Invited Commentary: Detecting Individual and Global Horizontal Pleiotropy in Mendelian Randomization—A Job for the Humble Heterogeneity Statistic?

Bowden, Jack; Hemani, Gibran; Smith, George Davey

doi:10.1093/aje/kwy185

Cited by 171 publications

(176 citation statements)

References 27 publications

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“…We also tested whether the Egger intercept is significantly different from zero as a measure of unbalanced pleiotropy or violation of the InSIDE assumption (59). Furthermore, heterogeneity amongst the IV ratio estimates was quantified using Cochran's Q statistic, given that horizontal pleiotropy may be one explanation for significant heterogeneity (44,60,61). A global pleiotropy test was implemented via the MR-PRESSO framework utilising the expected and observed RSS (56).…”

Section: Sensitivity and Pleiotropy Analysesmentioning

confidence: 99%

Investigating the effect of glycaemic traits on the risk of psychiatric illness using Mendelian randomisation

Adams

Geaghan

Cairns

2020

Preprint

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Data from observational studies have suggested an involvement of abnormal glycaemic regulation in the pathophysiology of psychiatric illness. This may be an attractive target for clinical intervention as glycaemia can be modulated by both lifestyle factors and pharmacological agents. However, observational studies are inherently confounded, and therefore causal relationships cannot be reliably established. We employed genetic variants rigorously associated with three glycaemic traits (fasting glucose, fasting insulin, and glycated haemoglobin) as instrumental variables in a two-sample Mendelian randomisation analysis to investigate the causal effect of these measures on the risk for eight psychiatric disorders. A significant protective effect of a unit increase in fasting insulin levels was observed for anorexia nervosa after the application of multiple testing correction (OR = 0.48 [95% CI: 0.33-0.71] -inverse-variance weighted estimate. The relationship between fasting insulin and anorexia nervosa was supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between insulin levels and anorexia.

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Section: Sensitivity and Pleiotropy Analysesmentioning

confidence: 99%

Investigating the effect of glycaemic traits on the risk of psychiatric illness using Mendelian randomisation

Adams

Geaghan

Cairns

2020

Preprint

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“…Full details are provided elsewhere 15 , but briefly, we used the so-called 'modified 2 nd order weighting' approach to estimate total Cochran's Q statistic as a measure of heterogeneity, as well as the individual contributions of each SNP, q i 15 . This has been shown to be comparable to the simulationbased approach in MR-PRESSO, providing a well-calibrated test statistic for outlier status whilst being computationally more efficient 14,20 . The probability of a SNP being an outlier is calculated based on q i being chi-square distributed with 1 degree of freedom.…”

Section: Outlier Detectionmentioning

confidence: 90%

MR-TRYX: A Mendelian randomization framework that exploits horizontal pleiotropy to infer novel causal pathways

Cho

Haycock

Sanderson

et al. 2018

Preprint

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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 novel pathways to the traits under investigation. Here, we developed the MR-TRYX framework, following the advice of William Bateson to "TReasure Your eXceptions". We begin by detecting outliers in a single exposure-outcome MR analysis, hypothesising they are due to horizontal pleiotropy. We search across thousands of complete GWAS summary datasets in the MR-Base database to systematically identify other ("candidate") traits that associate with the outliers. We developed 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 were uncovered with already established causal effects, validating the approach, but also novel putative causal pathways. Adjustment for pleiotropic pathways reduced the heterogeneity across the analyses.

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“…MR analyses based on single SNPs suggested that both SNPs contributed to the overall causal effects we observed (Supplementary Table 6). Heterogeneity analysis of the instruments suggested that causal estimates were consistent across both SNPs (P values of Cochran Q test > 0.05), with the exception of estimates for lumbar spine BMD and fracture risk, likely reflecting the lower power in these instances (44). Genetic signals for sclerostin and eBMD colocalized at both the B4GALNT3 locus (PP=99.7%) and GALNT1 locus (PP=99.8%) ( Supplementary Table 7), further strengthening the evidence of the putative causal relationship between sclerostin and eBMD.…”

Section: Mendelian Randomization and Colocalization Analysis Of Sclermentioning

confidence: 99%

Mendelian Randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures

Zheng

Maerz

Gergei

et al. 2018

Preprint

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In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two sample Mendelian Randomisation (MR). A genetic instrument for circulating sclerostin, derived from a genome wide association study (GWAS) meta-analysis of serum sclerostin in 10,584 Europeandescent individuals, was examined in relation to femoral neck bone mineral density (BMD; n= 32,744) in GEFOS, and estimated BMD by heel ultrasound (eBMD; n=426,824), and fracture risk (n=426,795), in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation (SD)) change in sclerostin per A allele (β=0.20, P=4.6x10 -49 ), and GALNT1 (β=0.11 per G allele, P=4.4x10 -11 ). B4GALNT3 is an N-acetylgalactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two SNPs as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β= -0.12, 95%CI= -0.20 to -0.05) and eBMD (β= -0.12, 95%CI= -0.14 to -0.10), and a positive relationship with fracture risk (β= 0.11, 95%CI= 0.01 to 0.21).Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis.

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Invited Commentary: Detecting Individual and Global Horizontal Pleiotropy in Mendelian Randomization—A Job for the Humble Heterogeneity Statistic?

Cited by 171 publications

References 27 publications

Investigating the effect of glycaemic traits on the risk of psychiatric illness using Mendelian randomisation

Investigating the effect of glycaemic traits on the risk of psychiatric illness using Mendelian randomisation

MR-TRYX: A Mendelian randomization framework that exploits horizontal pleiotropy to infer novel causal pathways

Mendelian Randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures

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