Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases

Niek de Klein; Ellen A Tsai; Martijn Vochteloo; Denis Baird; Yunfeng Huang; Chia-Yen Chen; Sipko van Dam; Roy Oelen; Patrick Deelen; Olivier B Bakker; Omar El Garwany; Zhengyu Ouyang; Eric E Marshall; Maria I Zavodszky; Wouter van Rheenen; Mark K Bakker; Jan Veldink; Tom R Gaunt; Heiko Runz; Lude Franke; Harm-Jan Westra

doi:10.1038/s41588-023-01300-6

Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases

Nat Genet. 2023 Mar;55(3):377-388. doi: 10.1038/s41588-023-01300-6. Epub 2023 Feb 23.

Authors

Niek de Klein^#^{1

2}, Ellen A Tsai^#³, Martijn Vochteloo^#^{1

4

5}, Denis Baird³, Yunfeng Huang³, Chia-Yen Chen³, Sipko van Dam^{1

6}, Roy Oelen^{1

5}, Patrick Deelen^{1

5}, Olivier B Bakker^{1

2}, Omar El Garwany^{1

2}, Zhengyu Ouyang⁷, Eric E Marshall³, Maria I Zavodszky³, Wouter van Rheenen⁸, Mark K Bakker⁸, Jan Veldink⁸, Tom R Gaunt⁹, Heiko Runz¹⁰, Lude Franke^{11

12}, Harm-Jan Westra^{13

14}

Affiliations

¹ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
² Wellcome Sanger Institute, Hinxton, UK.
³ Translational Biology, Research and Development, Biogen Inc., Cambridge, MA, USA.
⁴ Institute for Life Science and Technology, Hanze University of Applied Sciences, Groningen, The Netherlands.
⁵ Oncode Institute, Groningen, The Netherlands.
⁶ Ancora Health, Groningen, The Netherlands.
⁷ BioInfoRx, Inc., Madison, WI, USA.
⁸ Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
⁹ MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁰ Translational Biology, Research and Development, Biogen Inc., Cambridge, MA, USA. [email protected].
¹¹ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. [email protected].
¹² Oncode Institute, Groningen, The Netherlands. [email protected].
¹³ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. [email protected].
¹⁴ Oncode Institute, Groningen, The Netherlands. [email protected].

^# Contributed equally.

Abstract

Identification of therapeutic targets from genome-wide association studies (GWAS) requires insights into downstream functional consequences. We harmonized 8,613 RNA-sequencing samples from 14 brain datasets to create the MetaBrain resource and performed cis- and trans-expression quantitative trait locus (eQTL) meta-analyses in multiple brain region- and ancestry-specific datasets (n ≤ 2,759). Many of the 16,169 cortex cis-eQTLs were tissue-dependent when compared with blood cis-eQTLs. We inferred brain cell types for 3,549 cis-eQTLs by interaction analysis. We prioritized 186 cis-eQTLs for 31 brain-related traits using Mendelian randomization and co-localization including 40 cis-eQTLs with an inferred cell type, such as a neuron-specific cis-eQTL (CYP24A1) for multiple sclerosis. We further describe 737 trans-eQTLs for 526 unique variants and 108 unique genes. We used brain-specific gene-co-regulation networks to link GWAS loci and prioritize additional genes for five central nervous system diseases. This study represents a valuable resource for post-GWAS research on central nervous system diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain
Brain Diseases* / genetics
Gene Regulatory Networks / genetics
Genome-Wide Association Study
Humans
Phenotype
Polymorphism, Single Nucleotide / genetics
Quantitative Trait Loci* / genetics

Grants and funding

MC_UU_00011/4/MRC_/Medical Research Council/United Kingdom