Rare variant association test with multiple phenotypes.
Genet Epidemiol
; 41(3): 198-209, 2017 04.
Article
em En
| MEDLINE
| ID: mdl-28039885
ABSTRACT
Although genome-wide association studies (GWAS) have now discovered thousands of genetic variants associated with common traits, such variants cannot explain the large degree of "missing heritability," likely due to rare variants. The advent of next generation sequencing technology has allowed rare variant detection and association with common traits, often by investigating specific genomic regions for rare variant effects on a trait. Although multiple correlated phenotypes are often concurrently observed in GWAS, most studies analyze only single phenotypes, which may lessen statistical power. To increase power, multivariate analyses, which consider correlations between multiple phenotypes, can be used. However, few existing multivariant analyses can identify rare variants for assessing multiple phenotypes. Here, we propose Multivariate Association Analysis using Score Statistics (MAAUSS), to identify rare variants associated with multiple phenotypes, based on the widely used sequence kernel association test (SKAT) for a single phenotype. We applied MAAUSS to whole exome sequencing (WES) data from a Korean population of 1,058 subjects to discover genes associated with multiple traits of liver function. We then assessed validation of those genes by a replication study, using an independent dataset of 3,445 individuals. Notably, we detected the gene ZNF620 among five significant genes. We then performed a simulation study to compare MAAUSS's performance with existing methods. Overall, MAAUSS successfully conserved type 1 error rates and in many cases had a higher power than the existing methods. This study illustrates a feasible and straightforward approach for identifying rare variants correlated with multiple phenotypes, with likely relevance to missing heritability.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fenótipo
/
Variação Genética
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Predisposição Genética para Doença
/
Estudo de Associação Genômica Ampla
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Sequenciamento de Nucleotídeos em Larga Escala
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Hepatopatias
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
País/Região como assunto:
Asia
Idioma:
En
Revista:
Genet Epidemiol
Assunto da revista:
EPIDEMIOLOGIA
/
GENETICA MEDICA
Ano de publicação:
2017
Tipo de documento:
Article