作为揭示年龄相关性黄斑变性遗传率缺失的一种手段，统计驱动基因。
Statistical driver genes as a means to uncover missing heritability for age-related macular degeneration.
机构信息
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, 44106, USA.
出版信息
BMC Med Genomics. 2020 Jul 6;13(1):95. doi: 10.1186/s12920-020-00747-4.
BACKGROUND
Age-related macular degeneration (AMD) is a progressive retinal disease contributing to blindness worldwide. Multiple estimates for AMD heritability (h) exist; however, a substantial proportion of h is not attributable to known genomic loci. The International AMD Genomics Consortium (IAMDGC) gathered the largest dataset of advanced AMD (ADV) cases and controls available and identified 34 loci containing 52 independent risk variants defining known AMD h. To better define AMD heterogeneity, we used Pathway Analysis by Randomization Incorporating Structure (PARIS) on the IAMDGC data and identified 8 statistical driver genes (SDGs), including 2 novel SDGs not discovered by the IAMDGC. We chose to further investigate these pathway-based risk genes and determine their contribution to ADV h, as well as the differential ADV subtype h.
METHODS
We performed genomic-relatedness-based restricted maximum-likelihood (GREML) analyses on ADV, geographic atrophy (GA), and choroidal neovascularization (CNV) subtypes to investigate the h of genotyped variants on the full DNA array chip, 34 risk loci (n = 2758 common variants), 52 variants from the IAMDGC 2016 GWAS, and the 8 SDGs, specifically the novel 2 SDGs, PPARA and PLCG2.
RESULTS
Via GREML, full chip h was 44.05% for ADV, 46.37% for GA, and 62.03% for CNV. The lead 52 variants' h (ADV: 14.52%, GA: 8.02%, CNV: 13.62%) and 34 loci h (ADV: 13.73%, GA: 8.81%, CNV: 12.89%) indicate that known variants contribute ~ 14% to ADV h. SDG variants account for a small percentage of ADV, GA, and CNV heritability, but estimates based on the combination of SDGs and the 34 known loci are similar to those calculated for known loci alone. We identified modest epistatic interactions among variants in the 2 SDGs and the 52 IAMDGC variants, including modest interactions between variants in PPARA and PLCG2.
CONCLUSIONS
Pathway analyses, which leverage biological relationships among genes in a pathway, may be useful in identifying additional loci that contribute to the heritability of complex disorders in a non-additive manner. Heritability analyses of these loci, especially amongst disease subtypes, may provide clues to the importance of specific genes to the genetic architecture of AMD.
背景
年龄相关性黄斑变性（AMD）是一种导致全球失明的进行性视网膜疾病。AMD 遗传力（h）有多种估计值；然而，相当一部分 h 不能归因于已知的基因组位点。国际 AMD 基因组学联合会（IAMDGC）汇集了最大的 AMD 病例和对照数据集，并确定了包含 52 个独立风险变异的 34 个与 AMD 相关的位点，这些变异确定了已知 AMD h。为了更好地定义 AMD 的异质性，我们在 IAMDGC 数据上使用了基于随机化纳入结构的途径分析（PARIS），并确定了 8 个统计驱动基因（SDGs），包括 IAMDGC 未发现的 2 个新的 SDGs。我们选择进一步研究这些基于途径的风险基因，并确定它们对 ADV h 的贡献，以及 ADV 亚型 h 的差异。
方法
我们对 ADV、地理萎缩（GA）和脉络膜新生血管（CNV）亚型进行了基于基因组相关性的最大似然（GREML）分析，以研究全 DNA 芯片、34 个风险位点（n=2758 个常见变异）、IAMDGC 2016 GWAS 的 52 个变异和 8 个 SDGs，特别是新的 2 个 SDGs，PPARA 和 PLCG2，在 ADV 中的基因型变异的 h。
结果
通过 GREML，ADV 的全芯片 h 为 44.05%，GA 为 46.37%，CNV 为 62.03%。52 个主要变异的 h（ADV：14.52%，GA：8.02%，CNV：13.62%）和 34 个位点的 h（ADV：13.73%，GA：8.81%，CNV：12.89%）表明，已知变异对 ADV h 的贡献约为 14%。SDG 变异对 ADV、GA 和 CNV 的遗传力贡献很小，但基于 SDG 和 34 个已知位点的组合估计值与仅基于已知位点的估计值相似。我们在 2 个 SDG 和 52 个 IAMDGC 变异中的变异之间发现了适度的上位性相互作用，包括在 PPARA 和 PLCG2 中的变异之间的适度相互作用。
结论
途径分析利用途径中基因之间的生物学关系，可能有助于识别以非累加方式对复杂疾病遗传力有贡献的其他位点。这些位点，尤其是在疾病亚型中的遗传力分析，可能为特定基因对 AMD 遗传结构的重要性提供线索。
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