Phenome-wide functional dissection of pleiotropic effects highlights key molecular pathways for human complex traits

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Phenome-wide functional dissection of pleiotropic effects highlights key molecular pathways for human complex traits. / Shikov, Anton E.; Skitchenko, Rostislav K.; Predeus, Alexander V.; Barbitoff, Yury A.

In: Scientific Reports, Vol. 10, No. 1, 1037, 23.01.2020.

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

BibTeX

@article{d6dddce6948549d9b08bba123f5131ce,

title = "Phenome-wide functional dissection of pleiotropic effects highlights key molecular pathways for human complex traits",

abstract = "Over the recent decades, genome-wide association studies (GWAS) have dramatically changed the understanding of human genetics. A recent genetic data release by UK Biobank (UKB) has allowed many researchers worldwide to have comprehensive look into the genetic architecture of thousands of human phenotypes. In this study, we used GWAS summary statistics derived from the UKB cohort to investigate functional mechanisms of pleiotropic effects across the human phenome. We find that highly pleiotropic variants often correspond to broadly expressed genes with ubiquitous functions, such as matrisome components and cell growth regulators; and tend to colocalize with tissue-shared eQTLs. At the same time, signaling pathway components are more prevalent among highly pleiotropic genes compared to regulatory proteins such as transcription factors. Our results suggest that protein-level pleiotropy mediated by ubiquitously expressed genes is the most prevalent mechanism of pleiotropic genetic effects across the human phenome.",

keywords = "Genetic Pleiotropy/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study/methods, Humans, Multifactorial Inheritance/genetics, Phenomics/methods, Phenotype, Polymorphism, Single Nucleotide/genetics, Quantitative Trait, Heritable, Signal Transduction/genetics, SET, GENOME, ASSOCIATION",

author = "Shikov, {Anton E.} and Skitchenko, {Rostislav K.} and Predeus, {Alexander V.} and Barbitoff, {Yury A.}",

year = "2020",

month = jan,

day = "23",

doi = "10.1038/s41598-020-58040-4",

language = "English",

volume = "10",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

RIS

TY - JOUR

T1 - Phenome-wide functional dissection of pleiotropic effects highlights key molecular pathways for human complex traits

AU - Shikov, Anton E.

AU - Skitchenko, Rostislav K.

AU - Predeus, Alexander V.

AU - Barbitoff, Yury A.

PY - 2020/1/23

Y1 - 2020/1/23

N2 - Over the recent decades, genome-wide association studies (GWAS) have dramatically changed the understanding of human genetics. A recent genetic data release by UK Biobank (UKB) has allowed many researchers worldwide to have comprehensive look into the genetic architecture of thousands of human phenotypes. In this study, we used GWAS summary statistics derived from the UKB cohort to investigate functional mechanisms of pleiotropic effects across the human phenome. We find that highly pleiotropic variants often correspond to broadly expressed genes with ubiquitous functions, such as matrisome components and cell growth regulators; and tend to colocalize with tissue-shared eQTLs. At the same time, signaling pathway components are more prevalent among highly pleiotropic genes compared to regulatory proteins such as transcription factors. Our results suggest that protein-level pleiotropy mediated by ubiquitously expressed genes is the most prevalent mechanism of pleiotropic genetic effects across the human phenome.

AB - Over the recent decades, genome-wide association studies (GWAS) have dramatically changed the understanding of human genetics. A recent genetic data release by UK Biobank (UKB) has allowed many researchers worldwide to have comprehensive look into the genetic architecture of thousands of human phenotypes. In this study, we used GWAS summary statistics derived from the UKB cohort to investigate functional mechanisms of pleiotropic effects across the human phenome. We find that highly pleiotropic variants often correspond to broadly expressed genes with ubiquitous functions, such as matrisome components and cell growth regulators; and tend to colocalize with tissue-shared eQTLs. At the same time, signaling pathway components are more prevalent among highly pleiotropic genes compared to regulatory proteins such as transcription factors. Our results suggest that protein-level pleiotropy mediated by ubiquitously expressed genes is the most prevalent mechanism of pleiotropic genetic effects across the human phenome.

KW - Genetic Pleiotropy/genetics

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study/methods

KW - Humans

KW - Multifactorial Inheritance/genetics

KW - Phenomics/methods

KW - Phenotype

KW - Polymorphism, Single Nucleotide/genetics

KW - Quantitative Trait, Heritable

KW - Signal Transduction/genetics

KW - SET

KW - GENOME

KW - ASSOCIATION

UR - http://www.scopus.com/inward/record.url?scp=85078103806&partnerID=8YFLogxK

U2 - 10.1038/s41598-020-58040-4

DO - 10.1038/s41598-020-58040-4

M3 - Article

C2 - 31974475

AN - SCOPUS:85078103806

VL - 10

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 1037

ER -

ID: 70416970