Integrating molecular QTL data into genome-wide genetic association analysis: Probabilistic assessment of enrichment and colocalization

We propose a novel statistical framework for integrating the result from molecular quantitative trait loci (QTL) mapping into genome-wide genetic association analysis of complex traits, with the primary objectives of quantitatively assessing the enrichment of the molecular QTLs in complex trait-associated genetic variants and the colocalizations of the two types of association signals. We introduce a natural Bayesian hierarchical model that treats the latent association status of molecular QTLs as SNP-level annotations for candidate SNPs of complex traits. We detail a computational procedure to seamlessly perform enrichment, fine-mapping and colocalization analyses, which is a distinct feature compared to the existing colocalization analysis procedures in the literature. The proposed approach is computationally efficient and requires only summary-level statistics. We evaluate and demonstrate the proposed computational approach through extensive simulation studies and analyses of blood lipid data and the whole blood eQTL data from the GTEx project. In addition, a useful utility from our proposed method enables the computation of expected colocalization signals using simple characteristics of the association data. Using this utility, we further illustrate the importance of enrichment analysis on the ability to discover colocalized signals and the potential limitations of currently available molecular QTL data. The software pipeline that implements the proposed computation procedures, enloc, is freely available at https://github.com/xqwen/integrative.Author summary: Genome-wide association studies (GWAS) have been tremendously successful in identifying genetic variants that impact complex diseases. However, the roles of such studies in disease etiology remain poorly understood, primarily because a large proportion of the GWAS findings are located in the non-coding region of the genome. Recent advancements in high-throughput sequencing technology enable the systematic investigation of molecular quantitative trait loci (QTLs), which are genetic variants that directly affect molecular phenotypes (e.g., gene expression, transcription factor binding and DNA methylation). Linking molecular QTLs to GWAS findings intuitively represents an important step for interpreting the biological and clinical relevance of the GWAS results. In this paper, we describe a rigorous and efficient computational approach that assesses the enrichment and overlap between the GWAS findings and molecular QTLs. Importantly, we illustrate that the accurate quantification of overlapping between molecular QTL and GWAS signals requires reliable enrichment estimation. Our proposed approach fully accounts for the intrinsic uncertainty embedded in the association analyses of GWAS and molecular QTL mapping, and it outperforms the existing state-of-the-art approaches. Applying the proposed approach to the GWAS data of blood lipid traits and the whole blood expression QTLs (eQTLs) yields some novel biological insights and also illustrates the potential limitations of the currently available molecular QTL data.