Genetic risk for a disease in the population may be represented as a genetic risk score (GRS) constructed as the sum of inherited risk alleles, weighted by allelic effects established in an independent population. While this formulation captures overall genetic risk, it typically does not address risk due to specific biological mechanisms or pathways that may nevertheless be important for interpretation or treatment response. Here, a GRS for disease is resolved into independent or nearly independent components pertaining to biological mechanisms inferred from pleiotropic relationships. The component GRSs' weights are derived from the singular value decomposition (SVD) of the matrix of appropriately scaled genetic effects, i.e., beta coefficients, of the disease variants across a panel of the disease-related phenotypes. The SVD-based formalism also associates combinations of disease-related phenotypes with inferred disease pathways. Applied to incident type 2 diabetes (T2D) in the Women's Genome Health Study (N = 23,294), component GRSs discriminate glycemic control and lipid-based genetic risk, while revealing significant interactions between specific components and BMI or physical activity, the latter not observed with a GRS for overall T2D genetic liability. Applied to coronary artery disease (CAD) in both the WGHS and in JUPITER (N = 8,749), a randomized trial of rosuvastatin for primary prevention of CVD, component GRSs discriminate genetic risk associated with LDL-C from risk associated with reciprocal genetic effects on triglycerides and HDL-C. They also inform the pharmacogenetics of statin treatment by demonstrating that benefit from rosuvastatin is as strongly related to genetic risk from triglycerides and HDL-C as from LDL-C.

中文翻译：

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基于多效性的遗传风险评分分解：2型糖尿病和CAD的关联和相互作用分析。

人群中疾病的遗传风险可以表示为遗传风险评分（GRS），该遗传风险评分由遗传风险等位基因的总和构成，并由在独立人群中建立的等位基因效应加权。尽管该制剂捕获了总体遗传风险，但由于特定的生物学机制或途径对于解释或治疗反应可能仍然很重要，因此通常无法解决风险。在这里，疾病的GRS被分解为与多效性关系推断的生物学机制有关的独立或近乎独立的组成部分。组分GRS的权重来自一组疾病相关表型上适当缩放的遗传效应矩阵（即β系数）的矩阵的奇异值分解（SVD）。基于SVD的形式主义还将疾病相关表型的组合与推断的疾病途径相关联。在女性基因组健康研究中（N = 23,294）应用于2型糖尿病（T2D）事件，组分GRS区分血糖控制和基于脂质的遗传风险，同时揭示了特定组分与BMI或身体活动之间的显着相互作用，但未观察到后者与GRS有关的总体T2D遗传责任。瑞舒伐他汀用于心血管疾病一级预防的随机试验，在WGHS和JUPITER（N = 8,749）中均适用于冠状动脉疾病（CAD），组分GRS可将与LDL-C相关的遗传风险与与对LDL-C相关的相互遗传影响相关甘油三酸酯和HDL-C。