The Post-GWAS Era: From Association to Function

被引：513

作者：

Gallagher, Michael D. ^{[1
,2
]}

Chen-Plotkin, Alice S. ^{[1
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA

[2] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2018年 / 102卷 / 05期

关键词：

FRONTOTEMPORAL LOBAR DEGENERATION; BREAST-CANCER RISK; FACTOR-H POLYMORPHISM; ALPHA-SYNUCLEIN; TRANSCRIPTION FACTOR; REGULATORY VARIATION; FETAL-HEMOGLOBIN; GENETIC-VARIATION; COMPLEX TRAITS; VARIANTS;

D O I：

10.1016/j.ajhg.2018.04.002

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

During the past 12 years, genome-wide association studies (GWASs) have uncovered thousands of genetic variants that influence risk for complex human traits and diseases. Yet functional studies aimed at delineating the causal genetic variants and biological mechanisms underlying the observed statistical associations with disease risk have lagged. In this review, we highlight key advances in the field of functional genomics that may facilitate the derivation of biological meaning post-GWAS. We highlight the evidence suggesting that causal variants underlying disease risk often function through regulatory effects on the expression of target genes and that these expression effects might be modest and cell-type specific. We moreover discuss specific studies as proof-of-principle examples for current statistical, bioinformatic, and empirical bench-based approaches to downstream elucidation of GWAS-identified disease risk loci.

引用

页码：717 / 730

页数：14

共 107 条

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Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

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Winckler, Wendy ;

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Rivas, Manuel A. ;

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Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

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Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

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Cox, Nancy J. ;

Flutre, Timothee ;

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Battle, Alexis ;

Khan, Zia ;

Wang, Sidney H. ;

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Smith, Elenoe C. ;

Pinello, Luca ;

Sabo, Peter J. ;

Vierstra, Jeff ;

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Berndt, Sonja I. ;

Gustafsson, Stefan ;

Maegi, Reedik ;

Ganna, Andrea ;

Wheeler, Eleanor ;

Feitosa, Mary F. ;

Justice, Anne E. ;

Monda, Keri L. ;

Croteau-Chonka, Damien C. ;

Day, Felix R. ;

Esko, Tonu ;

Fall, Tove ;

Ferreira, Teresa ;

Gentilini, Davide ;

Jackson, Anne U. ;

Luan, Jian'an ;

Randall, Joshua C. ;

Vedantam, Sailaja ;

Willer, Cristen J. ;

Winkler, Thomas W. ;

Wood, Andrew R. ;

Workalemahu, Tsegaselassie ;

Hu, Yi-Juan ;

Lee, Sang Hong ;

Liang, Liming ;

Lin, Dan-Yu ;

Min, Josine L. ;

Neale, Benjamin M. ;

Thorleifsson, Gudmar ;

Yang, Jian ;

Albrecht, Eva ;

Amin, Najaf ;

Bragg-Gresham, Jennifer L. ;

Cadby, Gemma ;

den Heijer, Martin ;

Eklund, Niina ;

Fischer, Krista ;

Goel, Anuj ;

Hottenga, Jouke-Jan ;

Huffman, Jennifer E. ;

Jarick, Ivonne ;

Johansson, Asa ;

Johnson, Toby ;

Kanoni, Stavroula ;

Kleber, Marcus E. ;

Koenig, Inke R. ;

Kristiansson, Kati ;

Kutalik, Zoltn ;

Lamina, Claudia ;

Lecoeur, Cecile .

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Boyle, Evan A. ;

Li, Yang I. ;

Pritchard, Jonathan K. .

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← 1 2 3 4 5 6 7 8 9 10 →

共 107 条

[1] The role of regulatory variation in complex traits and disease [J].

Albert, Frank W. ;

Kruglyak, Leonid .

NATURE REVIEWS GENETICS, 2015, 16 (04) :197-212

[2] A global reference for human genetic variation [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Wang, Jun ;

Wilson, Richard K. ;

Boerwinkle, Eric ;

Doddapaneni, Harsha ;

Han, Yi ;

Korchina, Viktoriya ;

Kovar, Christie ;

Lee, Sandra ;

Muzny, Donna ;

Reid, Jeffrey G. ;

Zhu, Yiming ;

Chang, Yuqi ;

Feng, Qiang ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Lan, Tianming ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Liu, Shengmao ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Tang, Meifang ;

Wang, Bo .

NATURE, 2015, 526 (7571) :68-+

[3] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[4] Integrating common and rare genetic variation in diverse human populations [J].

Altshuler, David M. ;

Gibbs, Richard A. ;

Peltonen, Leena ;

Dermitzakis, Emmanouil ;

Schaffner, Stephen F. ;

Yu, Fuli ;

Bonnen, Penelope E. ;

de Bakker, Paul I. W. ;

Deloukas, Panos ;

Gabriel, Stacey B. ;

Gwilliam, Rhian ;

Hunt, Sarah ;

Inouye, Michael ;

Jia, Xiaoming ;

Palotie, Aarno ;

Parkin, Melissa ;

Whittaker, Pamela ;

Chang, Kyle ;

Hawes, Alicia ;

Lewis, Lora R. ;

Ren, Yanru ;

Wheeler, David ;

Muzny, Donna Marie ;

Barnes, Chris ;

Darvishi, Katayoon ;

Hurles, Matthew ;

Korn, Joshua M. ;

Kristiansson, Kati ;

Lee, Charles ;

McCarroll, Steven A. ;

Nemesh, James ;

Keinan, Alon ;

Montgomery, Stephen B. ;

Pollack, Samuela ;

Price, Alkes L. ;

Soranzo, Nicole ;

Gonzaga-Jauregui, Claudia ;

Anttila, Verneri ;

Brodeur, Wendy ;

Daly, Mark J. ;

Leslie, Stephen ;

McVean, Gil ;

Moutsianas, Loukas ;

Nguyen, Huy ;

Zhang, Qingrun ;

Ghori, Mohammed J. R. ;

McGinnis, Ralph ;

McLaren, William ;

Takeuchi, Fumihiko ;

Grossman, Sharon R. .

NATURE, 2010, 467 (7311) :52-58

[5] An atlas of active enhancers across human cell types and tissues [J].

Andersson, Robin ;

Gebhard, Claudia ;

Miguel-Escalada, Irene ;

Hoof, Ilka ;

Bornholdt, Jette ;

Boyd, Mette ;

Chen, Yun ;

Zhao, Xiaobei ;

Schmidl, Christian ;

Suzuki, Takahiro ;

Ntini, Evgenia ;

Arner, Erik ;

Valen, Eivind ;

Li, Kang ;

Schwarzfischer, Lucia ;

Glatz, Dagmar ;

Raithel, Johanna ;

Lilje, Berit ;

Rapin, Nicolas ;

Bagger, Frederik Otzen ;

Jorgensen, Mette ;

Andersen, Peter Refsing ;

Bertin, Nicolas ;

Rackham, Owen ;

Burroughs, A. Maxwell ;

Baillie, J. Kenneth ;

Ishizu, Yuri ;

Shimizu, Yuri ;

Furuhata, Erina ;

Maeda, Shiori ;

Negishi, Yutaka ;

Mungall, Christopher J. ;

Meehan, Terrence F. ;

Lassmann, Timo ;

Itoh, Masayoshi ;

Kawaji, Hideya ;

Kondo, Naoto ;

Kawai, Jun ;

Lennartsson, Andreas ;

Daub, Carsten O. ;

Heutink, Peter ;

Hume, David A. ;

Jensen, Torben Heick ;

Suzuki, Harukazu ;

Hayashizaki, Yoshihide ;

Mueller, Ferenc ;

Forrest, Alistair R. R. ;

Carninci, Piero ;

Rehli, Michael ;

Sandelin, Albin .

NATURE, 2014, 507 (7493) :455-+

[6] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[7] Impact of regulatory variation from RNA to protein [J].

Battle, Alexis ;

Khan, Zia ;

Wang, Sidney H. ;

Mitrano, Amy ;

Ford, Michael J. ;

Pritchard, Jonathan K. ;

Gilad, Yoav .

SCIENCE, 2015, 347 (6222) :664-667

[8] An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level [J].

Bauer, Daniel E. ;

Kamran, Sophia C. ;

Lessard, Samuel ;

Xu, Jian ;

Fujiwara, Yuko ;

Lin, Carrie ;

Shao, Zhen ;

Canver, Matthew C. ;

Smith, Elenoe C. ;

Pinello, Luca ;

Sabo, Peter J. ;

Vierstra, Jeff ;

Voit, Richard A. ;

Yuan, Guo-Cheng ;

Porteus, Matthew H. ;

Stamatoyannopoulos, John A. ;

Lettre, Guillaume ;

Orkin, Stuart H. .

SCIENCE, 2013, 342 (6155) :253-257

[9] Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture [J].

Berndt, Sonja I. ;

Gustafsson, Stefan ;

Maegi, Reedik ;

Ganna, Andrea ;

Wheeler, Eleanor ;

Feitosa, Mary F. ;

Justice, Anne E. ;

Monda, Keri L. ;

Croteau-Chonka, Damien C. ;

Day, Felix R. ;

Esko, Tonu ;

Fall, Tove ;

Ferreira, Teresa ;

Gentilini, Davide ;

Jackson, Anne U. ;

Luan, Jian'an ;

Randall, Joshua C. ;

Vedantam, Sailaja ;

Willer, Cristen J. ;

Winkler, Thomas W. ;

Wood, Andrew R. ;

Workalemahu, Tsegaselassie ;

Hu, Yi-Juan ;

Lee, Sang Hong ;

Liang, Liming ;

Lin, Dan-Yu ;

Min, Josine L. ;

Neale, Benjamin M. ;

Thorleifsson, Gudmar ;

Yang, Jian ;

Albrecht, Eva ;

Amin, Najaf ;

Bragg-Gresham, Jennifer L. ;

Cadby, Gemma ;

den Heijer, Martin ;

Eklund, Niina ;

Fischer, Krista ;

Goel, Anuj ;

Hottenga, Jouke-Jan ;

Huffman, Jennifer E. ;

Jarick, Ivonne ;

Johansson, Asa ;

Johnson, Toby ;

Kanoni, Stavroula ;

Kleber, Marcus E. ;

Koenig, Inke R. ;

Kristiansson, Kati ;

Kutalik, Zoltn ;

Lamina, Claudia ;

Lecoeur, Cecile .

NATURE GENETICS, 2013, 45 (05) :501-U69

[10] An Expanded View of Complex Traits: From Polygenic to Omnigenic [J].

Boyle, Evan A. ;

Li, Yang I. ;

Pritchard, Jonathan K. .

CELL, 2017, 169 (07) :1177-1186

← 1 2 3 4 5 6 7 8 9 10 →