Estimating heritability of drug-induced liver injury from common variants and implications for future study designs.
Estimating heritability of drug-induced liver injury from common variants and implications for future study designs.
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DOI：
10.1038/srep05762
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发表时间：
2014-07-21
影响因子：
4.6
通讯作者：
Shen Y
中科院分区：
文献类型：
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作者：
Overby CL;Hripcsak G;Shen Y
最近的全基因组关联研究确定某些人类白细胞抗原（HLA）等位基因是药物性肝损伤（DILI）的主要危险因素。虽然这些等位基因通常导致较大的相对风险，但由于特异质DILI的患病率较低，因此其预测值相当低。寻找额外的风险因素对精准医疗很重要。然而，进一步遗传研究的最佳设计受到DILI总体遗传力不确定的阻碍。这是低流行率药理学特征的常见问题，因为很难获得家庭的临床结局数据。在这里，我们估计遗传度（h2）的病例对照全基因组单核苷酸多态性数据使用的方法，基于随机效应模型。我们估计DILI的常见SNP捕获的h2比例在0.3和0.5之间。对于co-amoxiclav诱导的DILI，6号染色体解释了部分遗传性，表明尚未发现的常见变异的额外贡献，我们进行了模拟，以评估低prevelance下有限样本量的h2估计的稳健性，这是特异质药理学特征研究的典型条件。我们的研究结果表明，HLA以外的常见变异有助于DILI易发性;因此，通过扩大病例收集进行进一步的GWAS是有价值的。
Recent genome-wide association studies identified certain human leukocyote antigen (HLA) alleles as the major risk factors of drug-induced liver injuries (DILI). While these alleles often cause large relative risk, their predictive values are quite low due to low prevalence of idiosyncratic DILI. Finding additional risk factors is important for precision medicine. However, optimal design of further genetic studies is hindered by uncertain overall heritability of DILI. This is a common problem for low-prevalence pharmacological traits, since it is difficult to obtain clinical outcome data in families. Here we estimated the heritability (h2) of DILI from case-control genome-wide single nucleotide polymorphism data using a method based on random effect models. We estimated the proportion of h2 captured by common SNPs for DILI to be between 0.3 and 0.5. For co-amoxiclav induced DILI, chromosome 6 explained part of the heritability, indicating additional contributions from common variants yet to be found. We performed simulations to assess the robustness of the h2 estimate with limited sample size under low prevelance, a condition typical to studies on idiosyncratic pharmacological traits. Our findings suggest that common variants outside of HLA contribute to DILI susceptability; therefore, it is valuable to conduct further GWAS with expanded case collection.
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影响因子：
30.8
作者：
Anderson, Carl A.;Boucher, Gabrielle;Lees, Charlie W.;Franke, Andre;D'Amato, Mauro;Taylor, Kent D.;Lee, James C.;Goyette, Philippe;Imielinski, Marcin;Latiano, Anna;Lagace, Caroline;Scott, Regan;Amininejad, Leila;Bumpstead, Suzannah;Baidoo, Leonard;Baldassano, Robert N.;Barclay, Murray;Bayless, Theodore M.;Brand, Stephan;Buening, Carsten;Colombel, Jean-Frederic;Denson, Lee A.;De Vos, Martine;Dubinsky, Marla;Edwards, Cathryn;Ellinghaus, David;Fehrmann, Rudolf S. N.;Floyd, James A. B.;Florin, Timothy;Franchimont, Denis;Franke, Lude;Georges, Michel;Glas, Juergen;Glazer, Nicole L.;Guthery, Stephen L.;Haritunians, Talin;Hayward, Nicholas K.;Hugot, Jean-Pierre;Jobin, Gilles;Laukens, Debby;Lawrance, Ian;Lemann, Marc;Levine, Arie;Libioulle, Cecile;Louis, Edouard;McGovern, Dermot P.;Milla, Monica;Montgomery, Grant W.;Morley, Katherine I.;Mowat, Craig;Ng, Aylwin;Newman, William;Ophoff, Roel A.;Papi, Laura;Palmieri, Orazio;Peyrin-Biroulet, Laurent;Panes, Julian;Phillips, Anne;Prescott, Natalie J.;Proctor, Deborah D.;Roberts, Rebecca;Russell, Richard;Rutgeerts, Paul;Sanderson, Jeremy;Sans, Miquel;Schumm, Philip;Seibold, Frank;Sharma, Yashoda;Simms, Lisa A.;Seielstad, Mark;Steinhart, A. Hillary;Targan, Stephan R.;van den Berg, Leonard H.;Vatn, Morten;Verspaget, Hein;Walters, Thomas;Wijmenga, Cisca;Wilson, David C.;Westra, Harm-Jan;Xavier, Ramnik J.;Zhao, Zhen Z.;Ponsioen, Cyriel Y.;Andersen, Vibeke;Torkvist, Leif;Gazouli, Maria;Anagnou, Nicholas P.;Karlsen, Tom H.;Kupcinskas, Limas;Sventoraityte, Jurgita;Mansfield, John C.;Kugathasan, Subra;Silverberg, Mark S.;Halfvarson, Jonas;Rotter, Jerome I.;Mathew, Christopher G.;Griffiths, Anne M.;Gearry, Richard;Ahmad, Tariq;Brant, Steven R.;Chamaillard, Mathias;Satsangi, Jack;Cho, Judy H.;Schreiber, Stefan;Daly, Mark J.;Barrett, Jeffrey C.;Parkes, Miles;Annese, Vito;Hakonarson, Hakon;Radford-Smith, Graham;Duerr, Richard H.;Vermeire, Severine;Weersma, Rinse K.;Rioux, John D.
通讯作者：
Rioux, John D.
影响因子：
7.2
作者：
DANAN, G;BENICHOU, C
通讯作者：
BENICHOU, C
影响因子：
64.8
作者：
Nejentsev, Sergey;Howson, Joanna M. M.;Walker, Neil M.;Szeszko, Jeffrey;Field, Sarah F.;Stevens, Helen E.;Reynolds, Pamela;Hardy, Matthew;King, Erna;Masters, Jennifer;Hulme, John;Maier, Lisa M.;Smyth, Deborah;Bailey, Rebecca;Cooper, Jason D.;Ribas, Gloria;Campbell, R. Duncan;Clayton, David G.;Todd, John A.
通讯作者：
Todd, John A.
影响因子：
64.8
作者：
通讯作者：
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影响因子：
30.8
作者：
通讯作者：
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