UK Biobank Whole-Exome Sequence Binary Phenome Analysis with Robust Region-Based Rare-Variant Test.
Am J Hum Genet
; 106(1): 3-12, 2020 01 02.
Article
em En
| MEDLINE
| ID: mdl-31866045
ABSTRACT
In biobank data analysis, most binary phenotypes have unbalanced case-control ratios, and this can cause inflation of type I error rates. Recently, a saddle point approximation (SPA) based single-variant test has been developed to provide an accurate and scalable method to test for associations of such phenotypes. For gene- or region-based multiple-variant tests, a few methods exist that can adjust for unbalanced case-control ratios; however, these methods are either less accurate when case-control ratios are extremely unbalanced or not scalable for large data analyses. To address these problems, we propose SKAT- and SKAT-O- type region-based tests; in these tests, the single-variant score statistic is calibrated based on SPA and efficient resampling (ER). Through simulation studies, we show that the proposed method provides well-calibrated p values. In contrast, when the case-control ratio is 199, the unadjusted approach has greatly inflated type I error rates (90 times that of exome-wide sequencing α = 2.5 × 10-6). Additionally, the proposed method has similar computation time to the unadjusted approaches and is scalable for large sample data. In our application, the UK Biobank whole-exome sequence data analysis of 45,596 unrelated European samples and 791 PheCode phenotypes identified 10 rare-variant associations with p value < 10-7, including the associations between JAK2 and myeloproliferative disease, HOXB13 and cancer of prostate, and F11 and congenital coagulation defects. All analysis summary results are publicly available through a web-based visual server, and this availability can help facilitate the identification of the genetic basis of complex diseases.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
País/Região como assunto:
Europa
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article