Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

International Parkinson's Disease Genomics Consortium (IPDGC); UK Brain Expression Consortium (UKBEC)

doi:10.1038/s41467-020-14483-x

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

International Parkinson's Disease Genomics Consortium (IPDGC), UK Brain Expression Consortium (UKBEC)

Neurology

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/.

Original language	English (US)
Article number	1041
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14483-x
State	Published - Dec 1 2020

Funding

Mina Ryten, David Zhang, and Karishma D\u2019Sa were supported by the UK Medical Research Council (MRC) through the award of Tenure-track Clinician Scientist Fellowship to Mina Ryten (MR/N008324/1). Sebastian Guelfi was supported by Alzheimer\u2019s Research UK through the award of a PhD Fellowship (ARUK-PhD2014-16). Regina Reynolds was supported through the award of a Leonard Wolfson Doctoral Training Fellowship in Neuro-degeneration. All RNA sequencing data performed as part of this study were generated by the commercial company AROS Applied Biotechnology A/S (Denmark).

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-020-14483-x

Cite this

@article{53251927445245bab5379e9154dea9bb,

title = "Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information",

abstract = "Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/.",

author = "{International Parkinson's Disease Genomics Consortium (IPDGC)} and {UK Brain Expression Consortium (UKBEC)} and Sebastian Guelfi and Karishma D{\textquoteright}Sa and Bot{\'i}a, {Juan A.} and Jana Vandrovcova and Reynolds, {Regina H.} and David Zhang and Daniah Trabzuni and Leonardo Collado-Torres and Andrew Thomason and {Quijada Leyton}, Pedro and {Gagliano Taliun}, {Sarah A.} and Nalls, {Mike A.} and Noyce, {Alastair J.} and Aude Nicolas and Cookson, {Mark R.} and Sara Bandres-Ciga and Gibbs, {J. Raphael} and Hernandez, {Dena G.} and Singleton, {Andrew B.} and Xylena Reed and Hampton Leonard and Cornelis Blauwendraat and Faraz Faghri and Jose Bras and Rita Guerreiro and Arianna Tucci and Kia, {Demis A.} and Henry Houlden and Helene Plun-Favreau and Mok, {Kin Y.} and Wood, {Nicholas W.} and Ruth Lovering and Lea R{\textquoteright}Bibo and Mie Rizig and Viorica Chelban and Manuela Tan and Morris, {Huw R.} and Ben Middlehurst and John Quinn and Kimberley Billingsley and Peter Holmans and Kinghorn, {Kerri J.} and Patrick Lewis and Valentina Escott-Price and Nigel Williams and Thomas Foltynie and Alexis Brice and Fabrice Danjou and Steven Lubbe and Mencacci, {Niccolo E.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-14483-x",

language = "English (US)",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

AU - International Parkinson's Disease Genomics Consortium (IPDGC)

AU - UK Brain Expression Consortium (UKBEC)

AU - Guelfi, Sebastian

AU - D’Sa, Karishma

AU - Botía, Juan A.

AU - Vandrovcova, Jana

AU - Reynolds, Regina H.

AU - Zhang, David

AU - Trabzuni, Daniah

AU - Collado-Torres, Leonardo

AU - Thomason, Andrew

AU - Quijada Leyton, Pedro

AU - Gagliano Taliun, Sarah A.

AU - Nalls, Mike A.

AU - Noyce, Alastair J.

AU - Nicolas, Aude

AU - Cookson, Mark R.

AU - Bandres-Ciga, Sara

AU - Gibbs, J. Raphael

AU - Hernandez, Dena G.

AU - Singleton, Andrew B.

AU - Reed, Xylena

AU - Leonard, Hampton

AU - Blauwendraat, Cornelis

AU - Faghri, Faraz

AU - Bras, Jose

AU - Guerreiro, Rita

AU - Tucci, Arianna

AU - Kia, Demis A.

AU - Houlden, Henry

AU - Plun-Favreau, Helene

AU - Mok, Kin Y.

AU - Wood, Nicholas W.

AU - Lovering, Ruth

AU - R’Bibo, Lea

AU - Rizig, Mie

AU - Chelban, Viorica

AU - Tan, Manuela

AU - Morris, Huw R.

AU - Middlehurst, Ben

AU - Quinn, John

AU - Billingsley, Kimberley

AU - Holmans, Peter

AU - Kinghorn, Kerri J.

AU - Lewis, Patrick

AU - Escott-Price, Valentina

AU - Williams, Nigel

AU - Foltynie, Thomas

AU - Brice, Alexis

AU - Danjou, Fabrice

AU - Lubbe, Steven

AU - Mencacci, Niccolo E.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/.

AB - Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/.

UR - http://www.scopus.com/inward/record.url?scp=85081072099&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85081072099&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-14483-x

DO - 10.1038/s41467-020-14483-x

M3 - Article

C2 - 32098967

AN - SCOPUS:85081072099

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1041

ER -

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this