Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India Molecular and Human Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
Invest Ophthalmol Vis Sci. 2014 Apr 24;55(5):3258-64. doi: 10.1167/iovs.14-14339.
Large copy number variations (CNV) can contribute to increased burden for neurodegenerative diseases. In this study, we analyzed the genome-wide burden of large CNVs > 100 kb in primary open angle glaucoma (POAG), a neurodegenerative disease of the eye that is the largest cause of irreversible blindness.
Genome-wide analysis of CNVs > 100 kb were analyzed in a total of 1720 individuals, including an Indian cohort (347 POAG cases and 345 controls) and a Caucasian cohort (624 cases and 404 controls). All the CNV data were obtained from experiments performed on Illumina 660W-Quad (infinium) arrays.
We observed that for both the populations CNVs > 1 Mb was significantly enriched for gene-rich regions unique to the POAG cases (P < 10(-11)). In the Indian cohort CNVs > 1 Mb (39 calls) in patients influenced 125 genes while in controls 31 such CNVs influenced only 5 genes with no overlap. In both cohorts we observed 1.9-fold gene enrichment in patients for deletions compared to duplications, while such a bias was not observed in controls (0.3-fold). Overall duplications > 1 Mb were more than deletions (Del/Dup = 0.82) confirming that the enrichment of gene-rich deletions in patients was associated with the disease. Of the 39 CNVs > 1 Mb from Indian patients, 28 (72%) also were implicated in other neurodegenerative disorders, like autism, schizophrenia, sensorineural hearing loss, and so forth. We found one large duplication encompassing CNTN4 gene in Indian and Caucasian POAG patients that was absent in the controls.
To our knowledge, our study is the first report on large CNV bias for gene-rich regions in glaucomatous neurodegeneration, implicating its impact across populations of contrasting ethnicities. We identified CNTN4 as a novel candidate gene for POAG.
大片段拷贝数变异（CNV）可导致神经退行性疾病负担增加。在这项研究中，我们分析了原发性开角型青光眼（POAG）全基因组范围内大于 100kb 的大片段 CNV 的负担，POAG 是一种眼部神经退行性疾病，是不可逆失明的最大原因。
总共对 1720 个人进行了大于 100kb 的 CNV 全基因组分析，包括一个印度队列（347 例 POAG 病例和 345 例对照）和一个高加索队列（624 例病例和 404 例对照）。所有的 CNV 数据都是从 Illumina 660W-Quad（infinium）阵列上进行的实验中获得的。
我们观察到，对于两个群体，CNVs > 1Mb 在 POAG 病例特有的基因丰富区域中显著富集（P<10(-11)）。在印度队列中，患者的 39 个 CNVs > 1Mb（39 个）影响了 125 个基因，而对照者仅有 31 个这样的 CNVs 只影响了 5 个基因，没有重叠。在两个队列中，与重复相比，缺失导致患者的基因富集增加了 1.9 倍，而对照者则没有观察到这种偏向（0.3 倍）。总体而言，大于 1Mb 的重复比缺失更多（Del/Dup=0.82），这证实了患者中基因丰富缺失的富集与疾病有关。在来自印度患者的 39 个 CNVs > 1Mb 中，28 个（72%）也与其他神经退行性疾病有关，如自闭症、精神分裂症、感觉神经性听力损失等。我们发现一个包含 CNTN4 基因的大重复在印度和高加索 POAG 患者中存在，但在对照组中不存在。
据我们所知，我们的研究是第一个关于青光眼神经退行性变中基因丰富区域大片段 CNV 偏向的报告，表明其在不同种族人群中的影响。我们确定 CNTN4 是 POAG 的一个新候选基因。
