Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5

被引：61

作者：

Sobreira, Debora R. ^{[1
]}

Joslin, Amelia C. ^{[1
]}

Zhang, Qi ^{[1
,2
]}

Williamson, Iain ^{[3
]}

Hansen, Grace T. ^{[1
]}

Farris, Kathryn M. ^{[1
]}

Sakabe, Noboru J. ^{[1
]}

Sinnott-Armstrong, Nasa ^{[4
,5
,6
,7
]}

Bozek, Grazyna ^{[1
]}

Jensen-Cody, Sharon O. ^{[8
]}

Flippo, Kyle H. ^{[8
]}

Ober, Carole ^{[1
]}

Bickmore, Wendy A. ^{[3
]}

Potthoff, Matthew ^{[8
]}

Chen, Mengjie ^{[1
,2
]}

Claussnitzer, Melina ^{[5
,6
,7
,9
]}

Aneas, Ivy ^{[1
]}

Nobrega, Marcelo A. ^{[1
]}

机构：

[1] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[2] Univ Chicago, Dept Med, Sect Genet Med, Chicago, IL 60637 USA

[3] Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland

[4] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[5] MIT, Broad Inst, Metab Program, Cambridge, MA 02142 USA

[6] MIT, Broad Inst, Cardiovasc Dis Initiat, Cambridge, MA 02142 USA

[7] Harvard Univ, Cambridge, MA 02142 USA

[8] Univ Iowa, Dept Pharmacol, Carver Coll Med, Iowa City, IA 52242 USA

[9] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02131 USA

来源：

SCIENCE | 2021年 / 372卷 / 6546期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; MEASURED FOOD-INTAKE; CELL RNA-SEQ; FTO GENE; OBESITY; VARIANT; EXPRESSION; NEURONS; RISK;

D O I：

10.1126/science.abf1008

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Whereas coding variants often have pleiotropic effects across multiple tissues, noncoding variants are thought to mediate their phenotypic effects by specific tissue and temporal regulation of gene expression. Here, we investigated the genetic and functional architecture of a genomic region within the FTO gene that is strongly associated with obesity risk. We show that multiple variants on a common haplotype modify the regulatory properties of several enhancers targeting IRX3 and IRX5 from megabase distances. We demonstrate that these enhancers affect gene expression in multiple tissues, including adipose and brain, and impart regulatory effects during a restricted temporal window. Our data indicate that the genetic architecture of disease-associated loci may involve extensive pleiotropy, allelic heterogeneity, shared allelic effects across tissues, and temporally restricted effects.

引用

页码：1085 / +

页数：49

共 55 条

[31] Nuclear reorganisation and chromatin decondensation are conserved, but distinct, mechanisms linked to Hox gene activation
Morey, Celine
Da Silva, Nelly R.
Perry, Paul
Bickmore, Wendy A.
[J]. DEVELOPMENT, 2007, 134 (05): : 909 - 919
[32] LocusZoom: regional visualization of genome-wide association scan results
Pruim, Randall J.
Welch, Ryan P.
Sanna, Serena
Teslovich, Tanya M.
Chines, Peter S.
Gliedt, Terry P.
Boehnke, Michael
Abecasis, Goncalo R.
Willer, Cristen J.
[J]. BIOINFORMATICS, 2010, 26 (18) : 2336 - 2337
[33] The FTO Gene and Measured Food Intake in 5-to 10-Year-Old Children Without Obesity
Ranzenhofer, Lisa M.
Mayer, Laurel E. S.
Davis, Haley A.
Mielke-Maday, Hanna K.
McInerney, Hailey
Korn, Rachel
Gupta, Nikita
Brown, Amanda J.
Schebendach, Janet
Tanofsky-Kraff, Marian
Thaker, Vidhu
Chung, Wendy K.
Leibel, Rudolph L.
Walsh, B. Timothy
Rosenbaum, Michael
[J]. OBESITY, 2019, 27 (06) : 1023 - 1029
[34] edgeR: a Bioconductor package for differential expression analysis of digital gene expression data
Robinson, Mark D.
McCarthy, Davis J.
Smyth, Gordon K.
[J]. BIOINFORMATICS, 2010, 26 (01) : 139 - 140
[35] Molecular design of hypothalamus development
Romanov, Roman A.
Tretiakov, Evgenii O.
Kastriti, Maria Eleni
Zupancic, Maja
Haring, Martin
Korchynska, Solomiia
Popadin, Konstantin
Benevento, Marco
Rebernik, Patrick
Lallemend, Francois
Nishimori, Katsuhiko
Clotman, Frederic
Andrews, William D.
Parnavelas, John G.
Farlik, Matthias
Bock, Christoph
Adameyko, Igor
Hokfelt, Tomas
Keimpema, Erik
Harkany, Tibor
[J]. NATURE, 2020, 582 (7811) : 246 - +
[36] Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis
Shin, Jaehoon
Berg, Daniel A.
Zhu, Yunhua
Shin, Joseph Y.
Song, Juan
Bonaguidi, Michael A.
Enikolopov, Grigori
Nauen, David W.
Christian, Kimberly M.
Ming, Guo-li
Song, Hongjun
[J]. CELL STEM CELL, 2015, 17 (03) : 360 - 372
[37] Sinnott-Armstrong, CELL METAB, V33
[38] A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density
Sinnott-Armstrong, Nasa
Sousa, Isabel S.
Laber, Samantha
Rendina-Ruedy, Elizabeth
Dankel, Simon E. Nitter
Ferreira, Teresa
Mellgren, Gunnar
Karasik, David
Rivas, Manuel
Pritchard, Jonathan
Guntur, Anyonya R.
Cox, Roger D.
Lindgren, Cecilia M.
Hauner, Hans
Sallari, Richard
Rosen, Clifford J.
Hsu, Yi-Hsiang
Lander, Eric S.
Kiel, Douglas P.
Claussnitzer, Melina
[J]. CELL METABOLISM, 2021, 3 (03) : 615 - +
[39] Obesity-associated variants within FTO form long-range functional connections with IRX3
Smemo, Scott
Tena, Juan J.
Kim, Kyoung-Han
Gamazon, Eric R.
Sakabe, Noboru J.
Gomez-Marin, Carlos
Aneas, Ivy
Credidio, Flavia L.
Sobreira, Debora R.
Wasserman, Nora F.
Lee, Ju Hee
Puviindran, Vijitha
Tam, Davis
Shen, Michael
Son, Joe Eun
Vakili, Niki Alizadeh
Sung, Hoon-Ki
Naranjo, Silvia
Acemel, Rafael D.
Manzanares, Miguel
Nagy, Andras
Cox, Nancy J.
Hui, Chi-Chung
Luis Gomez-Skarmeta, Jose
Nobrega, Marcelo A.
[J]. NATURE, 2014, 507 (7492) : 371 - +
[40] Soneson C, 2018, NAT METHODS, V15, P255, DOI [10.1038/NMETH.4612, 10.1038/nmeth.4612]

← 1 2 3 4 5 6 →