@article{936a75dc12194922b79621eb6b5f6d46,
title = "Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk",
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.",
author = "Reshef, {Yakir A.} and Finucane, {Hilary K.} and Kelley, {David R.} and Alexander Gusev and Dylan Kotliar and Ulirsch, {Jacob C.} and Farhad Hormozdiari and Joseph Nasser and Luke O{\textquoteright}Connor and {van de Geijn}, Bryce and Loh, {Po Ru} and Grossman, {Sharon R.} and Gaurav Bhatia and Steven Gazal and Palamara, {Pier Francesco} and Luca Pinello and Nick Patterson and Adams, {Ryan P.} and Price, {Alkes L.}",
note = "Funding Information: We thank C. de Boer, L. Dicker, J. Engreitz, T. Finucane, N. Friedman, R. Gumpert, M. Kanai, S. Kim, X. Liu, M. Mitzenmacher, J. Perry, S. Reilly, D. Reshef, S. Raychaudhuri, A. Schoech, P. Sabeti, R. Tewhey, O. Troyanskaya, P. Turley, O. Weissbrod, J. Zhou, and the CGTA discussion group for helpful discussions. This research was conducted using the UK Biobank Resource under Application No. 16549 and was supported by US National Institutes of Health grants No. U01 HG009379, R01 MH101244, R01 MH109978, and R01 MH107649. Y.A.R. was supported by award No. T32GM007753 from the National Institute of General Medical Sciences, the National Defense Science and Engineering Graduate Fellowship, and the Paul and Daisy Soros Foundation. H.K.F. was supported by the Fannie and John Hertz Foundation and by Eric and Wendy Schmidt. F.H. is supported by National Institute of Health award No. T32 DK110919. L.P. is supported by National Institutes of Health award No. R00HG008399. R.P.A. is supported by NSF grant No. IIS-1421780. Computational analyses were performed on the Orchestra High Performance Compute Cluster at Harvard Medical School, which is partially supported by grant No. NCRR 1S10RR028832-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. Publisher Copyright: {\textcopyright} 2018, The Author(s).",
year = "2018",
month = oct,
day = "1",
doi = "10.1038/s41588-018-0196-7",
language = "English (US)",
volume = "50",
pages = "1483--1493",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "10",
}