Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, G1J 2G3, Département de Médecine Sociale et Préventive, Université Laval, Québec, G1V 0A6 Canada, Department of Biostatistics, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, PA 15219, Department of Pediatrics, School of Medicine, University of Iowa, IA 52242, USA, Institute of Human Genetics, University of Bonn, Bonn D-53127, Germany and Dr. Hejazi Clinic, P.O. Box 2519, Riyadh 11461, Saudi ArabiaCentre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, G1J 2G3, Département de Médecine Sociale et Préventive, Université Laval, Québec, G1V 0A6 Canada, Department of Biostatistics, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, PA 15219, Department of Pediatrics, School of Medicine, University of Iowa, IA 52242, USA, Institute of Human Genetics, University of Bonn, Bonn D-53127, Germany and Dr. Hejazi Clinic, P.O. Box 2519, Riyadh 11461, Saudi Arabia.
Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, G1J 2G3, Département de Médecine Sociale et Préventive, Université Laval, Québec, G1V 0A6 Canada, Department of Biostatistics, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, PA 15219, Department of Pediatrics, School of Medicine, University of Iowa, IA 52242, USA, Institute of Human Genetics, University of Bonn, Bonn D-53127, Germany and Dr. Hejazi Clinic, P.O. Box 2519, Riyadh 11461, Saudi Arabia.
Bioinformatics. 2014 Aug 1;30(15):2189-96. doi: 10.1093/bioinformatics/btu198. Epub 2014 Apr 16.
Family-based designs are regaining popularity for genomic sequencing studies because they provide a way to test cosegregation with disease of variants that are too rare in the population to be tested individually in a conventional case-control study.
Where only a few affected subjects per family are sequenced, the probability that any variant would be shared by all affected relatives-given it occurred in any one family member-provides evidence against the null hypothesis of a complete absence of linkage and association. A P-value can be obtained as the sum of the probabilities of sharing events as (or more) extreme in one or more families. We generalize an existing closed-form expression for exact sharing probabilities to more than two relatives per family. When pedigree founders are related, we show that an approximation of sharing probabilities based on empirical estimates of kinship among founders obtained from genome-wide marker data is accurate for low levels of kinship. We also propose a more generally applicable approach based on Monte Carlo simulations. We applied this method to a study of 55 multiplex families with apparent non-syndromic forms of oral clefts from four distinct populations, with whole exome sequences available for two or three affected members per family. The rare single nucleotide variant rs149253049 in ADAMTS9 shared by affected relatives in three Indian families achieved significance after correcting for multiple comparisons ([Formula: see text]).
Source code and binaries of the R package RVsharing are freely available for download at http://cran.r-project.org/web/packages/RVsharing/index.html.
alexandre.bureau@msp.ulaval.ca or ingo@jhu.edu
Supplementary data are available at Bioinformatics online.
基于家系的设计在基因组测序研究中重新受到欢迎，因为它们提供了一种方法来测试在人群中罕见的变体与疾病的共分离，而这些变体在传统的病例对照研究中由于个体数量太少而无法单独进行测试。
在仅对少数受影响的家系成员进行测序的情况下，任何变体都可能被所有受影响的亲属共享的概率 - 假设它发生在任何一个家庭成员中 - 提供了与完全不存在连锁和关联的零假设相悖的证据。可以将作为（或更）极端的共享事件的概率之和作为 P 值获得。我们将现有的用于精确共享概率的闭式表达式推广到每个家系中多于两个亲属的情况。当系谱创始人有关联时，我们表明，基于从全基因组标记数据中获得的创始人之间亲缘关系的经验估计的共享概率的近似值对于低水平的亲缘关系是准确的。我们还提出了一种更普遍适用的基于蒙特卡罗模拟的方法。我们将这种方法应用于来自四个不同人群的 55 个具有明显非综合征形式的口腔裂的多态性家系的研究，每个家系有两个或三个受影响的成员有全外显子组序列。在印度三个家庭中，受影响亲属共有的罕见单核苷酸变体 rs149253049 在经过多次比较校正后达到显著水平（[公式：见文本]）。
RVsharing R 包的源代码和二进制文件可在 http://cran.r-project.org/web/packages/RVsharing/index.html 上免费下载。
alexandre.bureau@msp.ulaval.ca 或 ingo@jhu.edu
补充数据可在 Bioinformatics 在线获得。
