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Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.

ABSTRACT: BACKGROUND:C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. METHODS AND RESULTS:We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ?5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. CONCLUSIONS:We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

SUBMITTER: Dehghan A

PROVIDER: S-EPMC3147232 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.

Dehghan Abbas A Dupuis Josée J Barbalic Maja M Bis Joshua C JC Eiriksdottir Gudny G Lu Chen C Pellikka Niina N Wallaschofski Henri H Kettunen Johannes J Henneman Peter P Baumert Jens J Strachan David P DP Fuchsberger Christian C Vitart Veronique V Wilson James F JF Paré Guillaume G Naitza Silvia S Rudock Megan E ME Surakka Ida I de Geus Eco J C EJ Alizadeh Behrooz Z BZ Guralnik Jack J Shuldiner Alan A Tanaka Toshiko T Zee Robert Y L RY Schnabel Renate B RB Nambi Vijay V Kavousi Maryam M Ripatti Samuli S Nauck Matthias M Smith Nicholas L NL Smith Albert V AV Sundvall Jouko J Scheet Paul P Liu Yongmei Y Ruokonen Aimo A Rose Lynda M LM Larson Martin G MG Hoogeveen Ron C RC Freimer Nelson B NB Teumer Alexander A Tracy Russell P RP Launer Lenore J LJ Buring Julie E JE Yamamoto Jennifer F JF Folsom Aaron R AR Sijbrands Eric J G EJ Pankow James J Elliott Paul P Keaney John F JF Sun Wei W Sarin Antti-Pekka AP Fontes João D JD Badola Sunita S Astor Brad C BC Hofman Albert A Pouta Anneli A Werdan Karl K Greiser Karin H KH Kuss Oliver O Meyer zu Schwabedissen Henriette E HE Thiery Joachim J Jamshidi Yalda Y Nolte Ilja M IM Soranzo Nicole N Spector Timothy D TD Völzke Henry H Parker Alexander N AN Aspelund Thor T Bates David D Young Lauren L Tsui Kim K Siscovick David S DS Guo Xiuqing X Rotter Jerome I JI Uda Manuela M Schlessinger David D Rudan Igor I Hicks Andrew A AA Penninx Brenda W BW Thorand Barbara B Gieger Christian C Coresh Joe J Willemsen Gonneke G Harris Tamara B TB Uitterlinden Andre G AG Järvelin Marjo-Riitta MR Rice Kenneth K Radke Dörte D Salomaa Veikko V Willems van Dijk Ko K Boerwinkle Eric E Vasan Ramachandran S RS Ferrucci Luigi L Gibson Quince D QD Bandinelli Stefania S Snieder Harold H Boomsma Dorret I DI Xiao Xiangjun X Campbell Harry H Hayward Caroline C Pramstaller Peter P PP van Duijn Cornelia M CM Peltonen Leena L Psaty Bruce M BM Gudnason Vilmundur V Ridker Paul M PM Homuth Georg G Koenig Wolfgang W Ballantyne Christie M CM Witteman Jacqueline C M JC Benjamin Emelia J EJ Perola Markus M Chasman Daniel I DI

Circulation 20110207 7

<h4>Background</h4>C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.<h4>Methods and results</h4>We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 ind ...[more]

PMID: 21300955

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Project description:Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

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Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.

Publications

Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.

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