Inflammatory Biomarkers and Risk of Schizophrenia

Hartwig, Fernando Pires; Borges, Maria Carolina; Horta, Bernardo Lessa; Bowden, Jack; Smith, George Davey

doi:10.1001/jamapsychiatry.2017.3191

Cited by 211 publications

(146 citation statements)

References 54 publications

(114 reference statements)

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“…The genetic instruments included variants in NOS3 (rs1799983, rs2070744, rs3918226), GUCY1A3 (guanylate cyclase 1, soluble alpha 3; rs7692387), and the L‐arginine transporter gene SLC7A1 (rs41318021); rs7539120 in the nitric oxide synthase 1 adaptor protein gene NOS1AP was not available for analysis in UKB. Considering BP in UKB as the exposure and AS as outcome, we found significant associations using the weighted median approach (OR = 1.11, p < 0.0001 for SBP; OR = 1.14, p < 0.0001 for DBP) and inverse variance weighted (IVW) effect estimate (OR = 1.15, p = 0.005 for SBP; OR = 1.19, p = 0.002 for DBP), suggesting a causal association of the instruments with stroke via BP (Fig ) with an estimated contribution of 4%. We found no evidence of heterogeneity in the IVW analyses, and the intercept in the MR‐Egger analyses were not significant (all p > 0.10), suggesting absence of significant pleiotropy.…”

Section: Resultsmentioning

confidence: 93%

Genome‐wide meta‐analysis identifies 3 novel loci associated with stroke

Malik

Rannikmäe

Traylor

et al. 2018

Annals of Neurology

133

152

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We conducted a European‐only and transancestral genome‐wide association meta‐analysis in 72,147 stroke patients and 823,869 controls using data from UK Biobank (UKB) and the MEGASTROKE consortium. We identified an exonic polymorphism in NOS3 (rs1799983, p.Glu298Asp; p = 2.2E‐8, odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.04–1.07) and variants in an intron of COL4A1 (rs9521634; p = 3.8E‐8, OR = 1.04, 95% CI = 1.03–1.06) and near DYRK1A (rs720470; p = 6.1E‐9, OR = 1.05, 95% CI = 1.03–1.07) at genome‐wide significance for stroke. Effect sizes of known stroke loci were highly correlated between UKB and MEGASTROKE. Using Mendelian randomization, we further show that genetic variation in the nitric oxide synthase–nitric oxide pathway in part affects stroke risk via variation in blood pressure. Ann Neurol 2018;84:934–939

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Section: Resultsmentioning

confidence: 93%

Genome‐wide meta‐analysis identifies 3 novel loci associated with stroke

Malik

Rannikmäe

Traylor

et al. 2018

Annals of Neurology

133

152

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“…Such a scenario can arise for complex traits such as gene expression or protein levels that have a few large effects and many small effects. For example, for C-reactive protein (CRP) levels, the SNP in the CRP gene region is likely the only valid instrument in some analyses 30 . In this context, bias due to horizontal pleiotropy cannot be avoided by selection of instruments since this approach may generate more bias 31 .…”

Section: Discussionmentioning

confidence: 99%

Exploiting horizontal pleiotropy to search for causal pathways within a Mendelian randomization framework

et al. 2020

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In Mendelian randomization (MR) analysis, variants that exert horizontal pleiotropy are typically treated as a nuisance. However, they could be valuable in identifying alternative pathways to the traits under investigation. Here, we develop MR-TRYX, a framework that exploits horizontal pleiotropy to discover putative risk factors for disease. We begin by detecting outliers in a single exposure-outcome MR analysis, hypothesising they are due to horizontal pleiotropy. We search across hundreds of complete GWAS summary datasets to systematically identify other (candidate) traits that associate with the outliers. We develop a multi-trait pleiotropy model of the heterogeneity in the exposure-outcome analysis due to pathways through candidate traits. Through detailed investigation of several causal relationships, many pleiotropic pathways are uncovered with already established causal effects, validating the approach, but also alternative putative causal pathways. Adjustment for pleiotropic pathways reduces the heterogeneity across the analyses.

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“…One interpretation of these findings is that altered immune system processes are associated with mental illness itself, owing to shared genetic or other mechanisms (Hartweg, Borges, Horta, Boweden, & Smith, ). We indeed observed higher rates of all physical health exposures among children whose mothers had been diagnosed with a mental illness (See Tables and ).…”

Section: Discussionmentioning

confidence: 99%