QIMR Berghofer Medical Research Institute, Brisbane, Australia.
School of Medicine, University of Queensland, Brisbane, Australia.
JAMA Ophthalmol. 2022 Jun 1;140(6):568-576. doi: 10.1001/jamaophthalmol.2022.0891.
Keratoconus can be a debilitating corneal ectasia in which the cornea thins, bulges, and steepens into a conical shape. Early features of keratoconus include myopia and irregular astigmatism, which affect vision and can be treated with contact lenses, collagen cross-linking, or, in advanced cases, corneal transplant. Recent estimates of the prevalence of keratoconus based on results of Scheimpflug imaging in young adults are as high as 1.2%. However, obtaining very large keratoconus data sets for a genome-wide association study (GWAS) is problematic because few population studies include Scheimpflug imaging and because severe keratoconus is relatively rare.
To identify novel keratoconus loci using corneal resistance factor (CRF) and central corneal thickness (CCT).
DESIGN, SETTING, AND PARTICIPANTS: This multitrait GWAS used European ancestry CRF data from UK Biobank (UKB) (n = 105 427) and the Canadian Longitudinal Study on Aging (CLSA) (n = 18 307) and European ancestry CCT data from the International Glaucoma Genetics Consortium (IGGC) (n = 17 803). The CRF and CCT variants in published keratoconus data sets (4669 cases and 116 547 controls) were compared. The data set from UKB was compiled March 24, 2020; data were released from the CLSA in July 2020; and IGGC data were available from May 1, 2018.
Association of CRF and CCT variants with keratoconus risk.
The GWAS included 4 cohorts: 105 427 UKB European ancestry (56 134 women [53.2%] and 49 293 men [46.7%]; mean [SD] age, 57 [8] years), 5029 UKB South Asian ancestry (2368 women [47.1%] and 2661 men [52.9%]; mean [SD] age, 54 [8] years), 902 UKB East Asian ancestry (622 women [68.9%] and 280 men [31.0%]; mean [SD] age, 53 [8] years), and 18 307 CLSA European ancestry (9260 women [50.6%] and 9047 men [49.4%]; mean [SD] age, 63 [10] years) participants. A total of 369 CRF and 233 CCT loci were identified, including 36 novel CRF loci and 114 novel CCT loci. Twenty-nine CRF loci and 24 CCT loci were associated with keratoconus. Polygenic risk scores (PRS) were constructed using CRF- and CCT-associated variants and published keratoconus variants. The PRS result showed that adding a CRF- or CCT-based PRS to the keratoconus PRS from previously published variants improved the prediction area under the receiver operating characteristic curve (from 0.705 to 0.756 for CRF and from 0.715 to 0.755 for CCT).
These findings support the use of multitrait modeling of corneal parameters in a relatively large data set to identify new keratoconus risk loci and enhance polygenic risk score models.
圆锥角膜是一种角膜扩张性疾病，可导致角膜变薄、隆起并逐渐呈圆锥形。圆锥角膜的早期特征包括近视和不规则散光，这些会影响视力，可以通过佩戴隐形眼镜、角膜交联或在晚期病例中进行角膜移植来治疗。最近基于年轻人的 Scheimpflug 成像结果对圆锥角膜患病率的估计高达 1.2%。然而，由于很少有研究进行 Scheimpflug 成像，并且严重的圆锥角膜相对罕见，因此获得大量的圆锥角膜全基因组关联研究（GWAS）数据集是有问题的。
使用角膜阻力因子（CRF）和中央角膜厚度（CCT）来鉴定新的圆锥角膜基因座。
设计、地点和参与者：这项多性状 GWAS 使用了 UK Biobank（UKB）（n=105427）和加拿大纵向老龄化研究（CLSA）（n=18307）的欧洲血统 CRF 数据和国际青光眼遗传学联合会（IGGC）（n=17803）的欧洲血统 CCT 数据。在已发表的圆锥角膜数据集中比较了 CRF 和 CCT 变体（4669 例病例和 116547 例对照）。UKB 的数据集于 2020 年 3 月 24 日编译；CLSA 的数据于 2020 年 7 月发布；IGGC 数据可从 2018 年 5 月 1 日获得。
CRF 和 CCT 变体与圆锥角膜风险的关联。
GWAS 包括 4 个队列：105427 名 UKB 欧洲血统（56134 名女性[53.2%]和 49293 名男性[46.7%]；平均[SD]年龄，57[8]岁）、5029 名 UKB 南亚血统（2368 名女性[47.1%]和 2661 名男性[52.9%]；平均[SD]年龄，54[8]岁）、902 名 UKB 东亚血统（622 名女性[68.9%]和 280 名男性[31.0%]；平均[SD]年龄，53[8]岁）和 18307 名 CLSA 欧洲血统（9260 名女性[50.6%]和 9047 名男性[49.4%]；平均[SD]年龄，63[10]岁）参与者。确定了 369 个 CRF 和 233 个 CCT 基因座，包括 36 个新的 CRF 基因座和 114 个新的 CCT 基因座。29 个 CRF 基因座和 24 个 CCT 基因座与圆锥角膜有关。使用 CRF 和 CCT 相关变体和已发表的圆锥角膜变体构建了多基因风险评分（PRS）。PRS 结果表明，将基于 CRF 或 CCT 的 PRS 添加到先前发表的变体的圆锥角膜 PRS 中可以提高接受者操作特征曲线下的预测面积（从 CRF 的 0.705 提高到 0.756，从 CCT 的 0.715 提高到 0.755）。
这些发现支持使用角膜参数的多性状建模在相对较大的数据集来识别新的圆锥角膜风险基因座，并增强多基因风险评分模型。
