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Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

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@article{88804ff4f7f94fb7b24b38a5bcaf39d0,
title = "Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders",
abstract = "C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0{\%} of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.",
author = "Symen Ligthart and Ahmad Vaez and Urmo V{\~o}sa and Stathopoulou, {Maria G} and {de Vries}, {Paul S} and Prins, {Bram P} and {Van der Most}, {Peter J} and Toshiko Tanaka and Elnaz Naderi and Rose, {Lynda M} and Ying Wu and Robert Karlsson and Maja Barbalic and Honghuang Lin and Ren{\'e} Pool and Gu Zhu and Aur{\'e}lien Mac{\'e} and Carlo Sidore and Stella Trompet and Massimo Mangino and Maria Sabater-Lleal and Kemp, {John P} and Ali Abbasi and Tim Kacprowski and Niek Verweij and Smith, {Albert V} and Tao Huang and Carola Marzi and Feitosa, {Mary F} and Lohman, {Kurt K} and Kleber, {Marcus E} and Yuri Milaneschi and Christian Mueller and Mahmudul Huq and Efthymia Vlachopoulou and Leo-Pekka Lyytik{\"a}inen and Christopher Oldmeadow and Joris Deelen and Markus Perola and Zhao, {Jing Hua} and Bjarke Feenstra and Marzyeh Amini and Jari Lahti and Schraut, {Katharina E} and Myriam Fornage and Bhoom Suktitipat and Wei-Min Chen and Ahluwalia, {Tarunveer S} and Pers, {Tune H} and Tine Jess and {LifeLines Cohort study}",
note = "Copyright {\circledC} 2018 American Society of Human Genetics. All rights reserved.",
year = "2018",
month = "11",
day = "1",
doi = "10.1016/j.ajhg.2018.09.009",
language = "English",
volume = "103",
pages = "691--706",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "5",

}

RIS

TY - JOUR

T1 - Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

AU - Ligthart, Symen

AU - Vaez, Ahmad

AU - Võsa, Urmo

AU - Stathopoulou, Maria G

AU - de Vries, Paul S

AU - Prins, Bram P

AU - Van der Most, Peter J

AU - Tanaka, Toshiko

AU - Naderi, Elnaz

AU - Rose, Lynda M

AU - Wu, Ying

AU - Karlsson, Robert

AU - Barbalic, Maja

AU - Lin, Honghuang

AU - Pool, René

AU - Zhu, Gu

AU - Macé, Aurélien

AU - Sidore, Carlo

AU - Trompet, Stella

AU - Mangino, Massimo

AU - Sabater-Lleal, Maria

AU - Kemp, John P

AU - Abbasi, Ali

AU - Kacprowski, Tim

AU - Verweij, Niek

AU - Smith, Albert V

AU - Huang, Tao

AU - Marzi, Carola

AU - Feitosa, Mary F

AU - Lohman, Kurt K

AU - Kleber, Marcus E

AU - Milaneschi, Yuri

AU - Mueller, Christian

AU - Huq, Mahmudul

AU - Vlachopoulou, Efthymia

AU - Lyytikäinen, Leo-Pekka

AU - Oldmeadow, Christopher

AU - Deelen, Joris

AU - Perola, Markus

AU - Zhao, Jing Hua

AU - Feenstra, Bjarke

AU - Amini, Marzyeh

AU - Lahti, Jari

AU - Schraut, Katharina E

AU - Fornage, Myriam

AU - Suktitipat, Bhoom

AU - Chen, Wei-Min

AU - Ahluwalia, Tarunveer S

AU - Pers, Tune H

AU - Jess, Tine

AU - LifeLines Cohort study

N1 - Copyright © 2018 American Society of Human Genetics. All rights reserved.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

AB - C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

U2 - 10.1016/j.ajhg.2018.09.009

DO - 10.1016/j.ajhg.2018.09.009

M3 - Journal article

VL - 103

SP - 691

EP - 706

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -

ID: 55632160