Genetic control of the human brain proteome
Chloe Robins,Yue Liu,Wen Fan,Duc M. Duong,Jacob Meigs,Nadia V. Harerimana,Ekaterina S. Gerasimov,Eric B. Dammer,David J. Cutler,Thomas G. Beach,Eric M. Reiman,Philip L. De Jager,David A. Bennett,James J. Lah,Aliza P. Wingo,Aliza P. Wingo,Allan I. Levey,Nicholas T. Seyfried,Thomas S. Wingo +18 more
Reads0
Chats0
TLDR
In this article, the authors generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older adults.Abstract:
We generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older adults. The identified pQTLs tend to be non-synonymous variation, are over-represented among variants associated with brain diseases, and replicate well (77%) in an independent brain dataset. Comparison to a large study of brain eQTLs revealed that about 75% of pQTLs are also eQTLs. In contrast, about 40% of eQTLs were identified as pQTLs. These results are consistent with lower pQTL mapping power and greater evolutionary constraint on protein abundance. The latter is additionally supported by observations of pQTLs with large effects' tending to be rare, deleterious, and associated with proteins that have evidence for fewer protein-protein interactions. Mediation analyses using matched transcriptomic and proteomic data provided additional evidence that pQTL effects are often, but not always, mediated by mRNA. Specifically, we identified roughly 1.6 times more mRNA-mediated pQTLs than mRNA-independent pQTLs (550 versus 341). Our pQTL resource provides insight into the functional consequences of genetic variation in the human brain and a basis for novel investigations of genetics and disease.read more
Citations
More filters
Journal ArticleDOI
Integrated analysis of the aging brain transcriptome and proteome in tauopathy
Carl Grant Mangleburg,Timothy Wu,Hari Krishna Yalamanchili,Caiwei Guo,Yi-Chen Hsieh,Duc M. Duong,Eric B. Dammer,Philip L. De Jager,Philip L. De Jager,Nicholas T. Seyfried,Zhandong Liu,Zhandong Liu,Joshua M. Shulman +12 more
TL;DR: The results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome.
Journal ArticleDOI
Integrating whole-genome sequencing with multi-omic data reveals the impact of structural variants on gene regulation in the human brain
TL;DR: In this paper , the impact of structural variants (SVs) on histone modifications, gene expression, splicing and protein abundance in postmortem brain tissues was quantified using quantitative trait locus (SV-xQTL) analyses.
Journal ArticleDOI
Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases
Huiling Zhao,Humaria Rasheed,Therese Haugdahl Nøst,Yoonsu Cho,Yi Liu,Laxmi Bhatta,Arjun Bhattacharya,Gibran Hemani,George Davey Smith,Ben Michael Brumpton,Wei Zhou,Benjamin M. Neale,Tom R. Gaunt,Jie Zheng +13 more
TL;DR: In this article , a multi-ancestry proteome-wide Mendelian randomization (MR) analysis based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI) is presented.
Journal ArticleDOI
Identifying causal genes for depression via integration of the proteome and transcriptome from brain and blood
Yue-Ting Deng,Ya-Nan Ou,Bang-Sheng Wu,Yu-Xiang Yang,Yan Jiang,Yu-Yuan Huang,Yi Liu,Lan Tan,Qiang Dong,John Suckling,Fei Li,Jingbo Yu +11 more
TL;DR: Collectively, four genes affect depression by influencing protein and gene expression level, which could guide future researches on candidate genes investigations in animal studies as well as prioritize antidepressant drug targets.
Journal ArticleDOI
Genetic Evidence Supporting a Causal Role of Depression in Alzheimer’s Disease
TL;DR: In this paper , the authors examined genetic correlation between depression and AD using linkage disequilibrium score regression and found that depression had a causal role in AD through Mendelian randomization.
References
More filters
Journal ArticleDOI
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li,Richard Durbin +1 more
TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
Journal ArticleDOI
STAR: ultrafast universal RNA-seq aligner
Alexander Dobin,Carrie A. Davis,Felix Schlesinger,Jorg Drenkow,Chris Zaleski,Sonali Jha,Philippe Batut,Mark Chaisson,Thomas R. Gingeras +8 more
TL;DR: The Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure outperforms other aligners by a factor of >50 in mapping speed.
Journal ArticleDOI
PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses
Shaun Purcell,Shaun Purcell,Benjamin M. Neale,Benjamin M. Neale,Kathe Todd-Brown,Lori Thomas,Manuel A. R. Ferreira,David Bender,David Bender,Julian Maller,Julian Maller,Pamela Sklar,Pamela Sklar,Paul I.W. de Bakker,Paul I.W. de Bakker,Mark J. Daly,Mark J. Daly,Pak C. Sham +17 more
TL;DR: This work introduces PLINK, an open-source C/C++ WGAS tool set, and describes the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation, which focuses on the estimation and use of identity- by-state and identity/descent information in the context of population-based whole-genome studies.
Journal ArticleDOI
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
Aaron McKenna,Matthew Hanna,Eric Banks,Andrey Sivachenko,Kristian Cibulskis,Andrew Kernytsky,Kiran V. Garimella,David Altshuler,Stacey Gabriel,Mark J. Daly,Mark A. DePristo +10 more
TL;DR: The GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.
Journal ArticleDOI
A framework for variation discovery and genotyping using next-generation DNA sequencing data
Mark A. DePristo,Eric Banks,Ryan Poplin,Kiran V. Garimella,Jared Maguire,Christopher Hartl,Anthony A. Philippakis,Anthony A. Philippakis,Anthony A. Philippakis,Guillermo del Angel,Manuel A. Rivas,Manuel A. Rivas,Matt Hanna,Aaron McKenna,Timothy Fennell,Andrew Kernytsky,Andrey Sivachenko,Kristian Cibulskis,Stacey Gabriel,David Altshuler,David Altshuler,Mark J. Daly,Mark J. Daly +22 more
TL;DR: A unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs is presented.
Related Papers (5)
Genome-wide pQTL analysis of protein expression regulatory networks in the human liver
Brain expression quantitative trait locus and network analysis reveals downstream effects and putative drivers for brain-related diseases
Niek de Klein,Niek de Klein,Ellen A. Tsai,Martijn Vochteloo,Martijn Vochteloo,Denis Baird,Denis Baird,Yunfeng Huang,Chia-Yen Chen,Sipko van Dam,Patrick Deelen,Olivier B. Bakker,Omar El Garwany,Omar El Garwany,Zhengyu Ouyang,Eric Marshall,Maria I. Zavodszky,Wouter van Rheenen,Mark K Bakker,Jan H. Veldink,Tom R. Gaunt,Heiko Runz,Lude Franke,Harm-Jan Westra +23 more
Hypothesis-free identification of modulators of genetic risk factors
Daria V. Zhernakova,Patrick Deelen,Martijn Vermaat,Maarten van Iterson,Michiel van Galen,Wibowo Arindrarto,Peter van ‘t Hof,Hailiang Mei,Freerk van Dijk,Harm-Jan Westra,Marc Jan Bonder,Jeroen van Rooij,Marijn Verkerk,P. Mila Jhamai,Matthijs Moed,Szymon M. Kielbasa,Jan Bot,Irene Nooren,René Pool,Jenny van Dongen,Jouke J. Hottenga,Coen D.A. Stehouwer,Carla J.H. van der Kallen,Casper G. Schalkwijk,Alexandra Zhernakova,Yang I. Li,Ettje F. Tigchelaar,Marian Beekman,Joris Deelen,Diana van Heemst,Leonard H. van den Berg,Albert Hofman,André G. Uitterlinden,Marleen M.J. van Greevenbroek,Jan H. Veldink,Dorret I. Boomsma,Cornelia M. van Duijn,Cisca Wijmenga,P. Eline Slagboom,Morris A. Swertz,Aaron Isaacs,Aaron Isaacs,Joyce B. J. van Meurs,Rick Jansen,Bastiaan T. Heijmans,Peter A C 't Hoen,Lude Franke +46 more