Khan Atlas, Shang Ning, Nestor Jordan G, Weng Chunhua, Hripcsak George, Harris Peter C, Gharavi Ali G, Kiryluk Krzysztof
Division of Nephrology, Dept of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY.
Department of Biomedical Informatics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
medRxiv. 2023 May 10:2023.05.07.23289614. doi: 10.1101/2023.05.07.23289614.
Chronic kidney disease (CKD) is a genetically complex disease determined by an interplay of monogenic, polygenic, and environmental risks. Most forms of monogenic kidney diseases have incomplete penetrance and variable expressivity. It is presently unknown if some of the variability in penetrance can be attributed to polygenic factors.
Using the UK Biobank (N=469,835 participants) and the All of Us (N=98,622 participants) datasets, we examined two most common forms of monogenic kidney disorders, autosomal dominant polycystic kidney disease (ADPKD) caused by deleterious variants in the or genes, and COL4A-associated nephropathy (COL4A-AN caused by deleterious variants in , , or genes). We used the eMERGE-III electronic CKD phenotype to define cases (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 or kidney failure) and controls (eGFR >90 mL/min/1.73m2 in the absence of kidney disease diagnoses). The effects of the genome-wide polygenic score (GPS) for CKD were tested in monogenic variant carriers and non-carriers using logistic regression controlling for age, sex, diabetes, and genetic ancestry.
As expected, the carriers of known pathogenic and rare predicted loss-of-function variants in or had a high risk of CKD (OR=17.1, 95% CI: 11.1-26.4, P=1.8E-37). The GPS was comparably predictive of CKD in both ADPKD variant carriers (OR=2.28 per SD, 95%CI: 1.55-3.37, P=2.6E-05) and non-carriers (OR=1.72 per SD, 95% CI=1.69-1.76, P< E-300) independent of age, sex, diabetes, and genetic ancestry. Compared to the middle tertile of the GPS distribution for non-carriers, ADPKD variant carriers in the top tertile had a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile had only a 3-fold increased risk of CKD. Similarly, the GPS was predictive of CKD in both COL4-AN variant carriers (OR=1.78, 95% CI=1.22-2.58, P=2.38E-03) and non-carriers (OR=1.70, 95%CI: 1.68-1.73 P<E-300). The carriers in the top tertile of the GPS had a 2.5-fold higher risk of CKD while the risk for carriers in the bottom tertile was similar to the middle tertile of non-carriers.
Variable penetrance of kidney disease in ADPKD and COL4-AN is partially explained by differences in polygenic risk profiles. Accounting for polygenic factors has the potential to improve risk stratification in monogenic kidney disease and may have implications for genetic counseling.
慢性肾脏病（CKD）是一种由单基因、多基因和环境风险相互作用所决定的遗传复杂性疾病。大多数形式的单基因肾病具有不完全外显率和可变表达性。目前尚不清楚外显率的某些变异性是否可归因于多基因因素。
利用英国生物银行（N = 469,835名参与者）和“我们所有人”（N = 98,622名参与者）数据集，我们研究了两种最常见的单基因肾病形式，即由PKD1或PKD2基因中的有害变异引起的常染色体显性多囊肾病（ADPKD），以及由COL4A1、COL4A2或COL4A3基因中的有害变异引起的COL4A相关肾病（COL4A-AN）。我们使用eMERGE-III电子CKD表型来定义病例（估计肾小球滤过率（eGFR）<60 mL/（min·1.73m²）或肾衰竭）和对照（在无肾病诊断的情况下eGFR>90 mL/（min·1.73m²））。使用逻辑回归，在控制年龄、性别、糖尿病和遗传血统的情况下，对CKD的全基因组多基因评分（GPS）在单基因变异携带者和非携带者中的作用进行了测试。
正如预期的那样，PKD1或PKD2中已知致病和罕见预测功能丧失变异的携带者患CKD的风险很高（OR = 17.1，95%CI：11.1 - 26.4，P = 1.8×10⁻³⁷）。在ADPKD变异携带者（每标准差OR = 2.28，95%CI：1.55 - 3.37，P = 2.6×10⁻⁰⁵）和非携带者（每标准差OR = 1.72，95%CI = 1.69 - 1.76，P < 10⁻³⁰⁰）中，GPS对CKD的预测作用相当，且与年龄、性别、糖尿病和遗传血统无关。与非携带者GPS分布的中间三分位数相比，ADPKD变异携带者中处于最高三分位数者患CKD的风险增加了54倍，而处于最低三分位数者患CKD的风险仅增加了3倍。同样，在COL4-AN变异携带者（OR = 1.78，95%CI = 1.22 - 2.58，P = 2.38×10⁻⁰³）和非携带者（OR = 1.70，95%CI：1.68 - 1.73，P < 10⁻³⁰⁰）中，GPS对CKD均有预测作用。GPS处于最高三分位数的携带者患CKD的风险高2.5倍，而处于最低三分位数的携带者的风险与非携带者的中间三分位数相似。
ADPKD和COL4-AN中肾病的可变外显率部分可由多基因风险概况的差异来解释。考虑多基因因素有可能改善单基因肾病的风险分层，并且可能对遗传咨询有影响。
