinal vascular occlusive disease.