Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics

Alvaro N. Barbeira, Scott P. Dickinson, Rodrigo Bonazzola, Jiamao Zheng, Heather E. Wheeler, Jason M. Torres, Eric S. Torstenson, Kaanan P. Shah, Tzintzuni Garcia, Todd L. Edwards, Eli A. Stahl, Laura M. Huckins, François Aguet, Kristin G. Ardlie, Beryl B. Cummings, Ellen T. Gelfand, Gad Getz, Kane Hadley, Robert E. Handsaker, Katherine H. Huang & 225 others Seva Kashin, Konrad J. Karczewski, Monkol Lek, Xiao Li, Daniel G. MacArthur, Jared L. Nedzel, Duyen T. Nguyen, Michael S. Noble, Ayellet V. Segrè, Casandra A. Trowbridge, Taru Tukiainen, Nathan S. Abell, Brunilda Balliu, Ruth Barshir, Omer Basha, Alexis Battle, Gireesh K. Bogu, Andrew Brown, Christopher D. Brown, Stephane E. Castel, Lin S. Chen, Colby Chiang, Donald F. Conrad, Farhan N. Damani, Joe R. Davis, Olivier Delaneau, Emmanouil T. Dermitzakis, Barbara E. Engelhardt, Eleazar Eskin, Pedro G. Ferreira, Laure Frésard, Eric R. Gamazon, Diego Garrido-Martín, Ariel D.H. Gewirtz, Genna Gliner, Michael J. Gloudemans, Roderic Guigo, Ira M. Hall, Buhm Han, Yuan He, Farhad Hormozdiari, Cedric Howald, Brian Jo, Eun Yong Kang, Yungil Kim, Sarah Kim-Hellmuth, Tuuli Lappalainen, Gen Li, Xin Li, Boxiang Liu, Serghei Mangul, Mark I. McCarthy, Ian C. McDowell, Pejman Mohammadi, Jean Monlong, Stephen B. Montgomery, Manuel Muñoz-Aguirre, Anne W. Ndungu, Andrew B. Nobel, Meritxell Oliva, Halit Ongen, John J. Palowitch, Nikolaos Panousis, Panagiotis Papasaikas, Yo Son Park, Princy Parsana, Anthony J. Payne, Christine B. Peterson, Jie Quan, Ferran Reverter, Chiara Sabatti, Ashis Saha, Michael Sammeth, Alexandra J. Scott, Andrey A. Shabalin, Reza Sodaei, Matthew Stephens, Barbara E. Stranger, Benjamin J. Strober, Jae Hoon Sul, Emily K. Tsang, Sarah Urbut, Martijn Van De Bunt, Gao Wang, Xiaoquan Wen, Fred A. Wright, Hualin S. Xi, Esti Yeger-Lotem, Zachary Zappala, Judith B. Zaugg, Yi Hui Zhou, Joshua M. Akey, Daniel Bates, Joanne Chan, Melina Claussnitzer, Kathryn Demanelis, Morgan Diegel, Jennifer A. Doherty, Andrew P. Feinberg, Marian S. Fernando, Jessica Halow, Kasper D. Hansen, Eric Haugen, Peter F. Hickey, Lei Hou, Farzana Jasmine, Ruiqi Jian, Lihua Jiang, Audra Johnson, Rajinder Kaul, Manolis Kellis, Muhammad G. Kibriya, Kristen Lee, Jin Billy Li, Qin Li, Jessica Lin, Shin Lin, Sandra Linder, Caroline Linke, Yaping Liu, Matthew T. Maurano, Benoit Molinie, Jemma Nelson, Fidencio J. Neri, Yongjin Park, Brandon L. Pierce, Nicola J. Rinaldi, Lindsay F. Rizzardi, Richard Sandstrom, Andrew Skol, Kevin S. Smith, Michael P. Snyder, John Stamatoyannopoulos, Hua Tang, Li Wang, Meng Wang, Nicholas Van Wittenberghe, Fan Wu, Rui Zhang, Concepcion R. Nierras, Philip A. Branton, Latarsha J. Carithers, Ping Guan, Helen M. Moore, Abhi Rao, Jimmie B. Vaught, Sarah E. Gould, Nicole C. Lockart, Casey Martin, Jeffery P. Struewing, Simona Volpi, Anjene M. Addington, Susan E. Koester, A. Roger Little, Lori E. Brigham, Richard Hasz, Marcus Hunter, Christopher Johns, Mark Johnson, Gene Kopen, William F. Leinweber, John T. Lonsdale, Alisa McDonald, Bernadette Mestichelli, Kevin Myer, Brian Roe, Michael Salvatore, Saboor Shad, Jeffrey A. Thomas, Gary Walters, Michael Washington, Joseph Wheeler, Jason Bridge, Barbara A. Foster, Bryan M. Gillard, Ellen Karasik, Rachna Kumar, Mark Miklos, Michael T. Moser, Scott D. Jewell, Robert G. Montroy, Daniel C. Rohrer, Dana R. Valley, David A. Davis, Deborah C. Mash, Anita H. Undale, Anna M. Smith, David E. Tabor, Nancy V. Roche, Jeffrey A. McLean, Negin Vatanian, Karna L. Robinson, Leslie Sobin, Mary E. Barcus, Kimberly M. Valentino, Liqun Qi, Steven Hunter, Pushpa Hariharan, Shilpi Singh, Ki Sung Um, Takunda Matose, Maria M. Tomaszewski, Laura K. Barker, Maghboeba Mosavel, Laura A. Siminoff, Heather M. Traino, Paul Flicek, Thomas Juettemann, Magali Ruffier, Dan Sheppard, Kieron Taylor, Stephen J. Trevanion, Daniel R. Zerbino, Brian Craft, Mary Goldman, Maximilian Haeussler, W. James Kent, Christopher M. Lee, Benedict Paten, Kate R. Rosenbloom, John Vivian, Jingchun Zhu, Dan L. Nicolae, Nancy J. Cox, Hae Kyung Im

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.

Original languageEnglish (US)
Article number1825
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

phenotype
gene expression
Genome-Wide Association Study
Gene expression
Genes
Statistics
statistics
genes
Tissue
Phenotype
Gene Expression
etiology
Chromosome Mapping
catalogs
Scanning
Meta-Analysis
scanning
causes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Barbeira, A. N., Dickinson, S. P., Bonazzola, R., Zheng, J., Wheeler, H. E., Torres, J. M., ... Im, H. K. (2018). Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. Nature communications, 9(1), [1825]. https://doi.org/10.1038/s41467-018-03621-1
Barbeira, Alvaro N. ; Dickinson, Scott P. ; Bonazzola, Rodrigo ; Zheng, Jiamao ; Wheeler, Heather E. ; Torres, Jason M. ; Torstenson, Eric S. ; Shah, Kaanan P. ; Garcia, Tzintzuni ; Edwards, Todd L. ; Stahl, Eli A. ; Huckins, Laura M. ; Aguet, François ; Ardlie, Kristin G. ; Cummings, Beryl B. ; Gelfand, Ellen T. ; Getz, Gad ; Hadley, Kane ; Handsaker, Robert E. ; Huang, Katherine H. ; Kashin, Seva ; Karczewski, Konrad J. ; Lek, Monkol ; Li, Xiao ; MacArthur, Daniel G. ; Nedzel, Jared L. ; Nguyen, Duyen T. ; Noble, Michael S. ; Segrè, Ayellet V. ; Trowbridge, Casandra A. ; Tukiainen, Taru ; Abell, Nathan S. ; Balliu, Brunilda ; Barshir, Ruth ; Basha, Omer ; Battle, Alexis ; Bogu, Gireesh K. ; Brown, Andrew ; Brown, Christopher D. ; Castel, Stephane E. ; Chen, Lin S. ; Chiang, Colby ; Conrad, Donald F. ; Damani, Farhan N. ; Davis, Joe R. ; Delaneau, Olivier ; Dermitzakis, Emmanouil T. ; Engelhardt, Barbara E. ; Eskin, Eleazar ; Ferreira, Pedro G. ; Frésard, Laure ; Gamazon, Eric R. ; Garrido-Martín, Diego ; Gewirtz, Ariel D.H. ; Gliner, Genna ; Gloudemans, Michael J. ; Guigo, Roderic ; Hall, Ira M. ; Han, Buhm ; He, Yuan ; Hormozdiari, Farhad ; Howald, Cedric ; Jo, Brian ; Kang, Eun Yong ; Kim, Yungil ; Kim-Hellmuth, Sarah ; Lappalainen, Tuuli ; Li, Gen ; Li, Xin ; Liu, Boxiang ; Mangul, Serghei ; McCarthy, Mark I. ; McDowell, Ian C. ; Mohammadi, Pejman ; Monlong, Jean ; Montgomery, Stephen B. ; Muñoz-Aguirre, Manuel ; Ndungu, Anne W. ; Nobel, Andrew B. ; Oliva, Meritxell ; Ongen, Halit ; Palowitch, John J. ; Panousis, Nikolaos ; Papasaikas, Panagiotis ; Park, Yo Son ; Parsana, Princy ; Payne, Anthony J. ; Peterson, Christine B. ; Quan, Jie ; Reverter, Ferran ; Sabatti, Chiara ; Saha, Ashis ; Sammeth, Michael ; Scott, Alexandra J. ; Shabalin, Andrey A. ; Sodaei, Reza ; Stephens, Matthew ; Stranger, Barbara E. ; Strober, Benjamin J. ; Sul, Jae Hoon ; Tsang, Emily K. ; Urbut, Sarah ; Van De Bunt, Martijn ; Wang, Gao ; Wen, Xiaoquan ; Wright, Fred A. ; Xi, Hualin S. ; Yeger-Lotem, Esti ; Zappala, Zachary ; Zaugg, Judith B. ; Zhou, Yi Hui ; Akey, Joshua M. ; Bates, Daniel ; Chan, Joanne ; Claussnitzer, Melina ; Demanelis, Kathryn ; Diegel, Morgan ; Doherty, Jennifer A. ; Feinberg, Andrew P. ; Fernando, Marian S. ; Halow, Jessica ; Hansen, Kasper D. ; Haugen, Eric ; Hickey, Peter F. ; Hou, Lei ; Jasmine, Farzana ; Jian, Ruiqi ; Jiang, Lihua ; Johnson, Audra ; Kaul, Rajinder ; Kellis, Manolis ; Kibriya, Muhammad G. ; Lee, Kristen ; Li, Jin Billy ; Li, Qin ; Lin, Jessica ; Lin, Shin ; Linder, Sandra ; Linke, Caroline ; Liu, Yaping ; Maurano, Matthew T. ; Molinie, Benoit ; Nelson, Jemma ; Neri, Fidencio J. ; Park, Yongjin ; Pierce, Brandon L. ; Rinaldi, Nicola J. ; Rizzardi, Lindsay F. ; Sandstrom, Richard ; Skol, Andrew ; Smith, Kevin S. ; Snyder, Michael P. ; Stamatoyannopoulos, John ; Tang, Hua ; Wang, Li ; Wang, Meng ; Van Wittenberghe, Nicholas ; Wu, Fan ; Zhang, Rui ; Nierras, Concepcion R. ; Branton, Philip A. ; Carithers, Latarsha J. ; Guan, Ping ; Moore, Helen M. ; Rao, Abhi ; Vaught, Jimmie B. ; Gould, Sarah E. ; Lockart, Nicole C. ; Martin, Casey ; Struewing, Jeffery P. ; Volpi, Simona ; Addington, Anjene M. ; Koester, Susan E. ; Little, A. Roger ; Brigham, Lori E. ; Hasz, Richard ; Hunter, Marcus ; Johns, Christopher ; Johnson, Mark ; Kopen, Gene ; Leinweber, William F. ; Lonsdale, John T. ; McDonald, Alisa ; Mestichelli, Bernadette ; Myer, Kevin ; Roe, Brian ; Salvatore, Michael ; Shad, Saboor ; Thomas, Jeffrey A. ; Walters, Gary ; Washington, Michael ; Wheeler, Joseph ; Bridge, Jason ; Foster, Barbara A. ; Gillard, Bryan M. ; Karasik, Ellen ; Kumar, Rachna ; Miklos, Mark ; Moser, Michael T. ; Jewell, Scott D. ; Montroy, Robert G. ; Rohrer, Daniel C. ; Valley, Dana R. ; Davis, David A. ; Mash, Deborah C. ; Undale, Anita H. ; Smith, Anna M. ; Tabor, David E. ; Roche, Nancy V. ; McLean, Jeffrey A. ; Vatanian, Negin ; Robinson, Karna L. ; Sobin, Leslie ; Barcus, Mary E. ; Valentino, Kimberly M. ; Qi, Liqun ; Hunter, Steven ; Hariharan, Pushpa ; Singh, Shilpi ; Um, Ki Sung ; Matose, Takunda ; Tomaszewski, Maria M. ; Barker, Laura K. ; Mosavel, Maghboeba ; Siminoff, Laura A. ; Traino, Heather M. ; Flicek, Paul ; Juettemann, Thomas ; Ruffier, Magali ; Sheppard, Dan ; Taylor, Kieron ; Trevanion, Stephen J. ; Zerbino, Daniel R. ; Craft, Brian ; Goldman, Mary ; Haeussler, Maximilian ; Kent, W. James ; Lee, Christopher M. ; Paten, Benedict ; Rosenbloom, Kate R. ; Vivian, John ; Zhu, Jingchun ; Nicolae, Dan L. ; Cox, Nancy J. ; Im, Hae Kyung. / Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. In: Nature communications. 2018 ; Vol. 9, No. 1.
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title = "Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics",
abstract = "Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.",
author = "Barbeira, {Alvaro N.} and Dickinson, {Scott P.} and Rodrigo Bonazzola and Jiamao Zheng and Wheeler, {Heather E.} and Torres, {Jason M.} and Torstenson, {Eric S.} and Shah, {Kaanan P.} and Tzintzuni Garcia and Edwards, {Todd L.} and Stahl, {Eli A.} and Huckins, {Laura M.} and Fran{\cc}ois Aguet and Ardlie, {Kristin G.} and Cummings, {Beryl B.} and Gelfand, {Ellen T.} and Gad Getz and Kane Hadley and Handsaker, {Robert E.} and Huang, {Katherine H.} and Seva Kashin and Karczewski, {Konrad J.} and Monkol Lek and Xiao Li and MacArthur, {Daniel G.} and Nedzel, {Jared L.} and Nguyen, {Duyen T.} and Noble, {Michael S.} and Segr{\`e}, {Ayellet V.} and Trowbridge, {Casandra A.} and Taru Tukiainen and Abell, {Nathan S.} and Brunilda Balliu and Ruth Barshir and Omer Basha and Alexis Battle and Bogu, {Gireesh K.} and Andrew Brown and Brown, {Christopher D.} and Castel, {Stephane E.} and Chen, {Lin S.} and Colby Chiang and Conrad, {Donald F.} and Damani, {Farhan N.} and Davis, {Joe R.} and Olivier Delaneau and Dermitzakis, {Emmanouil T.} and Engelhardt, {Barbara E.} and Eleazar Eskin and Ferreira, {Pedro G.} and Laure Fr{\'e}sard and Gamazon, {Eric R.} and Diego Garrido-Mart{\'i}n and Gewirtz, {Ariel D.H.} and Genna Gliner and Gloudemans, {Michael J.} and Roderic Guigo and Hall, {Ira M.} and Buhm Han and Yuan He and Farhad Hormozdiari and Cedric Howald and Brian Jo and Kang, {Eun Yong} and Yungil Kim and Sarah Kim-Hellmuth and Tuuli Lappalainen and Gen Li and Xin Li and Boxiang Liu and Serghei Mangul and McCarthy, {Mark I.} and McDowell, {Ian C.} and Pejman Mohammadi and Jean Monlong and Montgomery, {Stephen B.} and Manuel Mu{\~n}oz-Aguirre and Ndungu, {Anne W.} and Nobel, {Andrew B.} and Meritxell Oliva and Halit Ongen and Palowitch, {John J.} and Nikolaos Panousis and Panagiotis Papasaikas and Park, {Yo Son} and Princy Parsana and Payne, {Anthony J.} and Peterson, {Christine B.} and Jie Quan and Ferran Reverter and Chiara Sabatti and Ashis Saha and Michael Sammeth and Scott, {Alexandra J.} and Shabalin, {Andrey A.} and Reza Sodaei and Matthew Stephens and Stranger, {Barbara E.} and Strober, {Benjamin J.} and Sul, {Jae Hoon} and Tsang, {Emily K.} and Sarah Urbut and {Van De Bunt}, Martijn and Gao Wang and Xiaoquan Wen and Wright, {Fred A.} and Xi, {Hualin S.} and Esti Yeger-Lotem and Zachary Zappala and Zaugg, {Judith B.} and Zhou, {Yi Hui} and Akey, {Joshua M.} and Daniel Bates and Joanne Chan and Melina Claussnitzer and Kathryn Demanelis and Morgan Diegel and Doherty, {Jennifer A.} and Feinberg, {Andrew P.} and Fernando, {Marian S.} and Jessica Halow and Hansen, {Kasper D.} and Eric Haugen and Hickey, {Peter F.} and Lei Hou and Farzana Jasmine and Ruiqi Jian and Lihua Jiang and Audra Johnson and Rajinder Kaul and Manolis Kellis and Kibriya, {Muhammad G.} and Kristen Lee and Li, {Jin Billy} and Qin Li and Jessica Lin and Shin Lin and Sandra Linder and Caroline Linke and Yaping Liu and Maurano, {Matthew T.} and Benoit Molinie and Jemma Nelson and Neri, {Fidencio J.} and Yongjin Park and Pierce, {Brandon L.} and Rinaldi, {Nicola J.} and Rizzardi, {Lindsay F.} and Richard Sandstrom and Andrew Skol and Smith, {Kevin S.} and Snyder, {Michael P.} and John Stamatoyannopoulos and Hua Tang and Li Wang and Meng Wang and {Van Wittenberghe}, Nicholas and Fan Wu and Rui Zhang and Nierras, {Concepcion R.} and Branton, {Philip A.} and Carithers, {Latarsha J.} and Ping Guan and Moore, {Helen M.} and Abhi Rao and Vaught, {Jimmie B.} and Gould, {Sarah E.} and Lockart, {Nicole C.} and Casey Martin and Struewing, {Jeffery P.} and Simona Volpi and Addington, {Anjene M.} and Koester, {Susan E.} and Little, {A. Roger} and Brigham, {Lori E.} and Richard Hasz and Marcus Hunter and Christopher Johns and Mark Johnson and Gene Kopen and Leinweber, {William F.} and Lonsdale, {John T.} and Alisa McDonald and Bernadette Mestichelli and Kevin Myer and Brian Roe and Michael Salvatore and Saboor Shad and Thomas, {Jeffrey A.} and Gary Walters and Michael Washington and Joseph Wheeler and Jason Bridge and Foster, {Barbara A.} and Gillard, {Bryan M.} and Ellen Karasik and Rachna Kumar and Mark Miklos and Moser, {Michael T.} and Jewell, {Scott D.} and Montroy, {Robert G.} and Rohrer, {Daniel C.} and Valley, {Dana R.} and Davis, {David A.} and Mash, {Deborah C.} and Undale, {Anita H.} and Smith, {Anna M.} and Tabor, {David E.} and Roche, {Nancy V.} and McLean, {Jeffrey A.} and Negin Vatanian and Robinson, {Karna L.} and Leslie Sobin and Barcus, {Mary E.} and Valentino, {Kimberly M.} and Liqun Qi and Steven Hunter and Pushpa Hariharan and Shilpi Singh and Um, {Ki Sung} and Takunda Matose and Tomaszewski, {Maria M.} and Barker, {Laura K.} and Maghboeba Mosavel and Siminoff, {Laura A.} and Traino, {Heather M.} and Paul Flicek and Thomas Juettemann and Magali Ruffier and Dan Sheppard and Kieron Taylor and Trevanion, {Stephen J.} and Zerbino, {Daniel R.} and Brian Craft and Mary Goldman and Maximilian Haeussler and Kent, {W. 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}

Barbeira, AN, Dickinson, SP, Bonazzola, R, Zheng, J, Wheeler, HE, Torres, JM, Torstenson, ES, Shah, KP, Garcia, T, Edwards, TL, Stahl, EA, Huckins, LM, Aguet, F, Ardlie, KG, Cummings, BB, Gelfand, ET, Getz, G, Hadley, K, Handsaker, RE, Huang, KH, Kashin, S, Karczewski, KJ, Lek, M, Li, X, MacArthur, DG, Nedzel, JL, Nguyen, DT, Noble, MS, Segrè, AV, Trowbridge, CA, Tukiainen, T, Abell, NS, Balliu, B, Barshir, R, Basha, O, Battle, A, Bogu, GK, Brown, A, Brown, CD, Castel, SE, Chen, LS, Chiang, C, Conrad, DF, Damani, FN, Davis, JR, Delaneau, O, Dermitzakis, ET, Engelhardt, BE, Eskin, E, Ferreira, PG, Frésard, L, Gamazon, ER, Garrido-Martín, D, Gewirtz, ADH, Gliner, G, Gloudemans, MJ, Guigo, R, Hall, IM, Han, B, He, Y, Hormozdiari, F, Howald, C, Jo, B, Kang, EY, Kim, Y, Kim-Hellmuth, S, Lappalainen, T, Li, G, Li, X, Liu, B, Mangul, S, McCarthy, MI, McDowell, IC, Mohammadi, P, Monlong, J, Montgomery, SB, Muñoz-Aguirre, M, Ndungu, AW, Nobel, AB, Oliva, M, Ongen, H, Palowitch, JJ, Panousis, N, Papasaikas, P, Park, YS, Parsana, P, Payne, AJ, Peterson, CB, Quan, J, Reverter, F, Sabatti, C, Saha, A, Sammeth, M, Scott, AJ, Shabalin, AA, Sodaei, R, Stephens, M, Stranger, BE, Strober, BJ, Sul, JH, Tsang, EK, Urbut, S, Van De Bunt, M, Wang, G, Wen, X, Wright, FA, Xi, HS, Yeger-Lotem, E, Zappala, Z, Zaugg, JB, Zhou, YH, Akey, JM, Bates, D, Chan, J, Claussnitzer, M, Demanelis, K, Diegel, M, Doherty, JA, Feinberg, AP, Fernando, MS, Halow, J, Hansen, KD, Haugen, E, Hickey, PF, Hou, L, Jasmine, F, Jian, R, Jiang, L, Johnson, A, Kaul, R, Kellis, M, Kibriya, MG, Lee, K, Li, JB, Li, Q, Lin, J, Lin, S, Linder, S, Linke, C, Liu, Y, Maurano, MT, Molinie, B, Nelson, J, Neri, FJ, Park, Y, Pierce, BL, Rinaldi, NJ, Rizzardi, LF, Sandstrom, R, Skol, A, Smith, KS, Snyder, MP, Stamatoyannopoulos, J, Tang, H, Wang, L, Wang, M, Van Wittenberghe, N, Wu, F, Zhang, R, Nierras, CR, Branton, PA, Carithers, LJ, Guan, P, Moore, HM, Rao, A, Vaught, JB, Gould, SE, Lockart, NC, Martin, C, Struewing, JP, Volpi, S, Addington, AM, Koester, SE, Little, AR, Brigham, LE, Hasz, R, Hunter, M, Johns, C, Johnson, M, Kopen, G, Leinweber, WF, Lonsdale, JT, McDonald, A, Mestichelli, B, Myer, K, Roe, B, Salvatore, M, Shad, S, Thomas, JA, Walters, G, Washington, M, Wheeler, J, Bridge, J, Foster, BA, Gillard, BM, Karasik, E, Kumar, R, Miklos, M, Moser, MT, Jewell, SD, Montroy, RG, Rohrer, DC, Valley, DR, Davis, DA, Mash, DC, Undale, AH, Smith, AM, Tabor, DE, Roche, NV, McLean, JA, Vatanian, N, Robinson, KL, Sobin, L, Barcus, ME, Valentino, KM, Qi, L, Hunter, S, Hariharan, P, Singh, S, Um, KS, Matose, T, Tomaszewski, MM, Barker, LK, Mosavel, M, Siminoff, LA, Traino, HM, Flicek, P, Juettemann, T, Ruffier, M, Sheppard, D, Taylor, K, Trevanion, SJ, Zerbino, DR, Craft, B, Goldman, M, Haeussler, M, Kent, WJ, Lee, CM, Paten, B, Rosenbloom, KR, Vivian, J, Zhu, J, Nicolae, DL, Cox, NJ & Im, HK 2018, 'Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics', Nature communications, vol. 9, no. 1, 1825. https://doi.org/10.1038/s41467-018-03621-1

Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. / Barbeira, Alvaro N.; Dickinson, Scott P.; Bonazzola, Rodrigo; Zheng, Jiamao; Wheeler, Heather E.; Torres, Jason M.; Torstenson, Eric S.; Shah, Kaanan P.; Garcia, Tzintzuni; Edwards, Todd L.; Stahl, Eli A.; Huckins, Laura M.; Aguet, François; Ardlie, Kristin G.; Cummings, Beryl B.; Gelfand, Ellen T.; Getz, Gad; Hadley, Kane; Handsaker, Robert E.; Huang, Katherine H.; Kashin, Seva; Karczewski, Konrad J.; Lek, Monkol; Li, Xiao; MacArthur, Daniel G.; Nedzel, Jared L.; Nguyen, Duyen T.; Noble, Michael S.; Segrè, Ayellet V.; Trowbridge, Casandra A.; Tukiainen, Taru; Abell, Nathan S.; Balliu, Brunilda; Barshir, Ruth; Basha, Omer; Battle, Alexis; Bogu, Gireesh K.; Brown, Andrew; Brown, Christopher D.; Castel, Stephane E.; Chen, Lin S.; Chiang, Colby; Conrad, Donald F.; Damani, Farhan N.; Davis, Joe R.; Delaneau, Olivier; Dermitzakis, Emmanouil T.; Engelhardt, Barbara E.; Eskin, Eleazar; Ferreira, Pedro G.; Frésard, Laure; Gamazon, Eric R.; Garrido-Martín, Diego; Gewirtz, Ariel D.H.; Gliner, Genna; Gloudemans, Michael J.; Guigo, Roderic; Hall, Ira M.; Han, Buhm; He, Yuan; Hormozdiari, Farhad; Howald, Cedric; Jo, Brian; Kang, Eun Yong; Kim, Yungil; Kim-Hellmuth, Sarah; Lappalainen, Tuuli; Li, Gen; Li, Xin; Liu, Boxiang; Mangul, Serghei; McCarthy, Mark I.; McDowell, Ian C.; Mohammadi, Pejman; Monlong, Jean; Montgomery, Stephen B.; Muñoz-Aguirre, Manuel; Ndungu, Anne W.; Nobel, Andrew B.; Oliva, Meritxell; Ongen, Halit; Palowitch, John J.; Panousis, Nikolaos; Papasaikas, Panagiotis; Park, Yo Son; Parsana, Princy; Payne, Anthony J.; Peterson, Christine B.; Quan, Jie; Reverter, Ferran; Sabatti, Chiara; Saha, Ashis; Sammeth, Michael; Scott, Alexandra J.; Shabalin, Andrey A.; Sodaei, Reza; Stephens, Matthew; Stranger, Barbara E.; Strober, Benjamin J.; Sul, Jae Hoon; Tsang, Emily K.; Urbut, Sarah; Van De Bunt, Martijn; Wang, Gao; Wen, Xiaoquan; Wright, Fred A.; Xi, Hualin S.; Yeger-Lotem, Esti; Zappala, Zachary; Zaugg, Judith B.; Zhou, Yi Hui; Akey, Joshua M.; Bates, Daniel; Chan, Joanne; Claussnitzer, Melina; Demanelis, Kathryn; Diegel, Morgan; Doherty, Jennifer A.; Feinberg, Andrew P.; Fernando, Marian S.; Halow, Jessica; Hansen, Kasper D.; Haugen, Eric; Hickey, Peter F.; Hou, Lei; Jasmine, Farzana; Jian, Ruiqi; Jiang, Lihua; Johnson, Audra; Kaul, Rajinder; Kellis, Manolis; Kibriya, Muhammad G.; Lee, Kristen; Li, Jin Billy; Li, Qin; Lin, Jessica; Lin, Shin; Linder, Sandra; Linke, Caroline; Liu, Yaping; Maurano, Matthew T.; Molinie, Benoit; Nelson, Jemma; Neri, Fidencio J.; Park, Yongjin; Pierce, Brandon L.; Rinaldi, Nicola J.; Rizzardi, Lindsay F.; Sandstrom, Richard; Skol, Andrew; Smith, Kevin S.; Snyder, Michael P.; Stamatoyannopoulos, John; Tang, Hua; Wang, Li; Wang, Meng; Van Wittenberghe, Nicholas; Wu, Fan; Zhang, Rui; Nierras, Concepcion R.; Branton, Philip A.; Carithers, Latarsha J.; Guan, Ping; Moore, Helen M.; Rao, Abhi; Vaught, Jimmie B.; Gould, Sarah E.; Lockart, Nicole C.; Martin, Casey; Struewing, Jeffery P.; Volpi, Simona; Addington, Anjene M.; Koester, Susan E.; Little, A. Roger; Brigham, Lori E.; Hasz, Richard; Hunter, Marcus; Johns, Christopher; Johnson, Mark; Kopen, Gene; Leinweber, William F.; Lonsdale, John T.; McDonald, Alisa; Mestichelli, Bernadette; Myer, Kevin; Roe, Brian; Salvatore, Michael; Shad, Saboor; Thomas, Jeffrey A.; Walters, Gary; Washington, Michael; Wheeler, Joseph; Bridge, Jason; Foster, Barbara A.; Gillard, Bryan M.; Karasik, Ellen; Kumar, Rachna; Miklos, Mark; Moser, Michael T.; Jewell, Scott D.; Montroy, Robert G.; Rohrer, Daniel C.; Valley, Dana R.; Davis, David A.; Mash, Deborah C.; Undale, Anita H.; Smith, Anna M.; Tabor, David E.; Roche, Nancy V.; McLean, Jeffrey A.; Vatanian, Negin; Robinson, Karna L.; Sobin, Leslie; Barcus, Mary E.; Valentino, Kimberly M.; Qi, Liqun; Hunter, Steven; Hariharan, Pushpa; Singh, Shilpi; Um, Ki Sung; Matose, Takunda; Tomaszewski, Maria M.; Barker, Laura K.; Mosavel, Maghboeba; Siminoff, Laura A.; Traino, Heather M.; Flicek, Paul; Juettemann, Thomas; Ruffier, Magali; Sheppard, Dan; Taylor, Kieron; Trevanion, Stephen J.; Zerbino, Daniel R.; Craft, Brian; Goldman, Mary; Haeussler, Maximilian; Kent, W. James; Lee, Christopher M.; Paten, Benedict; Rosenbloom, Kate R.; Vivian, John; Zhu, Jingchun; Nicolae, Dan L.; Cox, Nancy J.; Im, Hae Kyung.

In: Nature communications, Vol. 9, No. 1, 1825, 01.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics

AU - Barbeira, Alvaro N.

AU - Dickinson, Scott P.

AU - Bonazzola, Rodrigo

AU - Zheng, Jiamao

AU - Wheeler, Heather E.

AU - Torres, Jason M.

AU - Torstenson, Eric S.

AU - Shah, Kaanan P.

AU - Garcia, Tzintzuni

AU - Edwards, Todd L.

AU - Stahl, Eli A.

AU - Huckins, Laura M.

AU - Aguet, François

AU - Ardlie, Kristin G.

AU - Cummings, Beryl B.

AU - Gelfand, Ellen T.

AU - Getz, Gad

AU - Hadley, Kane

AU - Handsaker, Robert E.

AU - Huang, Katherine H.

AU - Kashin, Seva

AU - Karczewski, Konrad J.

AU - Lek, Monkol

AU - Li, Xiao

AU - MacArthur, Daniel G.

AU - Nedzel, Jared L.

AU - Nguyen, Duyen T.

AU - Noble, Michael S.

AU - Segrè, Ayellet V.

AU - Trowbridge, Casandra A.

AU - Tukiainen, Taru

AU - Abell, Nathan S.

AU - Balliu, Brunilda

AU - Barshir, Ruth

AU - Basha, Omer

AU - Battle, Alexis

AU - Bogu, Gireesh K.

AU - Brown, Andrew

AU - Brown, Christopher D.

AU - Castel, Stephane E.

AU - Chen, Lin S.

AU - Chiang, Colby

AU - Conrad, Donald F.

AU - Damani, Farhan N.

AU - Davis, Joe R.

AU - Delaneau, Olivier

AU - Dermitzakis, Emmanouil T.

AU - Engelhardt, Barbara E.

AU - Eskin, Eleazar

AU - Ferreira, Pedro G.

AU - Frésard, Laure

AU - Gamazon, Eric R.

AU - Garrido-Martín, Diego

AU - Gewirtz, Ariel D.H.

AU - Gliner, Genna

AU - Gloudemans, Michael J.

AU - Guigo, Roderic

AU - Hall, Ira M.

AU - Han, Buhm

AU - He, Yuan

AU - Hormozdiari, Farhad

AU - Howald, Cedric

AU - Jo, Brian

AU - Kang, Eun Yong

AU - Kim, Yungil

AU - Kim-Hellmuth, Sarah

AU - Lappalainen, Tuuli

AU - Li, Gen

AU - Li, Xin

AU - Liu, Boxiang

AU - Mangul, Serghei

AU - McCarthy, Mark I.

AU - McDowell, Ian C.

AU - Mohammadi, Pejman

AU - Monlong, Jean

AU - Montgomery, Stephen B.

AU - Muñoz-Aguirre, Manuel

AU - Ndungu, Anne W.

AU - Nobel, Andrew B.

AU - Oliva, Meritxell

AU - Ongen, Halit

AU - Palowitch, John J.

AU - Panousis, Nikolaos

AU - Papasaikas, Panagiotis

AU - Park, Yo Son

AU - Parsana, Princy

AU - Payne, Anthony J.

AU - Peterson, Christine B.

AU - Quan, Jie

AU - Reverter, Ferran

AU - Sabatti, Chiara

AU - Saha, Ashis

AU - Sammeth, Michael

AU - Scott, Alexandra J.

AU - Shabalin, Andrey A.

AU - Sodaei, Reza

AU - Stephens, Matthew

AU - Stranger, Barbara E.

AU - Strober, Benjamin J.

AU - Sul, Jae Hoon

AU - Tsang, Emily K.

AU - Urbut, Sarah

AU - Van De Bunt, Martijn

AU - Wang, Gao

AU - Wen, Xiaoquan

AU - Wright, Fred A.

AU - Xi, Hualin S.

AU - Yeger-Lotem, Esti

AU - Zappala, Zachary

AU - Zaugg, Judith B.

AU - Zhou, Yi Hui

AU - Akey, Joshua M.

AU - Bates, Daniel

AU - Chan, Joanne

AU - Claussnitzer, Melina

AU - Demanelis, Kathryn

AU - Diegel, Morgan

AU - Doherty, Jennifer A.

AU - Feinberg, Andrew P.

AU - Fernando, Marian S.

AU - Halow, Jessica

AU - Hansen, Kasper D.

AU - Haugen, Eric

AU - Hickey, Peter F.

AU - Hou, Lei

AU - Jasmine, Farzana

AU - Jian, Ruiqi

AU - Jiang, Lihua

AU - Johnson, Audra

AU - Kaul, Rajinder

AU - Kellis, Manolis

AU - Kibriya, Muhammad G.

AU - Lee, Kristen

AU - Li, Jin Billy

AU - Li, Qin

AU - Lin, Jessica

AU - Lin, Shin

AU - Linder, Sandra

AU - Linke, Caroline

AU - Liu, Yaping

AU - Maurano, Matthew T.

AU - Molinie, Benoit

AU - Nelson, Jemma

AU - Neri, Fidencio J.

AU - Park, Yongjin

AU - Pierce, Brandon L.

AU - Rinaldi, Nicola J.

AU - Rizzardi, Lindsay F.

AU - Sandstrom, Richard

AU - Skol, Andrew

AU - Smith, Kevin S.

AU - Snyder, Michael P.

AU - Stamatoyannopoulos, John

AU - Tang, Hua

AU - Wang, Li

AU - Wang, Meng

AU - Van Wittenberghe, Nicholas

AU - Wu, Fan

AU - Zhang, Rui

AU - Nierras, Concepcion R.

AU - Branton, Philip A.

AU - Carithers, Latarsha J.

AU - Guan, Ping

AU - Moore, Helen M.

AU - Rao, Abhi

AU - Vaught, Jimmie B.

AU - Gould, Sarah E.

AU - Lockart, Nicole C.

AU - Martin, Casey

AU - Struewing, Jeffery P.

AU - Volpi, Simona

AU - Addington, Anjene M.

AU - Koester, Susan E.

AU - Little, A. Roger

AU - Brigham, Lori E.

AU - Hasz, Richard

AU - Hunter, Marcus

AU - Johns, Christopher

AU - Johnson, Mark

AU - Kopen, Gene

AU - Leinweber, William F.

AU - Lonsdale, John T.

AU - McDonald, Alisa

AU - Mestichelli, Bernadette

AU - Myer, Kevin

AU - Roe, Brian

AU - Salvatore, Michael

AU - Shad, Saboor

AU - Thomas, Jeffrey A.

AU - Walters, Gary

AU - Washington, Michael

AU - Wheeler, Joseph

AU - Bridge, Jason

AU - Foster, Barbara A.

AU - Gillard, Bryan M.

AU - Karasik, Ellen

AU - Kumar, Rachna

AU - Miklos, Mark

AU - Moser, Michael T.

AU - Jewell, Scott D.

AU - Montroy, Robert G.

AU - Rohrer, Daniel C.

AU - Valley, Dana R.

AU - Davis, David A.

AU - Mash, Deborah C.

AU - Undale, Anita H.

AU - Smith, Anna M.

AU - Tabor, David E.

AU - Roche, Nancy V.

AU - McLean, Jeffrey A.

AU - Vatanian, Negin

AU - Robinson, Karna L.

AU - Sobin, Leslie

AU - Barcus, Mary E.

AU - Valentino, Kimberly M.

AU - Qi, Liqun

AU - Hunter, Steven

AU - Hariharan, Pushpa

AU - Singh, Shilpi

AU - Um, Ki Sung

AU - Matose, Takunda

AU - Tomaszewski, Maria M.

AU - Barker, Laura K.

AU - Mosavel, Maghboeba

AU - Siminoff, Laura A.

AU - Traino, Heather M.

AU - Flicek, Paul

AU - Juettemann, Thomas

AU - Ruffier, Magali

AU - Sheppard, Dan

AU - Taylor, Kieron

AU - Trevanion, Stephen J.

AU - Zerbino, Daniel R.

AU - Craft, Brian

AU - Goldman, Mary

AU - Haeussler, Maximilian

AU - Kent, W. James

AU - Lee, Christopher M.

AU - Paten, Benedict

AU - Rosenbloom, Kate R.

AU - Vivian, John

AU - Zhu, Jingchun

AU - Nicolae, Dan L.

AU - Cox, Nancy J.

AU - Im, Hae Kyung

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.

AB - Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.

UR - http://www.scopus.com/inward/record.url?scp=85046840811&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046840811&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-03621-1

DO - 10.1038/s41467-018-03621-1

M3 - Article

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 1825

ER -