Quantifying prion disease penetrance using large population control cohorts.
Quantifying prion disease penetrance using large population control cohorts.
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DOI：
10.1126/scitranslmed.aad5169
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发表时间：
2016-01-20
影响因子：
17.1
通讯作者：
MacArthur DG
中科院分区：
文献类型：
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作者：
Minikel EV;Vallabh SM;Lek M;Estrada K;Samocha KE;Sathirapongsasuti JF;McLean CY;Tung JY;Yu LP;Gambetti P;Blevins J;Zhang S;Cohen Y;Chen W;Yamada M;Hamaguchi T;Sanjo N;Mizusawa H;Nakamura Y;Kitamoto T;Collins SJ;Boyd A;Will RG;Knight R;Ponto C;Zerr I;Kraus TF;Eigenbrod S;Giese A;Calero M;de Pedro-Cuesta J;Haïk S;Laplanche JL;Bouaziz-Amar E;Brandel JP;Capellari S;Parchi P;Poleggi A;Ladogana A;O'Donnell-Luria AH;Karczewski KJ;Marshall JL;Boehnke M;Laakso M;Mohlke KL;Kähler A;Chambert K;McCarroll S;Sullivan PF;Hultman CM;Purcell SM;Sklar P;van der Lee SJ;Rozemuller A;Jansen C;Hofman A;Kraaij R;van Rooij JG;Ikram MA;Uitterlinden AG;van Duijn CM;Exome Aggregation Consortium (ExAC);Daly MJ;MacArthur DG
据报道，超过100，000种遗传变异会导致人类孟德尔氏病，但通常不知道所谓的致病基因型的携带者确实会患上这种疾病的概率。在这里，我们通过分析16，025例朊病毒疾病病例，60，706个人群对照外显子组和531，575个个体，评估朊病毒蛋白基因（PRNP）变异对朊病毒疾病风险的影响。我们发现，以前报道的致病性PRNP中的错义变异在人群中的普遍性至少是基于遗传性朊病毒疾病患病率的预期的30倍。虽然其中一些过量可归因于被错误地分配为致病性的良性变体，但其他变体对疾病易感性具有真正的影响，但赋予的终身风险范围为<0.1%至~ 100%。我们还表明，截短的变体在PRNP有位置依赖性的影响，与真正的功能丧失等位基因在健康的老年人中发现，支持朊病毒蛋白表达的治疗抑制的安全性。
More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance - the probability that a carrier of the purported disease-causing genotype will indeed develop the disease - is generally unknown. Here we assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe, Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30× more common in the population than expected based on genetic prion disease prevalence. While some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1% to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, supporting the safety of therapeutic suppression of prion protein expression.