Prioritization of candidate causal genes in GWAS signals of asthma in UK Biobank

Abstract To identify susceptibility loci and candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS revealed 72 asthma-associated loci from 116 independent significant variants (PGWAS<5.0E-8). As expected, the yield of exonic variants associated with asthma was low, but nine were identified as potentially deleterious (CADD > 20) including a stop-gain mutation in the filaggrin (FLG) gene. The top lung TWAS gene on 17q12-q21 was GSDMB (PTWAS=1.42E-54). Other TWAS genes of interest include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). A novel risk locus was also revealed by the lung asthma TWAS on 1q23.3 with the putative gene encoding the gamma chain of the high-affinity IgE receptor (FCER1G, PTWAS=2.13E-6), which was also replicated in GTEx lung (PTWAS=3.71E-7). By testing a comprehensive set of cells and tissues, we then demonstrated that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants was in the blood. We mapped 485 eQTL-regulated genes associated with asthma in the blood and 50 of them were shown to be causally associated with asthma by Mendelian randomization. Prioritization of druggable genes revealed known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.

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Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank

Communications Biology ◽

10.1038/s42003-021-02227-6 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Kim Valette ◽

Zhonglin Li ◽

Valentin Bon-Baret ◽

Arnaud Chignon ◽

Jean-Christophe Bérubé ◽

...

Keyword(s):

Genome Wide Association Study ◽

Mendelian Randomization ◽

Association Studies ◽

Uk Biobank ◽

Susceptibility Loci ◽

Functional Annotations ◽

Fold Enrichment ◽

Genome Wide ◽

A Genome ◽

Causal Genes

AbstractTo identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (PGWAS < 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (PTWAS = 1.42E-54). Other TWAS genes include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). We demonstrate that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants is in the blood. We map 485 blood eQTL-regulated genes associated with asthma and 50 of them are causal by Mendelian randomization. Prioritization of druggable genes reveals known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.

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Iron Status and Cancer Risk in UK Biobank: A Two-Sample Mendelian Randomization Study

Nutrients ◽

10.3390/nu12020526 ◽

2020 ◽

Vol 12 (2) ◽

pp. 526 ◽

Cited By ~ 2

Author(s):

Shuai Yuan ◽

Paul Carter ◽

Mathew Vithayathil ◽

Siddhartha Kar ◽

Edward Giovannucci ◽

...

Keyword(s):

Liver Cancer ◽

Brain Cancer ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Iron Status ◽

Transferrin Saturation ◽

Nucleotide Polymorphisms ◽

Uk Biobank ◽

Odds Ratios ◽

A Genome

We conducted a two-sample Mendelian randomization study to explore the associations of iron status with overall cancer and 22 site-specific cancers. Single-nucleotide polymorphisms for iron status were obtained from a genome-wide association study of 48,972 European-descent individuals. Summary-level data for breast and other cancers were obtained from the Breast Cancer Association Consortium and UK Biobank. Genetically predicted iron status was positively associated with liver cancer and inversely associated with brain cancer but not associated with overall cancer or the other 20 studied cancer sites at p < 0.05. The odds ratios of liver cancer were 2.45 (95% CI, 0.81, 7.45; p = 0.11), 2.11 (1.16, 3.83; p = 0.02), 10.89 (2.44, 48.59; p = 0.002) and 0.30 (0.17, 0.53; p = 2 × 10−5) for one standard deviation increment of serum iron, transferrin saturation, ferritin and transferrin levels, respectively. For brain cancer, the corresponding odds ratios were 0.69 (0.48, 1.00; p = 0.05), 0.75 (0.59, 0.97; p = 0.03), 0.41 (0.20, 0.88; p = 0.02) and 1.49 (1.04, 2.14; p = 0.03). Genetically high iron status was positively associated with liver cancer and inversely associated with brain cancer.

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Circulating antioxidants and Alzheimer disease prevention: a Mendelian randomization study

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy225 ◽

2018 ◽

Vol 109 (1) ◽

pp. 90-98 ◽

Cited By ~ 4

Author(s):

Dylan M Williams ◽

Sara Hägg ◽

Nancy L Pedersen

Keyword(s):

Alzheimer Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Disease Risk ◽

Late Onset ◽

Association Studies ◽

Nucleotide Polymorphisms ◽

Primary Methods ◽

A Genome ◽

Β Carotene

ABSTRACT Background Higher circulating antioxidant concentrations are associated with a lower risk of late-onset Alzheimer disease (AD) in observational studies, suggesting that diet-sourced antioxidants may be modifiable targets for reducing disease risk. However, observational evidence is prone to substantial biases that limit causal inference, including residual confounding and reverse causation. Objectives In order to infer whether long-term circulating antioxidant exposure plays a role in AD etiology, we tested the hypothesis that AD risk would be lower in individuals with lifelong, genetically predicted increases in concentrations of 4 circulating antioxidants that are modifiable by diet. Methods Two-sample Mendelian randomization analyses were conducted. First, published genetic association studies were used to identify single-nucleotide polymorphisms (SNPs) that determine variation in circulating ascorbate (vitamin C), β-carotene, retinol (vitamin A), and urate. Second, for each set of SNP data, statistics for genotype associations with AD risk were extracted from data of a genome-wide association study of late-onset AD cases and controls (n = 17,008 and 37,154, respectively). Ratio-of-coefficients and inverse-variance-weighted meta-analyses were the primary methods used to assess the 4 sets of SNP-exposure and SNP-AD associations. Additional analyses assessed the potential impact of bias from pleiotropy on estimates. Results The models suggested that genetically determined differences in circulating ascorbate, retinol, and urate are not associated with differences in AD risk. All estimates were close to the null, with all ORs for AD ≥1 per unit increase in antioxidant exposure (ranging from 1.00 for ascorbate to 1.05 for retinol). There was little evidence to imply that pleiotropy had biased results. Conclusions Our findings suggest that higher exposure to ascorbate, β-carotene, retinol, or urate does not lower the risk of AD. Replication Mendelian randomization studies could assess this further, providing larger AD case-control samples and, ideally, using additional variants to instrument each exposure.

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A Trans-Omic Mendelian Randomization Study of Parental Lifespan Uncovers Novel Aging Biology and Drug Candidates for Human Healthspan Extension

10.1101/2020.07.06.20147520 ◽

2020 ◽

Author(s):

Nicolas Perrot ◽

William Pelletier ◽

Jerome Bourgeault ◽

Christian Couture ◽

Zhonglin Li ◽

...

Keyword(s):

Genome Wide Association Study ◽

Mendelian Randomization ◽

Drug Repositioning ◽

Tissue Expression ◽

Human Longevity ◽

Gene Encoding ◽

Association Analyses ◽

Drug Candidates ◽

A Genome ◽

The Uk

The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and healthspan. Here, we leveraged summary statistics of a genome-wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype-Tissue Expression project through a combination of multi-tissue transcriptome-wide association analyses and genetic colocalization. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan that may offer new drug repositioning opportunities for healthspan such as drugs targeting apolipoprotein-B-containing lipoproteins. Liver expression of HP, the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome-wide MR analyses were used to map genetically regulated genes, proteins and metabolites with the disease-related phenome in the UK Biobank and FinnGen. Altogether, this study identified novel biological determinants of aging and potential therapeutic targets for human healthspan extension.

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Association between genetically predicted telomere length and facial skin aging in the UK Biobank: a Mendelian randomization study

GeroScience ◽

10.1007/s11357-020-00283-0 ◽

2020 ◽

Author(s):

Yiqiang Zhan ◽

Sara Hägg

Keyword(s):

Telomere Length ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Large Population ◽

Uk Biobank ◽

Facial Aging ◽

Genome Wide ◽

A Genome ◽

Weighted Median ◽

The Uk

Abstract Are shorter telomeres causal risk factors for facial aging on a large population level? To examine if longer, genetically predicted telomeres were causally associated with less facial aging using Mendelian randomization analysis. Two-sample Mendelian randomization methods were applied to the summary statistics of a genome-wide association study (GWAS) for self-reported facial aging from 417, 772 participants of the UK Biobank data. Twenty single-nucleotide polymorphisms (SNPs) that were of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and were complemented with the MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. Longer genetically predicted telomeres were associated with a lower likelihood of facial aging (β = − 0.02, 95% confidence interval: − 0.04, − 0.002). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was close to zero (0.002) that was not suggestive of horizontal pleiotropy. Our findings provided evidence to support a potential causal relationship between longer genetically predicted telomeres and less facial aging.

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Genetic determinants of daytime napping and effects on cardiometabolic health

Nature Communications ◽

10.1038/s41467-020-20585-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hassan S. Dashti ◽

◽

Iyas Daghlas ◽

Jacqueline M. Lane ◽

Yunru Huang ◽

...

Keyword(s):

Drug Targets ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Cardiometabolic Health ◽

Uk Biobank ◽

Genetic Determinants ◽

Genome Wide ◽

A Genome ◽

The Uk

AbstractDaytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remain unclear. Here, we perform a genome-wide association study of self-reported daytime napping in the UK Biobank (n = 452,633) and identify 123 loci of which 61 replicate in the 23andMe research cohort (n = 541,333). Findings include missense variants in established drug targets for sleep disorders (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Association signals are concordant with accelerometer-measured daytime inactivity duration and 33 loci colocalize with loci for other sleep phenotypes. Cluster analysis identifies three distinct clusters of nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization shows potential causal links between more frequent daytime napping and higher blood pressure and waist circumference.

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EXPRESS: Effect of genetic liability to visceral adiposity on stroke and its subtypes: a Mendelian randomization study

International Journal of Stroke ◽

10.1177/17474930211006285 ◽

2021 ◽

pp. 174749302110062

Author(s):

Bin Yan ◽

Jian Yang ◽

Li Qian ◽

Fengjie Gao ◽

Ling Bai ◽

...

Keyword(s):

Sensitivity Analysis ◽

Ischemic Stroke ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Visceral Adiposity ◽

Large Artery ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

A Genome ◽

Increased Risk

Background: Observational studies have found an association between visceral adiposity and stroke. Aims: The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue (VAT) accumulation on stroke and its subtypes. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants (221 single nucleotide polymorphisms; P<5Ã10-8) using as instrumental variables for MR analysis was obtained from a genome-wide association study (GWAS) of VAT. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). MR standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analysis (MR-Egger, weighted median, MR-PRESSO) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable MR analysis was employed to adjust potential confounders. Results: In the standard MR analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.21-1.41, P=1.48Ã10-11), ischemic stroke (OR 1.30; 95% CI 1.20-1.41, P=4.01Ã10-10), and large artery stroke (OR 1.49; 95% CI 1.22-1.83, P=1.16Ã10-4). The significant association was also found in sensitivity analysis and multi-variable MR analysis. Conclusions: Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.

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Prioritization of genes associated with the pathogenesis of leukosis in cattle

Vavilov Journal of Genetics and Breeding ◽

10.18699/vj18.451 ◽

2019 ◽

Vol 22 (8) ◽

pp. 1063-1069 ◽

Cited By ~ 1

Author(s):

N. S. Yudin ◽

N. L. Podkolodnyy ◽

T. A. Agarkova ◽

E. V. Ignatieva

Keyword(s):

Protein Interactions ◽

Genome Wide Association Study ◽

Association Studies ◽

Mammalian Species ◽

Genome Wide Association ◽

Farm Animals ◽

Genome Wide Association Studies ◽

Protein Protein Interactions ◽

Genome Wide ◽

A Genome

Selection by means of genetic markers is a promising approach to the eradication of infectious diseases in farm animals, especially in the absence of eﬀective methods of treatment and prevention. Bovine leukemia virus (BLV) is spread throughout the world and represents one of the biggest problems for the livestock production and food security in Russia. However, recent genome-wide association studies have shown that sensitivity/resistance to BLV is polygenic. The aim of this study was to create a catalog of cattle genes and genes of other mammalian species involved in the pathogenesis of BLV-induced infection and to perform gene prioritization using bioinformatics methods. Based on manually collected information from a range of open sources, a total of 446 genes were included in the catalog of cattle genes and genes of other mammals involved in the pathogenesis of BLV-induced infection. The following criteria were used to prioritize 446 genes from the catalog: (1) the gene is associated with leukemia according to a genome-wide association study; (2) the gene is associated with leukemia according to a case-control study; (3) the role of the gene in leukemia development has been studied using knockout mice; (4) protein-protein interactions exist between the gene-encoded protein and either viral particles or individual viral proteins; (5) the gene is annotated with Gene Ontology terms that are overrepresented for a given list of genes; (6) the gene participates in biological pathways from the KEGG or REACTOME databases, which are over-represented for a given list of genes; (7) the protein encoded by the gene has a high number of protein-protein interactions with proteins encoded by other genes from the catalog. Based on each criterion, a rank was assigned to each gene. Then the ranks were summarized and an overall rank was determined. Prioritization of 446 candidate genes allowed us to identify 5 genes of interest (TNF,LTB,BOLA-DQA1,BOLA-DRB3,ATF2), which can aﬀect the sensitivity/resistance of cattle to leukemia.

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MR-pheWAS with stratification and interaction: Searching for the causal effects of smoking heaviness identified an effect on facial aging

10.1101/441907 ◽

2018 ◽

Cited By ~ 1

Author(s):

Louise A C Millard ◽

Marcus R Munafò ◽

Kate Tilling ◽

Robyn E Wootton ◽

George Davey Smith

Keyword(s):

Lung Function ◽

Detrimental Effect ◽

Genetic Variant ◽

Mendelian Randomization ◽

Association Studies ◽

Causal Effects ◽

Uk Biobank ◽

Facial Aging ◽

Heavy Smoking ◽

Never Smokers

AbstractMendelian randomization (MR) is an established approach for estimating the causal effect of an environmental exposure on a downstream outcome. The gene x environment (GxE) study design can be used within an MR framework to determine whether MR estimates may be biased if the genetic instrument affects the outcome through pathways other than via the exposure of interest (known as horizontal pleiotropy). MR phenome-wide association studies (MR-pheWAS) search for the effects of an exposure, and a recently published tool (PHESANT) means that it is now possible to do this comprehensively, across thousands of traits in UK Biobank. In this study, we introduce the GxE MR-pheWAS approach, and search for the causal effects of smoking heaviness – stratifying on smoking status (ever versus never) – as an exemplar. If a genetic variant is associated with smoking heaviness (but not smoking initiation), and this variant affects an outcome (at least partially) via tobacco intake, we would expect the effect of the variant on the outcome to differ in ever versus never smokers. If this effect is entirely mediated by tobacco intake, we would expect to see an effect in ever smokers but not never smokers. We used PHESANT to search for the causal effects of smoking heaviness, instrumented by genetic variant rs16969968, among never and ever smokers respectively, in UK Biobank. We ranked results by: 1) strength of effect of rs16969968 among ever smokers, and 2) strength of interaction between ever and never smokers. We replicated previously established causal effects of smoking heaviness, including a detrimental effect on lung function and pulse rate. Novel results included a detrimental effect of heavier smoking on facial aging. We have demonstrated how GxE MR-pheWAS can be used to identify causal effects of an exposure, while simultaneously assessing the extent that results may be biased by horizontal pleiotropy.Author summaryMendelian randomization uses genetic variants associated with an exposure to investigate causality. For instance, a genetic variant that relates to how heavily a person smokes has been used to test whether smoking causally affects health outcomes. Mendelian randomization is biased if the genetic variant also affects the outcome via other pathways. We exploit additional information – that the effect of heavy smoking only occurs in people who actually smoke – to overcome this problem. By testing associations in ever and never smokers separately we can assess whether the genetic variant affects an outcome via smoking or another pathway. If the effect is entirely via smoking heaviness, we would expect to see an effect in ever but not never smokers, and this would suggest that smoking causally influences the outcome. Previous Mendelian randomization studies of smoking heaviness focused on specific outcomes – here we searched for the causal effects of smoking heaviness across over 18,000 traits. We identified previously established effects (e.g. a detrimental effect on lung function) and novel results including a detrimental effect of heavier smoking on facial aging. Our approach can be used to search for the causal effects of other exposures, where the exposure only occurs in known subsets of the population.

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