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Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases

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Title: Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases
Author(s): Greene, D
NIHR BioResource
Richardson, S
Turro, E
Item Type: Journal Article
Abstract: Rare genetic disorders, which can now be studied systematically with affordable genome sequencing, are often caused by high-penetrance rare variants. Such disorders are often heterogeneous and characterized by abnormalities spanning multiple organ systems ascertained with variable clinical precision. Existing methods for identifying genes with variants responsible for rare diseases summarize phenotypes with unstructured binary or quantitative variables. The Human Phenotype Ontology (HPO) allows composite phenotypes to be represented systematically but association methods accounting for the ontological relationship between HPO terms do not exist. We present a Bayesian method to model the association between an HPO-coded patient phenotype and genotype. Our method estimates the probability of an association together with an HPO-coded phenotype characteristic of the disease. We thus formalize a clinical approach to phenotyping that is lacking in standard regression techniques for rare disease research. We demonstrate the power of our method by uncovering a number of true associations in a large collection of genome-sequenced and HPO-coded cases with rare diseases.
Publication Date: 25-Feb-2016
Date of Acceptance: 8-Jan-2016
URI: http://hdl.handle.net/10044/1/40391
DOI: http://dx.doi.org/10.1016/j.ajhg.2016.01.008
ISSN: 1537-6605
Publisher: Elsevier
Start Page: 490
End Page: 499
Journal / Book Title: American Journal of Human Genetics
Volume: 98
Issue: 3
Copyright Statement: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: Actinin
Adaptor Proteins, Signal Transducing
Bayes Theorem
Databases, Genetic
Genetic Association Studies
Guanine Nucleotide Exchange Factors
Humans
Logistic Models
Models, Genetic
Phenotype
Rare Diseases
NIHR BioResource
Humans
Rare Diseases
Adaptor Proteins, Signal Transducing
Guanine Nucleotide Exchange Factors
Actinin
Logistic Models
Bayes Theorem
Phenotype
Models, Genetic
Databases, Genetic
Genetic Association Studies
Genetics & Heredity
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care



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