Inferring Disease Risk Genes from Sequencing Data in Multiplex Pedigrees Through Sharing of Rare Variants

Abstract

1We previously demonstrated how sharing of rare variants (RVs) in distant affected relatives can be used to 2 identify variants causing a complex and heterogeneous disease. This approach tested whether single RVs 3 were shared by all sequenced affected family members. However, as with other study designs, joint analysis 4 of several RVs (e.g. within genes) is sometimes required to obtain sufficient statistical power. Further, 5 phenocopies can lead to false negatives for some causal RVs if complete sharing among affecteds is required. 6Here we extend our methodology (Rare Variant Sharing, RVS) to address these issues. Specifically, we 7 introduce gene-based analyses, refine RV definition based on haplotypes, and introduce a partial sharing 8 test based on RV sharing probabilities for subsets of affected family members. RVS also has the desirable 9 features of not requiring external estimates of variant frequency or control samples, provides functionality to 10 assess and address violations of key assumptions, and is available as open source software for genome-wide 11 analysis. Simulations including phenocopies, based on the families of an oral cleft study, revealed the partial 12 and complete sharing versions of RVS achieved similar statistical power compared to alternative methods 13 (RareIBD and the Gene-Based Segregation Test), and had superior power compared to the pedigree Variant 14 Annotation, Analysis and Search Tool (pVAAST) linkage statistic. In studies of multiplex cleft families, 15 analysis of rare single nucleotide variants in the exome of 151 affected relatives from 54 families revealed 16 no significant excess sharing in any one gene, but highlighted different patterns of sharing revealed by the 17 complete and partial sharing tests.18

A pedigree-based cohort to study the genetic risk factors for cardiometabolic diseases: study design, baseline characteristics and preliminary results

“…Because of the difficulties in recruitment, investigation, and follow-up of the pedigrees, there are only several extended-pedigreebased studies in the world, such as Nigerian families and Oman families (29, 33). In China, other types of family-based studies have been carried out to explore genetic risk factors, for example, twin studies enrolling monozygotic and dizygotic twins, sibling studies enrolling pairs of siblings with different disease statuses, and nuclear family studies enrolling case-parent trios (34)(35)(36)(37). In the present study, we initiated FTPC to enroll the extended pedigrees with multigenerations.…”