Genetically regulated gene expression underlies lipid traits in Hispanic cohorts

Andaleon, Angela; Mogil, Lauren S.; Wheeler, Heather E.

doi:10.1101/507905

Cited by 3 publications

(2 citation statements)

References 76 publications

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“…Interestingly, 11 out of these 13 genes had at least one VC-TWAS p-value <0.05 for one of the three pathologic AD showed that the genetic factor of gene ZNF234 on AD is potentially mediated through its gene expression, and the expression of this gene is also potentially involved in the mechanisms of both AD pathology indices of ߚ -amyloid and tangles. Besides AD, gene ZNF234 is also a known risk gene for lipid traits 42 . The genetically regulated gene expression of this gene might also affect lipid traits, thus leading to a pleiotropy phenomenon of AD and lipid traits 43 .…”

Section: Simulation Resultsmentioning

confidence: 99%

Novel Variance-Component TWAS method for studying complex human diseases with applications to Alzheimer’s dementia

Tang

Buchman

Jager

et al. 2020

Preprint

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Transcriptome-wide association studies (TWAS) have been widely used to integrate transcriptomic and genetic data to study complex human diseases. Within a test dataset lacking transcriptomic data, existing TWAS methods impute gene expression by creating a weighted sum that aggregates SNPs with their corresponding cis-eQTL effects on transcriptome estimated from reference datasets. Existing TWAS methods then apply a linear regression model to assess the association between imputed gene expression and test phenotype, thereby assuming the effect of a cis-eQTL SNP on test phenotype is a linear function of the eQTL's estimated effect on reference transcriptome. Thus, existing TWAS methods make a strong assumption that cis-eQTL effect sizes on reference transcriptome are reflective of their corresponding SNP effect sizes on test phenotype. To increase TWAS robustness to this assumption, we propose a Variance-Component TWAS procedure (VC-TWAS) that assumes the effects of cis-eQTL SNPs on phenotype are random (with variance proportional to corresponding cis-eQTL effects in reference dataset) rather than fixed. By doing so, we show VC-TWAS is more powerful than traditional TWAS when cis-eQTL SNP effects on test phenotype truly differ from their eQTL effects within reference dataset. We further applied VC-TWAS using cis-eQTL effect sizes estimated by a nonparametric Bayesian method to study Alzheimer's dementia (AD) related phenotypes and detected 13 genes significantly associated with AD, including 6 known GWAS risk loci. All significant loci are proximal to the major known risk loci APOE for AD. Further, we add this VC-TWAS function into our previously developed tool TIGAR for public use.

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Section: Simulation Resultsmentioning

confidence: 99%

Novel Variance-Component TWAS method for studying complex human diseases with applications to Alzheimer’s dementia

Tang

Buchman

Jager

et al. 2020

Preprint

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“…54 ’ 55 For adequately powered colocalisation analyses, we considered a PP4 > 0.7 as being consistent with colocalisation between the two traits, similar to other recent studies. 56-59 We visualised colocalisation using the LocusCompareR R library. 60…”

Section: Statistical Analysesmentioning

confidence: 99%

Assessing the efficacy and safety of angiotensinogen inhibition using human genetics

Bovijn

Censin

Lindgren

et al. 2020

Preprint

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Background Novel angiotensinogen (AGT) inhibitors are in early clinical development for treatment of hypertension. Evidence that this therapeutic approach will safely reduce risk of cardiovascular outcomes in humans is limited. We leveraged genetic data from more than one million individuals to characterise the effects of AGT inhibition. Methods We identified a genetic instrument for AGT inhibition from systolic blood pressure (SBP) genome-wide association study data, and investigated its relationship with AGT gene expression and circulating AGT protein concentration. We examined the instrument's association with cardiovascular and renal outcomes, and compared the effect of the instrument with that of genetic instruments for other renin-angiotensin system (RAS) components and the causal effect of SBP overall. We performed phenome-wide association analyses to identify unanticipated effects of AGT inhibition. Results The AGT instrument (rs2478539; 0.49 mmHg lower SBP per G-allele) was strongly associated with hypertension, and showed evidence of colocalisation with AGT mRNA expression across various tissues. Scaled to a 10 mmHg lower SBP, the AGT instrument was associated with a 41% lower risk of major cardiovascular events, a composite of myocardial infarction, coronary revascularisation and stroke (111,549 cases; odds ratio 0.59, 95% confidence interval, 0.47 ‒ 0.74; P = 3.1 × 10-6). There was little evidence of heterogeneity between the AGT vascular estimates when compared to equivalent estimates from other RAS targets and the effect of SBP lowering more broadly, and no strong evidence of potential target-mediated adverse effects. Conclusion Our findings suggest that inhibition of AGT safely reduces risk of major vascular events. These results support ongoing clinical development programmes for AGT inhibitors.

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Colocalization highlights genes in hypothalamic–pituitary–gonadal axis as potentially mediating polycystic ovary syndrome risk

Censin

Bovijn

Holmes

et al. 2020

Preprint

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Polycystic ovary syndrome (PCOS) is a common disease in women with consequences for reproductive, metabolic and psychological health. Women with PCOS have disrupted signalling in the hypothalamic-pituitary-gonadal axis and studies have indicated that the disease has a large genetic component. While a recent genome-wide association study of PCOS performed in up to 10,074 cases and 103,164 controls of European decent identified 14 PCOS-associated regions, much of the disease pathophysiology remains unclear.Here, we use a Bayesian colocalization approach to highlight genes that may have a potential role in PCOS pathophysiology and thus are of particular interest for further functional follow-up. We evaluated the posterior probabilities of shared causal variants between PCOS genetic risk loci and intermediate cellular phenotypes in one protein and two expression quantitative trait locus datasets, respectively. Sample sizes ranged from 80 to 31,684. In total, we identified seven proteins or genes with evidence of a shared causal variant for almost a third of PCOS signals, including follicle stimulating hormone (FSH) and the genes ERBB3, IKZF4, RPS26, SUOX, ZFP36L2, and C8orf49. Several of these genes and proteins have been implicated in the hypothalamic-pituitary-gonadal signalling pathway.In summary, our results suggest potential effector proteins and genes for PCOS association signals. This highlights genes for functional follow-up in order to demonstrate a causal role in PCOS pathophysiology.

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Genetically regulated gene expression underlies lipid traits in Hispanic cohorts

Cited by 3 publications

References 76 publications

Novel Variance-Component TWAS method for studying complex human diseases with applications to Alzheimer’s dementia

Novel Variance-Component TWAS method for studying complex human diseases with applications to Alzheimer’s dementia

Assessing the efficacy and safety of angiotensinogen inhibition using human genetics

Colocalization highlights genes in hypothalamic–pituitary–gonadal axis as potentially mediating polycystic ovary syndrome risk

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