The Molecular Genetics of High Myopia

描述（由申请人提供）：近视或近视是世界上最常见的人类眼部疾病，是一个重要的全球公共卫生问题。沿着白内障、黄斑变性、感染性疾病和维生素A缺乏，近视是世界范围内视力损害的最重要原因之一。严重或高度近视是失明的主要原因，因为其相关的眼部发病率视网膜脱离、黄斑脉络膜变性、过早白内障和青光眼。充分的证据证明了这种疾病的非综合征形式的遗传性，特别是对于高度近视，通常称为5-6屈光度或更高的近视球镜屈光力。多个高度近视遗传基因座已被确定在研究中主要在我们的实验室进行。在其他研究实验室也进行了鉴定近视位点的验证性和额外研究。一般来说，近视易感基因是未知的，很少进行相关研究，也没有在其他研究实验室或单独的患者队列测试中得到证实。我们的国际联盟由来自英国、法国、丹麦、澳大利亚和美国的近视和统计遗传学家组成。在过去的8年中，我们已经确定并获得了250多个家庭单位的DNA样本，主要是北方欧洲血统的高度近视。在这个国际队列中，我们已经建立了近视的显著遗传性和/或家族聚集性。我们所有的DNA样本都在手上，并已被验证用于基因分型。我们在国立卫生研究院遗传疾病研究中心（CIDR）获得了单核苷酸多态性（SNP）基因组筛查的批准，以确定与高度近视状况相关的基因座。正在对CIDR提供的基因分型数据进行作图和关联分析。已经制定了对已确定的连锁间隔进行后续研究的详细计划，其中包括重复研究。 公共卫生相关性：我们的国际近视联盟代表了早期高度威胁视力的近视家庭和病例的最大集合之一，仔细收集以记录临床表型和相关协变量。这一独特而珍贵的资源将成为拟议研究的基础，研究导致近视发展的过度眼睛生长的遗传影响。我们假设，近视易感基因的鉴定不仅可以深入了解这种重要眼部疾病的分子基础，而且还可以确定参与眼睛生长和发育的途径。这一努力可能会导致有效的治疗方法来治疗或潜在地预防这种常见的眼部疾病。

DESCRIPTION (provided by applicant): Myopia, or nearsightedness, is the most common human eye disorder in the world, and is a significant global public health concern. Along with cataract, macular degeneration, infectious disease, and vitamin A deficiency, myopia is one of the most important causes of visual impairment worldwide. Severe or high-grade myopia is a leading cause of blindness because of its associated ocular morbidities of retinal detachment, macular choroidal degeneration, premature cataract, and glaucoma. Ample evidence documents the heritability of the non-syndromic forms of this condition, especially for high-grade myopia, commonly referred to as myopic spherical refractive power of 5-6 diopters or higher. Multiple high-grade myopia genetic loci have been identified in studies primarily performed in our laboratories. Confirmatory and additional studies identifying myopia loci have also occurred in other research laboratories. In general, myopia susceptibility genes are unknown with few association studies performed, and without confirmation in other research laboratories or testing of separate patient cohorts. Our international consortium is composed of myopia and statistical geneticists from the United Kingdom, France, Denmark, Australia, and the United States. Over the course of the past 8 years we have ascertained and obtained DNA samples on more than 250 family units primarily of Northern European descent with high- grade myopia. Within this international cohort, we have established significant heritability and/or familial aggregation for myopia. All of our samples for DNA are in hand and have been verified for genotyping. We gained approval for a single nucleotide polymorphism (SNP) genome screen at the Center for Inherited Disease Research (CIDR) of the National Institutes of Health to identify loci associated with the high-grade myopia condition. Mapping and association analyses are in process for the genotyping data provided by CIDR. Detailed plans for follow-up studies for established linkage intervals have been devised which include replication studies. PUBLIC HEALTH RELEVANCE: Our international myopia consortium represents one of the largest assemblies of families and cases with high-grade, sight-threatening myopia at an early age, carefully collected to document clinical phenotypes and related covariates. This unique and precious resource will be the basis for the proposed study of the genetic influences for exaggerated eye growth leading to myopic development. We hypothesize that the identification of myopia susceptibility genes will not only provide insight into the molecular basis of this significant eye disorder, but will also identify pathways involved in eye growth and development. This effort may lead to effective therapies to treat or potentially prevent this common eye condition.