Details

Autor(en) / Beteiligte

• Zhou, Wei
• Nielsen, Jonas B
• Fritsche, Lars G
• Dey, Rounak
• Gabrielsen, Maiken E
• Wolford, Brooke N
• LeFaive, Jonathon
• VandeHaar, Peter
• Gagliano, Sarah A
• Gifford, Aliya
• Bastarache, Lisa A
• Wei, Wei-Qi
• Denny, Joshua C
• Lin, Maoxuan
• Hveem, Kristian
• Kang, Hyun Min
• Abecasis, Goncalo R
• Willer, Cristen J
• Lee, Seunggeun

Titel

Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies

Ist Teil von

• Nature genetics, 2018-09, Vol.50 (9), p.1335-1341

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• In genome-wide association studies (GWAS) for thousands of phenotypes in large biobanks, most binary traits have substantially fewer cases than controls. Both of the widely used approaches, the linear mixed model and the recently proposed logistic mixed model, perform poorly; they produce large type I error rates when used to analyze unbalanced case-control phenotypes. Here we propose a scalable and accurate generalized mixed model association test that uses the saddlepoint approximation to calibrate the distribution of score test statistics. This method, SAIGE (Scalable and Accurate Implementation of GEneralized mixed model), provides accurate P values even when case-control ratios are extremely unbalanced. SAIGE uses state-of-art optimization strategies to reduce computational costs; hence, it is applicable to GWAS for thousands of phenotypes by large biobanks. Through the analysis of UK Biobank data of 408,961 samples from white British participants with European ancestry for > 1,400 binary phenotypes, we show that SAIGE can efficiently analyze large sample data, controlling for unbalanced case-control ratios and sample relatedness.