Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches

The American Journal of Human Genetics, Journal Year: 2022, Volume and Issue: 109(5), P. 767 - 782

Published: April 21, 2022

Language: Английский

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Fine-mapping from summary data with the “Sum of Single Effects” model

PLoS Genetics, Journal Year: 2022, Volume and Issue: 18(7), P. e1010299 - e1010299

Published: July 19, 2022

In recent work, Wang et al introduced the "Sum of Single Effects" (SuSiE) model, and showed that it provides a simple efficient approach to fine-mapping genetic variants from individual-level data. Here we present new methods for fitting SuSiE model summary data, example single-SNP z-scores an association study linkage disequilibrium (LD) values estimated suitable reference panel. To develop these methods, first describe simple, generic strategy extending any data method deal with The key idea is replace usual regression likelihood analogous based on We show existing such as FINEMAP CAVIAR also (implicitly) use this strategy, but in different ways, so common framework understanding fine-mapping. investigate other practical issues including problems caused by inconsistencies between LD estimates, diagnostics identify inconsistencies. refinement procedure improves fits some sets, hence overall reliability results. Detailed evaluations range simulated sets applied competitive, both speed accuracy, best available

Language: Английский

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Current sequence-based models capture gene expression determinants in promoters but mostly ignore distal enhancers

Genome biology, Journal Year: 2023, Volume and Issue: 24(1)

Published: March 27, 2023

Abstract Background The largest sequence-based models of transcription control to date are obtained by predicting genome-wide gene regulatory assays across the human genome. This setting is fundamentally correlative, as those exposed during training solely sequence variation between genes that arose through evolution, questioning extent which capture genuine causal signals. Results Here we confront predictions state-of-the-art regulation against data from two large-scale observational studies and five deep perturbation assays. most advanced these models, Enformer, large, captures determinants promoters. However, fail effects enhancers on expression, notably in medium long distances particularly for highly expressed More generally, predicted impact distal elements expression small ability correctly integrate long-range information significantly more limited than receptive fields suggest. likely caused escalating class imbalance actual candidate distance increases. Conclusions Our results suggest have point silico study promoter regions variants can provide meaningful insights practical guidance how use them. Moreover, foresee it will require new kinds train accurately accounting elements.

Language: Английский

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Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program

Science, Journal Year: 2024, Volume and Issue: 385(6706)

Published: July 18, 2024

One of the justifiable criticisms human genetic studies is underrepresentation participants from diverse populations. Lack inclusion must be addressed at-scale to identify causal disease factors and understand causes health disparities. We present genome-wide associations for 2068 traits 635,969 in Department Veterans Affairs Million Veteran Program, a longitudinal study United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European Fine-mapping identified variants at 6318 signals across 613 traits. One-third ( n = 2069) This reveals broadly similar architecture populations, highlights insights gained underrepresented groups, presents an extensive atlas associations.

Language: Английский

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Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(5), P. 792 - 808

Published: April 18, 2024

Language: Английский

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A disease-associated gene desert directs macrophage inflammation through ETS2

Nature, Journal Year: 2024, Volume and Issue: 630(8016), P. 447 - 456

Published: June 5, 2024

Abstract Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health 1 . This is compounded by the limited efficacy available treatments high failure during drug development 2 , highlighting an urgent need better understand mechanisms. Here we show how functional genomics could address this challenge. By investigating intergenic haplotype on chr21q22—which has been independently linked bowel disease, ankylosing spondylitis, primary sclerosing cholangitis Takayasu’s arteritis 3–6 —we identify that causal gene, ETS2 central regulator macrophages delineate shared mechanism amplifies expression. Genes regulated were prominently expressed in diseased tissues more enriched for GWAS hits than most previously described pathways. Overexpressing resting reproduced state observed chr21q22-associated diseases, with upregulation multiple targets, including TNF IL-23. Using database cellular signatures 7 identified drugs might modulate pathway validated potent anti-inflammatory activity one class small molecules vitro ex vivo. Together, illustrates power genomics, applied directly cells, immune-mediated mechanisms potential therapeutic opportunities.

Language: Английский

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Adjusting for genetic confounders in transcriptome-wide association studies improves discovery of risk genes of complex traits

Nature Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 26, 2024

Abstract Many methods have been developed to leverage expression quantitative trait loci (eQTL) data nominate candidate genes from genome-wide association studies. These methods, including colocalization, transcriptome-wide studies (TWAS) and Mendelian randomization-based methods; however, all suffer a key problem—when assessing the role of gene in using its eQTLs, nearby variants genetic components other genes’ may be correlated with these eQTLs direct effects on trait, acting as potential confounders. Our extensive simulations showed that existing fail account for ‘genetic confounders’, resulting severe inflation false positives. new method, causal-TWAS (cTWAS), borrows ideas statistical fine-mapping allows us adjust cTWAS calibrated discovery rates simulations, application several common traits discovered genes. In conclusion, provides robust framework discovery.

Language: Английский

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Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 30, 2024

To date only a fraction of the genetic footprint thyroid function has been clarified. We report genome-wide association study meta-analysis in up to 271,040 individuals European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well dichotomized high low TSH levels. revealed 259 independent significant associations (61% novel), 85 FT4 (67% 62 novel signals T3 related traits. The loci explained 14.1%, 6.0%, 9.5% 1.1% variation TSH, FT4, concentrations, respectively. Genetic correlations indicate that associated reflect determined by T3, whereas represent hormone metabolism. Polygenic risk score Mendelian randomization analyses showed effects genetically on various clinical outcomes, cardiovascular factors diseases, autoimmune cancer. In conclusion, our results improve understanding physiology highlight pleiotropic diseases.

Language: Английский

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Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood

Science, Journal Year: 2024, Volume and Issue: 384(6698)

Published: May 23, 2024

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study posttraumatic stress disorder (PTSD) and major depressive (MDD) included the central nucleus amygdala, hippocampal dentate gyrus, medial prefrontal cortex (mPFC). Genes exons within mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal synaptic regulation, hormones. Multiomic factor gene network analyses provided underlying genomic structure. Single RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) non-neuronal cell types. Analyses brain-blood intersections >50,000 UK Biobank participants were conducted along with fine-mapping results PTSD MDD genome-wide association studies distinguish risk from processes. data suggest shared distinct both propose potential therapeutic targets biomarkers.

Language: Английский

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MESuSiE enables scalable and powerful multi-ancestry fine-mapping of causal variants in genome-wide association studies

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(1), P. 170 - 179

Published: Jan. 1, 2024

Language: Английский

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