Chromatin marks identify critical cell types for fine mapping complex trait variants
Gosia Trynka,Cynthia Sandor,Buhm Han,Han Xu,Han Xu,Barbara E. Stranger,Barbara E. Stranger,Barbara E. Stranger,X. Shirley Liu,Soumya Raychaudhuri +9 more
TLDR
It is shown how cell type–specific H3K4me3 peaks can inform the fine mapping of associated SNPs to identify causal variation.Abstract:
If trait-associated variants alter regulatory regions, then they should fall within chromatin marks in relevant cell types. However, it is unclear which of the many marks are most useful in defining cell types associated with disease and fine mapping variants. We hypothesized that informative marks are phenotypically cell type specific; that is, SNPs associated with the same trait likely overlap marks in the same cell type. We examined 15 chromatin marks and found that those highlighting active gene regulation were phenotypically cell type specific. Trimethylation of histone H3 at lysine 4 (H3K4me3) was the most phenotypically cell type specific (P < 1 × 10(-6)), driven by colocalization of variants and marks rather than gene proximity (P < 0.001). H3K4me3 peaks overlapped with 37 SNPs for plasma low-density lipoprotein concentration in the liver (P < 7 × 10(-5)), 31 SNPs for rheumatoid arthritis within CD4(+) regulatory T cells (P = 1 × 10(-4)), 67 SNPs for type 2 diabetes in pancreatic islet cells (P = 0.003) and the liver (P = 0.003), and 14 SNPs for neuropsychiatric disease in neuronal tissues (P = 0.007). We show how cell type-specific H3K4me3 peaks can inform the fine mapping of associated SNPs to identify causal variation.read more
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Integrative analysis of 111 reference human epigenomes
Anshul Kundaje,Wouter Meuleman,Wouter Meuleman,Jason Ernst,Misha Bilenky,Angela Yen,Angela Yen,Alireza Heravi-Moussavi,Pouya Kheradpour,Pouya Kheradpour,Zhizhuo Zhang,Zhizhuo Zhang,Jianrong Wang,Jianrong Wang,Michael J. Ziller,Viren Amin,John W. Whitaker,Matthew D. Schultz,Lucas D. Ward,Lucas D. Ward,Abhishek Sarkar,Abhishek Sarkar,Gerald Quon,Gerald Quon,Richard Sandstrom,Matthew L. Eaton,Matthew L. Eaton,Yi-Chieh Wu,Yi-Chieh Wu,Andreas R. Pfenning,Andreas R. Pfenning,Xinchen Wang,Xinchen Wang,Melina Claussnitzer,Melina Claussnitzer,Yaping Liu,Yaping Liu,Cristian Coarfa,R. Alan Harris,Noam Shoresh,Charles B. Epstein,Elizabeta Gjoneska,Elizabeta Gjoneska,Danny Leung,Wei Xie,R. David Hawkins,Ryan Lister,Chibo Hong,Philippe Gascard,Andrew J. Mungall,Richard A. Moore,Eric Chuah,Angela Tam,Theresa K. Canfield,R. Scott Hansen,Rajinder Kaul,Peter J. Sabo,Mukul S. Bansal,Mukul S. Bansal,Mukul S. Bansal,Annaick Carles,Jesse R. Dixon,Kai How Farh,Soheil Feizi,Soheil Feizi,Rosa Karlic,Ah Ram Kim,Ah Ram Kim,Ashwinikumar Kulkarni,Daofeng Li,Rebecca F. Lowdon,Ginell Elliott,Tim R. Mercer,Shane Neph,Vitor Onuchic,Paz Polak,Paz Polak,Nisha Rajagopal,Pradipta R. Ray,Richard C Sallari,Richard C Sallari,Kyle Siebenthall,Nicholas A Sinnott-Armstrong,Nicholas A Sinnott-Armstrong,Michael Stevens,Robert E. Thurman,Jie Wu,Bo Zhang,Xin Zhou,Arthur E. Beaudet,Laurie A. Boyer,Philip L. De Jager,Philip L. De Jager,Peggy J. Farnham,Susan J. Fisher,David Haussler,Steven J.M. Jones,Steven J.M. Jones,Wei Li,Marco A. Marra,Michael T. McManus,Shamil R. Sunyaev,Shamil R. Sunyaev,James A. Thomson,Thea D. Tlsty,Li-Huei Tsai,Li-Huei Tsai,Wei Wang,Robert A. Waterland,Michael Q. Zhang,Lisa Helbling Chadwick,Bradley E. Bernstein,Bradley E. Bernstein,Bradley E. Bernstein,Joseph F. Costello,Joseph R. Ecker,Martin Hirst,Alexander Meissner,Aleksandar Milosavljevic,Bing Ren,John A. Stamatoyannopoulos,Ting Wang,Manolis Kellis,Manolis Kellis +123 more
TL;DR: It is shown that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease.
Integrative analysis of 111 reference human epigenomes
Anshul Kundaje,Wouter Meuleman,Jason Ernst,Angela Yen,Pouya Kheradpour,Zhizhuo Zhang,Jianrong Wang,Lucas D. Ward,Abhishek Sarkar,Gerald Quon,Matthew L. Eaton,Yi-Chieh Wu,Andreas R. Pfenning,Xinchen Wang,Melina Claussnitzer,Yaping Liu,Mukul S. Bansal,Soheil Feizi-Khankandi,Ah Ram Kim,Richard C Sallari,Nicholas A Sinnott-Armstrong,Laurie A. Boyer,Elizabeta Gjoneska,Li-Huei Tsai,Manolis Kellis +24 more
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Journal ArticleDOI
An Expanded View of Complex Traits: From Polygenic to Omnigenic
TL;DR: It is proposed that gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liable to affect the functions of core disease-related genes and that most heritability can be explained by effects on genes outside core pathways.
Journal ArticleDOI
Partitioning heritability by functional annotation using genome-wide association summary statistics.
Hilary K. Finucane,Hilary K. Finucane,Brendan Bulik-Sullivan,Brendan Bulik-Sullivan,Alexander Gusev,Gosia Trynka,Yakir A. Reshef,Po-Ru Loh,Verneri Anttila,Verneri Anttila,Han Xu,Chongzhi Zang,Kyle Kai-How Farh,Kyle Kai-How Farh,Stephan Ripke,Stephan Ripke,Felix R. Day,Shaun Purcell,Shaun Purcell,Eli A. Stahl,Sara Lindström,John R. B. Perry,Yukinori Okada,Soumya Raychaudhuri,Mark J. Daly,Mark J. Daly,Nick Patterson,Benjamin M. Neale,Benjamin M. Neale,Alkes L. Price,Alkes L. Price +30 more
TL;DR: A new method is introduced, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers, which is computationally tractable at very large sample sizes and leverages genome-wide information.
Journal ArticleDOI
Genetics of rheumatoid arthritis contributes to biology and drug discovery
Yukinori Okada,Yukinori Okada,Di Wu,Di Wu,Di Wu,Gosia Trynka,Gosia Trynka,Towfique Raj,Towfique Raj,Chikashi Terao,Katsunori Ikari,Yuta Kochi,Koichiro Ohmura,Akari Suzuki,Shinji Yoshida,Robert R. Graham,A. Manoharan,Ward Ortmann,Tushar Bhangale,Joshua C. Denny,Robert J. Carroll,Anne E. Eyler,Jeff Greenberg,Joel M. Kremer,Dimitrios A. Pappas,Lei Jiang,Jian Yin,Lingying Ye,Ding Feng Su,Jian Yang,Gang Xie,E.C. Keystone,Harm-Jan Westra,Tõnu Esko,Tõnu Esko,Tõnu Esko,Andres Metspalu,Xuezhong Zhou,Namrata Gupta,Daniel B. Mirel,Eli A. Stahl,Dorothee Diogo,Dorothee Diogo,Jing Cui,Jing Cui,Katherine P. Liao,Katherine P. Liao,Michael H. Guo,Michael H. Guo,Keiko Myouzen,Takahisa Kawaguchi,Marieke J H Coenen,Piet L. C. M. van Riel,Mart A F J van de Laar,Henk-Jan Guchelaar,Tom W J Huizinga,Philippe Dieudé,Xavier Mariette,S. Louis Bridges,Alexandra Zhernakova,Alexandra Zhernakova,René E. M. Toes,Paul P. Tak,Paul P. Tak,Paul P. Tak,Corinne Miceli-Richard,So Young Bang,Hye Soon Lee,Javier Martin,Miguel A. Gonzalez-Gay,Luis Rodriguez-Rodriguez,Solbritt Rantapää-Dahlqvist,Lisbeth Ärlestig,Hyon K. Choi,Hyon K. Choi,Yoichiro Kamatani,Pilar Galan,Mark Lathrop,Steve Eyre,Steve Eyre,John Bowes,John Bowes,Anne Barton,Niek de Vries,Larry W. Moreland,Lindsey A. Criswell,Elizabeth W. Karlson,Atsuo Taniguchi,Ryo Yamada,Michiaki Kubo,Jun Liu,Sang Cheol Bae,Jane Worthington,Jane Worthington,Leonid Padyukov,Lars Klareskog,Peter K. Gregersen,Soumya Raychaudhuri,Soumya Raychaudhuri,Barbara E. Stranger,Philip L. De Jager,Philip L. De Jager,Lude Franke,Peter M. Visscher,Matthew A. Brown,Hisashi Yamanaka,Tsuneyo Mimori,Atsushi Takahashi,Huji Xu,Timothy W. Behrens,Katherine A. Siminovitch,Shigeki Momohara,Fumihiko Matsuda,Kazuhiko Yamamoto,Robert M. Plenge,Robert M. Plenge +115 more
TL;DR: A genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries provides empirical evidence that the genetics of RA can provide important information for drug discovery, and sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis.
References
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