Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with human complex traits. However, the genes or functional DNA elements through which these variants exert their effects on the traits are often unknown. We propose a method (called SMR) that integrates summary-level data from GWAS with data from expression quantitative trait locus (eQTL) studies to identify genes whose expression levels are associated with a complex trait because of pleiotropy. We apply the method to five human complex traits using GWAS data on up to 339,224 individuals and eQTL data on 5,311 individuals, and we prioritize 126 genes (for example, TRAF1 and ANKRD55 for rheumatoid arthritis and SNX19 and NMRAL1 for schizophrenia), of which 25 genes are new candidates; 77 genes are not the nearest annotated gene to the top associated GWAS SNP. These genes provide important leads to design future functional studies to understand the mechanism whereby DNA variation leads to complex trait variation.

Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets

The Analysis of Variance.

A survey of recent developments in the theory and application of com- posite likelihood is provided, building on the review paper of Varin(2008). A range of application areas, including geostatistics, spatial extremes, and space-time mod- els, as well as clustered and longitudinal data and time series are considered. The important area of applications to statistical genetics is omitted, in light ofLarribe and Fearnhead(2011). Emphasis is given to the development of the theory, and the current state of knowledge on e!ciency and robustness of composite likelihood inference.

/pdf/an-overview-of-composite-likelihood-methods-2lgbmk7ee2.pdf

An overview of composite likelihood methods

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.

/pdf/efficiently-controlling-for-case-control-imbalance-and-3ufw8meimo.pdf

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

Short communication: A new chi-square approximation to the distribution of non-negative definite quadratic forms in non-central normal variables

Reference STAT-ARTICLE-1999-001doi:101093/biomet/864929View record in Web of Science Record created on 2006-04-21, modified on 2017-05-12

/pdf/saddlepoint-approximations-for-distributions-of-quadratic-3x50bsjqq8.pdf

D Kuonen

Papers

Saddlepoint approximations for distributions of quadratic forms in normal variables