TY - JOUR
T1 - Inferring disease risk genes from sequencing data in multiplex pedigrees through sharing of rare variants
AU - Bureau, Alexandre
AU - Begum, Ferdouse
AU - Taub, Margaret A.
AU - Hetmanski, Jacqueline B.
AU - Parker, Margaret M.
AU - Albacha-Hejazi, Hasan
AU - Scott, Alan F.
AU - Murray, Jeffrey C.
AU - Marazita, Mary L.
AU - Bailey-Wilson, Joan E.
AU - Beaty, Terri H.
AU - Ruczinski, Ingo
N1 - Funding Information:
We thank the members of the families who participated in the oral cleft sequencing studies and the field and laboratory staff who made this analysis possible. We thank Thomas Sherman (Johns Hopkins Bloomberg School of Public Health) for programming the RVS package and Saeed Sabbah (Université Laval) for performing the haplotyping of SNVs in the WES sample. The statistical analysis work was partly funded by the Canadian Statistical Sciences Institute through a Collaborative Research Team grant of which A. B. is the leader. National Institute of Dental and Craniofacial Research grant R03‐DE‐02579 to I. R. The oral cleft sequencing studies were supported by the National Institutes of Health (NIH; R01‐DE‐014581, U01‐DE‐018993, and U01 DE020073 to T. H. B.; R01‐DE‐016148 and R01‐DE‐009886 to M. L. M.; P50‐DE‐016215 and R37‐DE‐08559 to J. C. M.). Recruitment of Syrian families was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, USA and the Ibn Al‐Nafees Hospital, Syrian Arab Republic. Additional support from X01HG006177 to T. H. B., M. L. M., and J. C. M. for whole exome sequencing at the Center for Inherited Disease Research, which is funded through a federal contract from the NIH to Johns Hopkins University (Contract No. HHSN268200782096C). The FaceBase database was funded by NIH grant U01‐DE024425 to M. L. M.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - We previously demonstrated how sharing of rare variants (RVs) in distant affected relatives can be used to identify variants causing a complex and heterogeneous disease. This approach tested whether single RVs were shared by all sequenced affected family members. However, as with other study designs, joint analysis of several RVs (e.g., within genes) is sometimes required to obtain sufficient statistical power. Further, phenocopies can lead to false negatives for some causal RVs if complete sharing among affected is required. Here, we extend our methodology (Rare Variant Sharing, RVS) to address these issues. Specifically, we introduce gene-based analyses, a partial sharing test based on RV sharing probabilities for subsets of affected relatives and a haplotype-based RV definition. RVS also has the desirable feature of not requiring external estimates of variant frequency or control samples, provides functionality to assess and address violations of key assumptions, and is available as open source software for genome-wide analysis. Simulations including phenocopies, based on the families of an oral cleft study, revealed the partial and complete sharing versions of RVS achieved similar statistical power compared with alternative methods (RareIBD and the Gene-Based Segregation Test), and had superior power compared with the pedigree Variant Annotation, Analysis, and Search Tool (pVAAST) linkage statistic. In studies of multiplex cleft families, analysis of rare single nucleotide variants in the exome of 151 affected relatives from 54 families revealed no significant excess sharing in any one gene, but highlighted different patterns of sharing revealed by the complete and partial sharing tests.
AB - We previously demonstrated how sharing of rare variants (RVs) in distant affected relatives can be used to identify variants causing a complex and heterogeneous disease. This approach tested whether single RVs were shared by all sequenced affected family members. However, as with other study designs, joint analysis of several RVs (e.g., within genes) is sometimes required to obtain sufficient statistical power. Further, phenocopies can lead to false negatives for some causal RVs if complete sharing among affected is required. Here, we extend our methodology (Rare Variant Sharing, RVS) to address these issues. Specifically, we introduce gene-based analyses, a partial sharing test based on RV sharing probabilities for subsets of affected relatives and a haplotype-based RV definition. RVS also has the desirable feature of not requiring external estimates of variant frequency or control samples, provides functionality to assess and address violations of key assumptions, and is available as open source software for genome-wide analysis. Simulations including phenocopies, based on the families of an oral cleft study, revealed the partial and complete sharing versions of RVS achieved similar statistical power compared with alternative methods (RareIBD and the Gene-Based Segregation Test), and had superior power compared with the pedigree Variant Annotation, Analysis, and Search Tool (pVAAST) linkage statistic. In studies of multiplex cleft families, analysis of rare single nucleotide variants in the exome of 151 affected relatives from 54 families revealed no significant excess sharing in any one gene, but highlighted different patterns of sharing revealed by the complete and partial sharing tests.
KW - family studies
KW - identity by descent
KW - oral clefts
KW - variant sharing
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U2 - 10.1002/gepi.22155
DO - 10.1002/gepi.22155
M3 - Article
C2 - 30246882
AN - SCOPUS:85053721411
VL - 43
SP - 37
EP - 49
JO - Genetic Epidemiology
JF - Genetic Epidemiology
SN - 0741-0395
IS - 1
ER -