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Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

Author(s): Reshef, Yakir A; Finucane, Hilary K; Kelley, David R; Gusev, Alexander; Kotliar, Dylan; et al

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Abstract: Biological interpretation of genome-wide association study data frequently involves assessing whether SNPs linked to a biological process, for example, binding of a transcription factor, show unsigned enrichment for disease signal. However, signed annotations quantifying whether each SNP allele promotes or hinders the biological process can enable stronger statements about disease mechanism. We introduce a method, signed linkage disequilibrium profile regression, for detecting genome-wide directional effects of signed functional annotations on disease risk. We validate the method via simulations and application to molecular quantitative trait loci in blood, recovering known transcriptional regulators. We apply the method to expression quantitative trait loci in 48 Genotype-Tissue Expression tissues, identifying 651 transcription factor-tissue associations including 30 with robust evidence of tissue specificity. We apply the method to 46 diseases and complex traits (average n = 290 K), identifying 77 annotation-trait associations representing 12 independent transcription factor-trait associations, and characterize the underlying transcriptional programs using gene-set enrichment analyses. Our results implicate new causal disease genes and new disease mechanisms.
Publication Date: Sep-2018
Citation: Reshef, Yakir A., Hilary K. Finucane, David R. Kelley, Alexander Gusev, Dylan Kotliar, Jacob C. Ulirsch, Farhad Hormozdiari, Joseph Nasser, Luke O’Connor, Bryce van de Geijn, Po-Ru Loh, Sharon R. Grossman, Gaurav Bhatia, Steven Gazal, Pier Francesco Palamara, Luca Pinello, Nick Patterson, Ryan P. Adams, and Alkes L Price. "Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk." Nature Genetics 50, no. 10 (2018): 1483-1493. doi:10.1038/s41588-018-0196-7
DOI: 10.1038/s41588-018-0196-7
ISSN: 1061-4036
EISSN: 1546-1718
Pages: 1483 - 1493
Type of Material: Journal Article
Journal/Proceeding Title: Nature Genetics
Version: Author's manuscript

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