Imperial College London
Alternate

ProfessorJorgeFerrer

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Chair in Medicine and Genetics
 
 
 
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Contact

 

+44 (0)20 7594 0968j.ferrer

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Wessel:2020:10.1101/2020.11.13.20221812,
author = {Wessel, J and Majarian, TD and Highland, HM and Raghavan, S and Szeto, MD and Hasbani, NR and de, Vries PS and Brody, JA and Sarnowski, C and DiCorpo, D and Yin, X and Hidalgo, B and Guo, X and Perry, J and OConnell, JR and Lent, S and Montasser, ME and Cade, BE and Jain, D and Wang, H and Wu, P and Bonàs-Guarch, S and DOliveira, Albanus R and Leong, A and Miguel-Escalada, I and Varshney, A and Kinney, GL and Yanek, LR and Lange, L and Almeida, M and Peralta, JM and Aslibekyan, S and Baldridge, AS and Bertoni, AG and Bielak, LF and Bowden, DW and Chen, C-S and Chen, Y-DI and Choi, SH and Choi, WJ and Darbar, D and Floyd, JS and Freedman, BI and Goodarzi, MO and Irvin, R and Kalyani, RR and Kelly, T and Lee, S and Liu, C-T and Loesch, D and Manson, JE and Nassir, R and Palmer, ND and Pankow, JS and Rasmussen-Torvik, LJ and Reiner, AP and Selvin, E and Shadyab, AH and Smith, JA and Weeks, DE and Weng, L-C and Xu, H and Yao, J and Yoneda, Z and Zhao, W and Ferrer, J and Mahajan, A and McC},
doi = {10.1101/2020.11.13.20221812},
title = {Rare Non-coding Variation Identified by Large Scale Whole Genome Sequencing Reveals Unexplained Heritability of Type 2 Diabetes},
url = {http://dx.doi.org/10.1101/2020.11.13.20221812},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - <jats:p>Type 2 diabetes is increasing in all ancestry groups<jats:sup>1</jats:sup>. Part of its genetic basis may reside among the rare (minor allele frequency <0.1%) variants that make up the vast majority of human genetic variation<jats:sup>2</jats:sup>. We analyzed high-coverage (mean depth 38.2x) whole genome sequencing from 9,639 individuals with T2D and 34,994 controls in the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program<jats:sup>2</jats:sup> to show that rare, non-coding variants that are poorly captured by genotyping arrays or imputation panels contribute h<jats:sup>2</jats:sup>=53% (P=4.2×10<jats:sup>−5</jats:sup>) to the genetic component of risk in the largest (European) ancestry subset. We coupled sequence variation with islet epigenomic signatures<jats:sup>3</jats:sup> to annotate and group rare variants with respect to gene expression<jats:sup>4</jats:sup>, chromatin state<jats:sup>5</jats:sup> and three-dimensional chromatin architecture<jats:sup>6</jats:sup>, and show that pancreatic islet regulatory elements contribute to T2D genetic risk (h<jats:sup>2</jats:sup>=8%, P=2.4×10<jats:sup>−3</jats:sup>). We used islet annotation to create a non-coding framework for rare variant aggregation testing. This approach identified five loci containing rare alleles in islet regulatory elements that suggest novel biological mechanisms readily linked to hypotheses about variant-to-function. Large scale whole genome sequence analysis reveals the substantial contribution of rare, non-coding variation to the genetic architecture of T2D and highlights the value of tissue-specific regulatory annotation for variant-to-function discovery.</jats:p>
AU  - Wessel,J
AU  - Majarian,TD
AU  - Highland,HM
AU  - Raghavan,S
AU  - Szeto,MD
AU  - Hasbani,NR
AU  - de,Vries PS
AU  - Brody,JA
AU  - Sarnowski,C
AU  - DiCorpo,D
AU  - Yin,X
AU  - Hidalgo,B
AU  - Guo,X
AU  - Perry,J
AU  - OConnell,JR
AU  - Lent,S
AU  - Montasser,ME
AU  - Cade,BE
AU  - Jain,D
AU  - Wang,H
AU  - Wu,P
AU  - Bonàs-Guarch,S
AU  - DOliveira,Albanus R
AU  - Leong,A
AU  - Miguel-Escalada,I
AU  - Varshney,A
AU  - Kinney,GL
AU  - Yanek,LR
AU  - Lange,L
AU  - Almeida,M
AU  - Peralta,JM
AU  - Aslibekyan,S
AU  - Baldridge,AS
AU  - Bertoni,AG
AU  - Bielak,LF
AU  - Bowden,DW
AU  - Chen,C-S
AU  - Chen,Y-DI
AU  - Choi,SH
AU  - Choi,WJ
AU  - Darbar,D
AU  - Floyd,JS
AU  - Freedman,BI
AU  - Goodarzi,MO
AU  - Irvin,R
AU  - Kalyani,RR
AU  - Kelly,T
AU  - Lee,S
AU  - Liu,C-T
AU  - Loesch,D
AU  - Manson,JE
AU  - Nassir,R
AU  - Palmer,ND
AU  - Pankow,JS
AU  - Rasmussen-Torvik,LJ
AU  - Reiner,AP
AU  - Selvin,E
AU  - Shadyab,AH
AU  - Smith,JA
AU  - Weeks,DE
AU  - Weng,L-C
AU  - Xu,H
AU  - Yao,J
AU  - Yoneda,Z
AU  - Zhao,W
AU  - Ferrer,J
AU  - Mahajan,A
AU  - McCarthy,MI
AU  - Parker,S
AU  - Alonso,A
AU  - Arnett,DK
AU  - Blangero,J
AU  - Boerwinkle,E
AU  - Cho,MH
AU  - Correa,A
AU  - Cupples,LA
AU  - Curran,JE
AU  - Duggirala,R
AU  - Ellinor,PT
AU  - He,J
AU  - Heckbert,SR
AU  - Kardia,SLR
AU  - Kim,RW
AU  - Kooperberg,C
AU  - Liu,S
AU  - Lubitz,SA
AU  - Mathias,RA
AU  - McGarvey,S
AU  - Mitchell,BD
AU  - Morrison,AC
AU  - Peyser,PA
AU  - Psaty,BM
AU  - Redline,S
AU  - Roden,D
AU  - Shoemaker,MB
AU  - Smith,NL
AU  - Taylor,KD
AU  - Vasan,RS
AU  - Viaud-Martinez,KA
AU  - Florez,JC
AU  - Wilson,JG
AU  - Sladek,R
AU  - Dupuis,J
AU  - Rich,SS
AU  - Rotter,JI
AU  - Meigs,JB
AU  - Manning,AK
DO  - 10.1101/2020.11.13.20221812
PY  - 2020///
TI  - Rare Non-coding Variation Identified by Large Scale Whole Genome Sequencing Reveals Unexplained Heritability of Type 2 Diabetes
UR  - http://dx.doi.org/10.1101/2020.11.13.20221812
ER  -
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