Transcriptome-wide association study in UK Biobank Europeans identifies associations with blood cell traits.

Previous genome-wide association studies (GWAS) of hematological traits have identified over 10,000 distinct trait-specific risk loci, but the underlying causal mechanisms at these loci remain incompletely characterized. We performed a transcriptome-wide association study (TWAS) of 29 hematological traits in 399,835 UK Biobank (UKB) participants of European ancestry using gene expression prediction models trained from whole blood RNA-seq data in 922 individuals. We discovered 557 TWAS signals associated with hematological traits distinct from previously discovered GWAS variants, including 10 completely novel gene-trait pairs corresponding to 9 unique genes. Among the 557 associations, 301 were available for replication in a cohort of 141,286 participants of European ancestry from the Million Veteran Program (MVP). Of these 301 associations, 199 replicated at a nominal threshold (α = 0.05) and 108 replicated at a strict Bonferroni adjusted threshold (α = 0.05/301). Using our TWAS results, we systematically assigned 4,261 out of 16,900 previously identified hematological trait GWAS variants to putative target genes. Compared to coloc, our TWAS results show reduced specificity and increased sensitivity to assign variants to target genes.

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A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes

Genome Medicine ◽

10.1186/s13073-021-00959-y ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Yanfa Sun ◽

Jingjing Zhu ◽

Dan Zhou ◽

Saranya Canchi ◽

Chong Wu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Target Genes ◽

Prediction Models ◽

Association Studies ◽

Strong Support ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide

Abstract Background Genome-wide association studies (GWAS) have identified over 56 susceptibility loci associated with Alzheimer’s disease (AD), but the genes responsible for these associations remain largely unknown. Methods We performed a large transcriptome-wide association study (TWAS) leveraging modified UTMOST (Unified Test for MOlecular SignaTures) prediction models of ten brain tissues that are potentially related to AD to discover novel AD genetic loci and putative target genes in 71,880 (proxy) cases and 383,378 (proxy) controls of European ancestry. Results We identified 53 genes with predicted expression associations with AD risk at Bonferroni correction threshold (P value < 3.38 × 10−6). Based on fine-mapping analyses, 21 genes at nine loci showed strong support for being causal. Conclusions Our study provides new insights into the etiology and underlying genetic architecture of AD.

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Polygenic transcriptome risk scores (PTRS) can improve portability of polygenic risk scores across ancestries

Genome Biology ◽

10.1186/s13059-021-02591-w ◽

2022 ◽

Vol 23 (1) ◽

Author(s):

Yanyu Liang ◽

Milton Pividori ◽

Ani Manichaikul ◽

Abraham A. Palmer ◽

Nancy J. Cox ◽

...

Keyword(s):

Association Studies ◽

Poor Performance ◽

Genome Wide Association ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Transcript Levels ◽

Polygenic Risk ◽

Genome Wide

Abstract Background Polygenic risk scores (PRS) are valuable to translate the results of genome-wide association studies (GWAS) into clinical practice. To date, most GWAS have been based on individuals of European-ancestry leading to poor performance in populations of non-European ancestry. Results We introduce the polygenic transcriptome risk score (PTRS), which is based on predicted transcript levels (rather than SNPs), and explore the portability of PTRS across populations using UK Biobank data. Conclusions We show that PTRS has a significantly higher portability (Wilcoxon p=0.013) in the African-descent samples where the loss of performance is most acute with better performance than PRS when used in combination.

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Chromatin-based techniques map DNA interaction landscapes in psoriasis susceptibility loci and highlight KLF4 as a target gene in 9q31

10.1101/822304 ◽

2019 ◽

Author(s):

Helen Ray-Jones ◽

Kate Duffus ◽

Amanda McGovern ◽

Paul Martin ◽

Chenfu Shi ◽

...

Keyword(s):

Target Gene ◽

Target Genes ◽

Association Studies ◽

Dna Interaction ◽

Genome Wide Association Studies ◽

Susceptibility Loci ◽

Rna Seq ◽

Causal Gene ◽

Genome Wide ◽

Crispr Activation

AbstractGenome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. Here, we use a disease-focused Capture Hi-C experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. In the 9q31 risk locus we combine further epigenomic evidence to demonstrate how the psoriasis association forms a functional interaction with the distant (>500 kb) KLF4 gene. We use CRISPR activation coupled with RNA-seq to demonstrate how activation of psoriasis-associated enhancers upregulates KLF4 in HaCaT cells. Our study design provides a robust pipeline for following up on GWAS disease-associated variants, paving the way for functional translation of genetic findings into clinical benefit.

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Shared Genetic Architecture between Asthma and Allergic Diseases: A Genome-Wide Cross Trait Analysis of 112,000 Individuals from UK Biobank

10.1101/133322 ◽

2017 ◽

Cited By ~ 3

Author(s):

Zhaozhong Zhu ◽

Phil H. Lee ◽

Mark D. Chaffin ◽

Wonil Chung ◽

Po-Ru Loh ◽

...

Keyword(s):

Molecular Mechanisms ◽

Association Studies ◽

Allergic Diseases ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Trait Analysis ◽

Genome Wide ◽

A Genome ◽

Shared Genetic

AbstractClinical and epidemiological data suggest that asthma and allergic diseases are associated. And may share a common genetic etiology. We analyzed genome-wide single-nucleotide polymorphism (SNP) data for asthma and allergic diseases in 35,783 cases and 76,768 controls of European ancestry from the UK Biobank. Two publicly available independent genome wide association studies (GWAS) were used for replication. We have found a strong genome-wide genetic correlation between asthma and allergic diseases (rg = 0.75, P = 6.84×10−62). Cross trait analysis identified 38 genome-wide significant loci, including novel loci such as D2HGDH and GAL2ST2. Computational analysis showed that shared genetic loci are enriched in immune/inflammatory systems and tissues with epithelium cells. Our work identifies common genetic architectures shared between asthma and allergy and will help to advance our understanding of the molecular mechanisms underlying co-morbid asthma and allergic diseases.

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Genetic liability to insomnia in relation to cardiovascular diseases: a Mendelian randomisation study

European Journal of Epidemiology ◽

10.1007/s10654-021-00737-5 ◽

2021 ◽

Author(s):

Shuai Yuan ◽

Amy M. Mason ◽

Stephen Burgess ◽

Susanna C. Larsson

Keyword(s):

Cardiovascular Diseases ◽

Association Studies ◽

European Ancestry ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genetic Liability ◽

Genome Wide ◽

Increased Risk ◽

The Uk

AbstractThe present study aimed to determine the associations between insomnia and cardiovascular diseases (CVDs) using Mendelian randomisation (MR) analysis. As instrumental variables, we used 208 independent single-nucleotide polymorphisms associated with insomnia at the genome-wide significance threshold in a meta-analysis of genome-wide association studies in the UK Biobank and 23andMe including a total of 397 959 self-reported insomnia cases and 933 057 non-cases. Summary-level data for nine CVDs were obtained from the UK Biobank including 367 586 individuals of European ancestry. After correction for multiple testing, genetic liability to insomnia was associated with higher odds of six CVDs, including peripheral arterial disease (odd ratio (OR) 1.22; 95% confidence interval (CI), 1.21, 1.33), heart failure (OR 1.21; 95% CI, 1.13, 1.30), coronary artery disease (OR 1.19; 95% CI, 1.14, 1.25), ischaemic stroke (OR 1.15; 95% CI, 1.06, 1.25), venous thromboembolism (OR 1.13; 95% CI, 1.07, 1.19) and atrial fibrillation (OR 1.10; 95% CI, 1.05, 1.15). There were suggestive associations for aortic valve stenosis (OR, 1.17; 95% CI, 1.04, 1.32) and haemorrhagic stroke (OR 1.14; 95% CI, 1.00, 1.29) but no association for abdominal aortic aneurysm (OR, 1.14, 95% CI, 0.98, 1.33). The patterns of associations remained with mild attenuation in multivariable MR analyses adjusting for genetically correlated phenotypes and potential mediators, including sleep duration, depression, body mass index, type 2 diabetes and smoking. The present MR study suggests potential causal associations of genetic liability to insomnia with increased risk of a broad range of CVDs.

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Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00854-z ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Hang-Rai Kim ◽

Sang-Hyuk Jung ◽

Jaeho Kim ◽

Hyemin Jang ◽

Sung Hoon Kang ◽

...

Keyword(s):

Genetic Variants ◽

Prediction Models ◽

Association Studies ◽

Genome Wide Association ◽

Korean Population ◽

European Ancestry ◽

Eqtl Analysis ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

Abstract Background Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer’s disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid β (Aβ) positivity using a large sample of Korean population. Methods One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aβ positivity (measured by amyloid positron emission tomography). Aβ prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. Results In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aβ positivity (p < 0.05) in the replication dataset. In a meta-analysis, two SNPs (rs7337542 and rs2903923) reached a genome-wide significant level (p < 5.0 × 10−8). Prediction performance for Aβ positivity increased when rs73375428 were incorporated (area under curve = 0.75; 95% CI = 0.74–0.76) in addition to clinical factors and APOE genotype. Cis-eQTL analysis demonstrated that the rs73375428 was associated with decreased expression levels of FGL2 in the brain. Conclusion The novel genetic variants associated with FGL2 decreased risk of Aβ positivity in the Korean population. This finding may provide a candidate therapeutic target for AD, highlighting the importance of genetic studies in diverse populations.

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Redefining replication in multi-ancestry genome-wide association studies

10.1101/2021.04.20.440612 ◽

2021 ◽

Author(s):

Samuel Pattillo Smith ◽

Sahar Shahamatdar ◽

Wei Cheng ◽

Selena Zhang ◽

Joseph Paik ◽

...

Keyword(s):

Latin American ◽

Alaska Native ◽

Prediction Models ◽

Association Studies ◽

Complex Trait ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Heritability Estimation

AbstractSince 2005, genome-wide association (GWA) datasets have been largely biased toward sampling European ancestry individuals, and recent studies have shown that GWA results estimated from European ancestry individuals apply heterogeneously in non-European ancestry individuals. Here, we argue that enrichment analyses which aggregate SNP-level association statistics at multiple genomic scales—to genes and pathways—have been overlooked and can generate biologically interpretable hypotheses regarding the genetic basis of complex trait architecture. We illustrate examples of the insights generated by enrichment analyses while studying 25 continuous traits assayed in 566,786 individuals from seven self-identified human ancestries in the UK Biobank and the Biobank Japan, as well as 44,348 admixed individuals from the PAGE consortium including cohorts of African-American, Hispanic and Latin American, Native Hawaiian, and American Indian/Alaska Native individuals. By testing for statistical associations at multiple genomic scales, enrichment analyses also illustrate the importance of reconciling contrasting results from association tests, heritability estimation, and prediction models in order to make personalized medicine a reality for all.

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Comparison of Two Genome-Wide Association Studies for Heart Rate Response to Exercise from the UK Biobank

10.1101/2021.07.07.21259806 ◽

2021 ◽

Author(s):

Abhinav Thakral ◽

Andrew D Paterson

Keyword(s):

Heart Rate ◽

Association Studies ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Post Exercise ◽

Genome Wide ◽

The Difference ◽

The Uk

The short-term changes in heart rate (HR) during and after exercise are important physiologic traits mediated via the autonomic nervous system. Variations in these traits are associated with mortality from cardiovascular causes. We conducted a systematic review of genome-wide association studies for these traits (with >10,000 participants) with the aim of comparing Polygenic Risk Scores (PRS) from different studies. Additionally, we applied the STrengthening of Reporting of Genetic Association Studies (STREGA) statement for assessing the completeness of reporting of evidence. Our systematic search yielded two studies (Verweij et al. and Ramirez et al.) that met our inclusion criteria. Both were conducted on the UK Biobank. Both defined their exercise traits as the difference between resting HR and the maximum HR during exercise. Their recovery traits were defined differently. Verweij et al. defined 5 recovery traits as the differences between the peak HR during exercise and the HRs at 10-50 sec post exercise cessation. Ramirez et al. defined their recovery trait as the difference between peak HR during exercise and the minimum HR during the minute post exercise cessation. While Ramirez et al. divided their sample into discovery and replication subsets, Verweij et al. analyzed the whole sample together. In terms of results, there were several common SNPs identified between studies and traits. There was evidence for the phenomenon of winners curse operating for a SNP from the Ramirez studys HR recovery analysis. Many of the SNPs were mutually exclusive between the studies. However, there was a good agreement of PRS from the studies. The differences in the results could be attributed to the different exclusion criteria, analytic approaches, and definitions of traits used. Both studies had an under-representation of individuals of non-European ancestry compared to those of European ancestry. Further studies with proportionate representation of individuals of all ancestries would help address this gap.

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VAMPIRE: A model blood cell trait focused annotation tool for interpretation and prioritization of complex trait genome-wide association study results

10.1101/2021.02.16.431409 ◽

2021 ◽

Author(s):

Cheynna Crowley ◽

Quan Sun ◽

Le Huang ◽

Erik L. Bao ◽

Paul Auer ◽

...

Keyword(s):

Blood Cell ◽

Association Study ◽

Complex Traits ◽

Web Application ◽

Target Genes ◽

Association Studies ◽

Complex Trait ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

AbstractThousands of genetic loci have been identified as associated with hematological indices (red blood cell, white blood cell, and platelet related traits), as well as other complex traits and disease. However, most loci identified are noncoding and not clearly linked to target genes, and tools are needed to prioritize the most likely functional variants for experimental follow-up. We here describe VAMPIRE: Variant Annotation Method Pointing to Interesting Regulatory Effects, an interactive web application implemented in R Shiny (http://shiny.bios.unc.edu/vampire/) for blood cell trait associated loci from recent large multi-ethnic genome-wide association studies (GWAS). This tool efficiently displays information from blood cell relevant tissues on epigenomic signatures, functional and conservation summary scores, variant impact on protein and gene expression, chromatin conformation information from Hi-C and similar technologies, as well as publicly available GWAS and phenome-wide association study (PheWAS) results. Variants are classified into multiple prioritization categories according to these functional signatures. Leveraging data generated from independent functional validation experiments, we demonstrate that our prioritized variants are enriched within experimentally validated variant sets. VAMPIRE allows rapid prioritization and interpretation of blood cell trait GWAS variants and could be easily adapted for use with other complex trait GWAS results and extended to new annotation sources.Author SummaryMany large genome-wide association studies (GWAS) have recently been performed for blood cell traits, with thousands of associations identified. However, most of the associated variants are in noncoding regions and are often hard to interpret, link to genes, and prioritize for functional follow-up. Similar challenges exist for genetic studies of many other traits and diseases. Trying to translate knowledge of GWAS significant variants to target genes and biological insights, we here describe VAMPIRE: Variant Annotation Method Pointing to Interesting Regulatory Effects, an interactive web application implemented in R Shiny (http://shiny.bios.unc.edu/vampire/) for blood cell trait associated loci from recent large multi-ethnic GWAS. This tool displays a variety of information including epigenomic signatures, variant impact on protein and gene expression, chromatin conformation information, and publicly available GWAS and phenome-wide association study (PheWAS) results for other traits. We classified variants into annotation categories using this information, and show that variants in the highest priority categories are enriched in likely causal variant sets from previous functional experiments. We anticipate this tool will guide appropriate variants to prioritize for experimental validation for researchers studying blood cell traits, as well as providing an easily adaptable model for the creation of similar annotation tools for other complex traits and diseases.

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Analysing electrocardiographic traits and predicting cardiac risk in UK biobank

JRSM Cardiovascular Disease ◽

10.1177/20480040211023664 ◽

2021 ◽

Vol 10 ◽

pp. 204800402110236

Author(s):

Julia Ramírez ◽

Stefan van Duijvenboden ◽

William J Young ◽

Michele Orini ◽

Aled R Jones ◽

...

Keyword(s):

Genetic Information ◽

Association Studies ◽

Cardiac Risk ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Biological Mechanisms ◽

Clinical Tool ◽

Genome Wide ◽

Response To Exercise ◽

Electrocardiogram Ecg

The electrocardiogram (ECG) is a commonly used clinical tool that reflects cardiac excitability and disease. Many parameters are can be measured and with the improvement of methodology can now be quantified in an automated fashion, with accuracy and at scale. Furthermore, these measurements can be heritable and thus genome wide association studies inform the underpinning biological mechanisms. In this review we describe how we have used the resources in UK Biobank to undertake such work. In particular, we focus on a substudy uniquely describing the response to exercise performed at scale with accompanying genetic information.

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