Genome-wide association study identifies 17 new loci influencing concentrations of circulating cytokines and growth factors

Ahola‐Olli, Ari; Würtz, Peter; Havulinna, Aki S.; Aalto, Kristiina; Pitkänen, Niina; Lehtimäki, Terho; Kähönen, Mika; Lyytikäinen, Leo-Pekka; Raitoharju, Emma; Seppälä, Ilkka; Sarin, Antti‐Pekka; Ripatti, Samuli; Palotie, Aarno; Perola, Markus; Viikari, Jorma; Jalkanen, Sirpa; Maksimow, Mikael; Salomaa, Veikko; Salmi, Marko; Kettunen, Johannes; Raitakari, Olli T.

doi:10.1101/045005

Cited by 24 publications

(31 citation statements)

References 49 publications

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“…Additionally, large ancestry-specific PD LD reference panels, such as those for Ashkenazi Jewish patients, will help us further unravel the genetic architecture of loci such as GBA and LRRK2. This may be particularly crucial at these loci where LD patterns may be variable within European populations, accentuating the possible influence of LD reference series on conditional analyses in some cases (48). Finally, our work utilized state-of-the-art QTL datasets to nominate candidate genes, but many QTL associations are hampered by both small sample size and low cis-SNP density.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Nalls¹,

Blauwendraat²,

Vallerga³

et al. 2019

The Lancet Neurology

1,626

1,969

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Background Genome-wide association studies (GWASs) in Parkinson's disease (PD) have increased the scope of biological knowledge about the disease over the past decade. We sought to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into disease etiology. Methods We performed the largest meta-GWAS of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases (having a first degree relative with PD), and 1.4M controls. We carried out a meta-analysis of this GWAS data to nominate novel loci. We then evaluated heritable risk estimates and predictive models using this data. We also utilized large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type and biological pathway enrichments for the identified risk factors. Additionally we examined shared genetic risk between PD and other phenotypes of interest via genetic correlations followed by Mendelian randomization. Findings We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of PD depending on prevalence. Integrating methylation and expression data within a Mendelian randomization framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested PD loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. Mendelian randomization between cognitive performance and PD risk showed a robust association. Interpretation These data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified. Funding See supplemental materials (Text S2). lead to earlier detection and refined diagnostics, which may help improve clinical trials (4). The generation of copious amounts of public summary statistics created by this effort relating to both the GWAS and subsequent analyses of gene expression and methylation patterns may be of use to investigators planning follow-up functional studies in stem cells or other cellular screens, allowing them to prioritize targets more efficiently using our data as additional evidence. We hope our findings may have some downstream clinical impact in the future such as improved patient stratification for clinical trials and genetically informed drug targets.

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Section: Discussionmentioning

confidence: 99%

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Nalls¹,

Blauwendraat²,

Vallerga³

et al. 2019

The Lancet Neurology

1,626

1,969

View full text Add to dashboard Cite

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“…The genetic instruments were taken from publicly available summary statistics. 14 For each of the 41 cytokines (full list provided in Supplemental Table 2) we selected single nucleotide polymorphisms (SNPs) associated with its circulating levels at a significance threshold of a false discovery rate (FDR) <5%. 16 To avoid bias by selection of false positive instruments, we performed additional analyses using a genome-wide threshold of significance (p <5x10 -8 ).…”

Section: Study Design and Data Sourcesmentioning

confidence: 99%

“…15 Sensitivity analyses restricted to individuals of European ancestry (40,528 cases; 445,396 controls) were conducted, to minimize ancestral mismatch with the Finnish population used for the discovery GWAS on cytokines. 14 We computed F-statistics to quantify the strength of the selected instruments 19 and performed power calculations. 20 The F-statistic for the 489 instrument SNPs ranged from 17 to 789 (Supplemental Table 3), well above the threshold of F >10 typically recommended for MR analyses.…”

Section: Study Design and Data Sourcesmentioning

confidence: 99%

“…By using genetic variants as instrumental variables for a trait, MR enables an investigation of causal effects. 12,13 A recent genome-wide association study (GWAS) in 8,293 healthy subjects of Finnish ancestry identified multiple common genetic variants that influence circulating levels of 41 cytokines and growth factors (referred to hereafter as 'cytokines' for simplicity), 14 thus providing comprehensive data on genetic determinants of circulating inflammatory biomarkers. 14 Here, by leveraging data from this recent GWAS on cytokines 14 and the largest GWAS metaanalysis on stroke and stroke subtypes to date, 15 we implemented a two-sample MR study to: (i) explore the causal associations between circulating cytokine levels with risk of any stroke;…”

Section: Introductionmentioning

confidence: 99%

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Genetically Determined Levels of Circulating Cytokines and Risk of Stroke

et al. 2019

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Background: Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether circulating levels of cytokines and growth factors are causally associated with stroke and its etiologic subtypes by conducting a two-sample Mendelian randomization (MR) study. Methods: Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study (GWAS) of 8,293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE GWAS dataset (67,162 cases; 454,450 controls) applying inverse-variance-weighted meta-analysis, weighted-median analysis, MR-Egger regression, and multivariable MR. The UK Biobank cohort was used as an independent validation sample (4,985 cases; 364,434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits using publicly available GWAS data. Results: Genetic predisposition to higher MCP-1 levels was associated with increased risk of

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“…We used the most comprehensive and largest publicly available GWAS meta-analysis on concentrations of 41 circulating cytokines including up to 8,293 individuals from three independent population cohorts (The Cardiovascular Risk in Young Finns Study (YFS), FINRISK 1997 and FINRISK 2002) (17). Cytokines GWAS were adjusted for sex, age and body mass index (BMI).…”

Section: Gwas Summary Datamentioning

confidence: 99%

Causal effects of circulating cytokine concentrations on risk of Alzheimer’s disease: A bidirectional two-sample Mendelian randomization study

Pagoni

Howe

et al. 2020

Preprint

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BackgroundThere is considerable interest in the role of neuroinflammation in the pathogenesis of Alzheimer’s disease. Evidence from observational studies suggests an association between cytokine concentrations and Alzheimer’s disease. However, establishing a causal role of cytokine concentrations on risk of Alzheimer’s disease is challenging due to bias from reverse causation and residual confounding.MethodsWe used two-sample MR to explore causal effects of circulating cytokine concentrations on Alzheimer’s disease and vice versa, employing genetic variants associated with cytokine concentrations (N=8,293) and Alzheimer’s disease (71,880 cases / 383,378 controls) from the largest non-overlapping genome-wide association studies (GWAS) of European ancestry.ResultsThere was weak evidence to suggest that 1 standard deviation (SD) increase in levels of CTACK (CCL27) (OR= 1.09 95%CI: 1.01 to 1.19, p=0.03) increased risk of Alzheimer’s disease. There was also weak evidence of a causal effect of 1 SD increase in levels of MIP-1b (CCL4) (OR=1.04 95%CI: 0.99 to 1.09, p=0.08), Eotaxin (OR=1.08 95%CI: 0.99 to 1.17, p =0.10), GROa (CXCL1) (OR=1.04 95%CI: 0.99 to 1.10, p=0.15), MIG (CXCL9) (OR=1.17 95%CI: 0.97 to 1.41, p=0.10), IL-8 (Wald Ratio: OR=1.21 95%CI: 0.97 to 1.51, p=0.09) and IL-2 (Wald Ratio: OR=1.21 95%CI: 0.94 to 1.56, p=0.14) on greater risk of Alzheimer’s disease. There was little evidence of a causal effect of genetic liability to Alzheimer’s disease on circulating cytokine concentrations.ConclusionsOur study provides some evidence supporting a causal role of cytokines in the pathogenesis of Alzheimer’s disease. However, more studies are needed to elucidate the specific mechanistic pathways via which cytokines alter the risk of Alzheimer’s disease.

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Genome-wide association study identifies 17 new loci influencing concentrations of circulating cytokines and growth factors

Cited by 24 publications

References 49 publications

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Genetically Determined Levels of Circulating Cytokines and Risk of Stroke

Causal effects of circulating cytokine concentrations on risk of Alzheimer’s disease: A bidirectional two-sample Mendelian randomization study

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