Modelling the Effects of Penetrance and Family Size on Rates of Sporadic and Familial Disease
Modelling the Effects of Penetrance and Family Size on Rates of Sporadic and Familial Disease
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DOI：
10.1159/000330167
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发表时间：
2011-01-01
期刊：
影响因子：
1.8
通讯作者：
Lewis, Cathryn M.
中科院分区：
文献类型：
--
作者：
Al-Chalabi, Ammar;Lewis, Cathryn M.
背景/目的：许多复杂疾病表现出遗传模式的多样性，从表现为常染色体显性遗传的家族性疾病，到表现为明显散发疾病的单纯性家庭。确定偏差在产生明显遗传模式中的作用经常被忽视。因此，我们探讨了影响确定的两个关键参数，外显率和家庭规模在观察到的亲疏率中的作用。方法：我们建立了一个疾病熟悉度的数学模型，包括外显率、突变频率和家族大小等参数，并在肌萎缩性侧索硬化症这一复杂疾病中进行了测试。结果：单基因、高外显率变异可以解释复杂疾病的遗传模式，并在没有明显家族史的人群中占很大比例。按照目前的人口趋势，熟悉率将进一步下降。例如，外显率为0.5的变异会在12%的10号家族中引起明显的散发疾病，但在80%的1号家族中会引起散发疾病。一个外显率为0.9的变异，在过去类似爱尔兰的家庭中，只有11%的几率出现偶发，而在中国的独生子女家庭中，这一几率为57%。结论：这些发现对遗传咨询、疾病分类和基因搜寻研究的设计具有启示意义。家族性疾病和明显散发疾病之间的区别应该被认为是人为的。巴塞尔S. Karger股份有限公司版权所有
Background/Aims: Many complex diseases show a diversity of inheritance patterns ranging from familial disease, manifesting with autosomal dominant inheritance, through to simplex families in which only one person is affected, manifesting as apparently sporadic disease. The role of ascertainment bias in generating apparent patterns of inheritance is often overlooked. We therefore explored the role of two key parameters that influence ascertainment, penetrance and family size, in rates of observed familiality. Methods: We develop a mathematical model of familiality of disease, with parameters for penetrance, mutation frequency and family size, and test this in a complex disease: amyotrophic lateral sclerosis. Results: Monogenic, high-penetrance variants can explain patterns of inheritance in complex diseases and account for a large proportion of those with no apparent family history. With current demographic trends, rates of familiality will drop further. For example, a variant with penetrance 0.5 will cause apparently sporadic disease in 12% of families of size 10, but 80% of families of size 1.A variant with penetrance 0.9 has only an 11% chance of appearing sporadic in families of a size similar to those of Ireland in the past, compared with 57% in one-child families like many in China. Conclusions: These findings have implications for genetic counselling, disease classification and the design of gene-hunting studies. The distinction between familial and apparently sporadic disease should be considered artificial. Copyright (C) 2011 S. Karger AG, Basel