Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.
Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.
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DOI：
10.1038/ng.2794
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发表时间：
2013-11
期刊：
影响因子：
30.8
通讯作者：
Altshuler D
中科院分区：
文献类型：
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作者：
Flannick J;Beer NL;Bick AG;Agarwala V;Molnes J;Gupta N;Burtt NP;Florez JC;Meigs JB;Taylor H;Lyssenko V;Irgens H;Fox E;Burslem F;Johansson S;Brosnan MJ;Trimmer JK;Newton-Cheh C;Tuomi T;Molven A;Wilson JG;O'Donnell CJ;Kathiresan S;Hirschhorn JN;Njølstad PR;Rolph T;Seidman JG;Gabriel S;Cox DR;Seidman CE;Groop L;Altshuler D
基因组测序可以在普通人群中识别出孟德尔疾病基因中携带罕见编码变异的个体，因此可能增加疾病风险。然而，以前的研究罕见的变异表型极端的个人有确认偏差，并可能显示夸大的效应大小估计。我们在表型良好的人群样本（n= 4，003）中对青年人成熟型糖尿病（MODY）的7个基因进行了测序。根据用于鉴定致病突变的预测标准过滤罕见变体：i）先前在MODY中报告的，和ii）满足严格的从头阈值（罕见、保守、蛋白质损伤）。在随机选择的Fragrance和杰克逊心脏研究个体中，分别约有1.5%和0.5%携带这两类变异。然而，绝大多数携带者在中年时仍保持血糖正常。需要准确估计基于人群的测序的变异效应大小，以避免错误地预测一个显着比例的个体为MODY或其他孟德尔疾病的风险。
Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders – and who consequently may have increased disease risk. However, previous studies of rare variants in phenotypically extreme individuals have ascertainment bias and may demonstrate inflated effect size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n=4,003). Rare variants were filtered according to prediction criteria used to identify disease-causing mutations: i) previously-reported in MODY, and ii) stringent de novo thresholds satisfied (rare, conserved, protein damaging). Approximately 1.5% and 0.5% of randomly selected Framingham and Jackson Heart Study individuals carried variants from these two classes, respectively. However, the vast majority of carriers remained euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a significant fraction of individuals as at risk for MODY or other Mendelian diseases.