TY - JOUR
T1 - VARPRISM
T2 - Incorporating variant prioritization in tests of de novo mutation association
AU - Hu, Hao
AU - Coon, Hilary
AU - Li, Man
AU - Yandell, Mark
AU - Huff, Chad D.
N1 - Funding Information:
This work was supported by US National Institutes of Health grant R01 GM104390 and Pediatric Cardiac Genomics Consortium grant 1UM1HL128711. H.C. was supported by NIH R01 MH094400. H.H. was supported by University of Texas MD Anderson Odyssey fellowship.
Publisher Copyright:
© 2016 The Author(s).
PY - 2016/8/25
Y1 - 2016/8/25
N2 - Background: Patients with certain genetic diseases, such as autism spectrum disorder, have increased rates of de novo mutations within some protein-coding genes. Results: We introduce the VARiant PRIoritization SuM (VARPRISM), a software package which incorporates functional variant prioritization information to improve the power to detect de novo mutations influencing disease risk. VARPRISM evaluates the consequence of any given exonic mutation on the protein sequence to estimate the likelihood that the mutation is benign or damaging and conducts a likelihood ratio test on the gene level. We analyzed the Simons Simplex Collection of 2508 parent-offspring autism trios using VARPRISM, replicating 44 genes previously implicated in autism susceptibility and identifying 20 additional candidate genes, including MYO1E, KCND3, PDCD1, DLX3, and TSPAN4 (false discovery rate < 0.3). Conclusion: By incorporating functional predictions, VARPRISM improved the statistical power to identify de novo mutations increasing disease risks. VARPRISM is available at http://www.hufflab.org/software/VARPRISM.
AB - Background: Patients with certain genetic diseases, such as autism spectrum disorder, have increased rates of de novo mutations within some protein-coding genes. Results: We introduce the VARiant PRIoritization SuM (VARPRISM), a software package which incorporates functional variant prioritization information to improve the power to detect de novo mutations influencing disease risk. VARPRISM evaluates the consequence of any given exonic mutation on the protein sequence to estimate the likelihood that the mutation is benign or damaging and conducts a likelihood ratio test on the gene level. We analyzed the Simons Simplex Collection of 2508 parent-offspring autism trios using VARPRISM, replicating 44 genes previously implicated in autism susceptibility and identifying 20 additional candidate genes, including MYO1E, KCND3, PDCD1, DLX3, and TSPAN4 (false discovery rate < 0.3). Conclusion: By incorporating functional predictions, VARPRISM improved the statistical power to identify de novo mutations increasing disease risks. VARPRISM is available at http://www.hufflab.org/software/VARPRISM.
KW - Autism spectrum disorder
KW - De novo mutations
KW - Likelihood ratio test
KW - Simons Simplex Collection
KW - Variant prioritization
UR - http://www.scopus.com/inward/record.url?scp=84983605201&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84983605201&partnerID=8YFLogxK
U2 - 10.1186/s13073-016-0341-9
DO - 10.1186/s13073-016-0341-9
M3 - Article
C2 - 27562213
AN - SCOPUS:84983605201
SN - 1756-994X
VL - 8
JO - Genome medicine
JF - Genome medicine
IS - 1
M1 - 91
ER -