Evidence for causality of rare variants based on exact sharing probabilities in affected relatives. I. Ruczinski1, A. Bureau2, MM. Parker1, MA. Taub1, ML. Marazita3, JC. Murray4, JE. Bailey-Wilson5, CD. Cropp5, E. Mangold6, M. Noethen6, JB. Hetmanski1, P. Balakrishnan1, H. Wang1, H. Ling1, AF. Scott1, TH. Beaty1 1) Johns Hopkins University, Baltimore, MD; 2) Universite Laval, Quebec, Canada; 3) University of Pittsburgh, Pittsburgh, PA; 4) University of Iowa, Iowa City, IA; 5) National Human Genome Research Institute, Baltimore, MD; 6) Universitaet Bonn, Bonn, Germany.

   Family based study designs are regaining popularity because large-scale sequencing can help to interrogate the relationship between disease and variants too rare in the population to be detected through any test of association in a conventional case-control study, but may nonetheless co-segregate with disease within families. When only a few affected subjects per family are sequenced, evidence that a rare variant may be causal can be quantified from the probability of sharing alleles by all affected relatives given it was seen in any one family member under the null hypothesis of complete absence of linkage and association. We present a general framework for calculating such sharing probabilities when two or more affected subjects per family are sequenced, and show how information from multiple families can be combined by calculating a p-value as the sum of the probabilities of sharing events as (or more) extreme. We also examine the impact of unknown relationships and propose methods to approximate sharing probabilities based on empirical estimates of kinship between family members obtained from genome-wide marker data. We apply this method to a study of 55 multiplex families with apparent non-syndromic forms of oral clefts from four distinct populations. Whole exome sequencing was performed by the Center for Inherited Disease Research (CIDR) on two or three affected members from each family. The rare single nucleotide variant rs149253049 in the gene ADAMTS9 was shared by affected relatives in three Indian families (p=2x10-6), illustrating the power of this sharing approach.

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