| Title: | Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies |
| Journal: | Nature Genetics |
| Published: | 13 Aug 2018 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/30104761/ |
| DOI: | https://doi.org/10.1038/s41588-018-0184-y |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/6119127 |
| Citations: | 973 (344 in last 2 years) as of 8 Aug 2024 |
Publication 8557
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Abstract
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.</p>
9 Keywords
- Case-Control Studies
- Computer Simulation
- Genome-Wide Association Study
- Humans
- Linear Models
- Logistic Models
- Models, Genetic
- Phenotype
- Polymorphism, Single Nucleotide
19 Authors
- Wei Zhou
- Jonas B. Nielsen
- Lars G. Fritsche
- Rounak Dey
- Maiken E. Gabrielsen
- Brooke N. Wolford
- Jonathon LeFaive
- Peter VandeHaar
- Sarah A. Gagliano
- Aliya Gifford
- Lisa A. Bastarache
- Wei-Qi Wei
- Joshua C. Denny
- Maoxuan Lin
- Kristian Hveem
- Hyun Min Kang
- Goncalo R. Abecasis
- Cristen J. Willer
- Seunggeun Lee
1 Application
| Application ID | Title |
|---|---|
| 24460 | Genetic causes of complex human traits: emphasis on psychiatric, ocular, dermatological, and cardiovascular diseases. |
Enabling scientific discoveries that improve human health