Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Võsa, Urmo; Claringbould, Annique; Westra, Harm-Jan; Deelen, Patrick; Zeng, Biao; Kirsten, Holger; Saha, Ashis; Kreuzhuber, Roman; Yazar, Seyhan; Brugge, Harm; Oelen, Roy; Vries, Dylan de; Wijst, Monique G.P. van der; Kasela, Silva; Pervjakova, Natalia; Alves, Isabel; Favé, Marie-Julie; Agbessi, Mawussé; Christiansen, Mark; Jansen, Ritsert C.; Seppälä, Ilkka; Lin, Tong; Teumer, Alexander; Schramm, Katharina; Hemani, Gibran; Verlouw, Joost A M; Yaghootkar, Hanieh; Flitman, Reyhan Sönmez; Brown, Andrew Anand; Kukushkina, Viktorija; Kalnapenkis, Anette; Rüeger, Sina; Porcu, Eleonora; Kronberg, Jaanika; Kettunen, Johannes; Lee, Bernett; Zhang, Futao; Qi, Ting; Alquicira-Hernández, José; Arindrarto, Wibowo; Beutner, Frank; Hoen, Peter A.C. ‘t; Bonder, Marc Jan; Dmitrieva, Julia; Elansary, Mahmoud; Fairfax, Benjamin P.; Georges, Michel; Heijmans, Bastiaan T.; Hewitt, Alex W.; Kähönen, Mika; Kim, Yungil; Knight, Julian C.; Kovacs, Peter; Krohn, Knut; Li, Shuang; Loeffler, Markus; Marigorta, Urko M.; Mei, Hailang; Momozawa, Yukihide; Müller‐Nurasyid, Martina; Nauck, Matthias; Nivard, Michel G.; Penninx, Brenda W. J. H.; Pritchard, Jonathan K.; Raitakari, Olli T.; Rötzschke, Olaf; Slagboom, P. Eline; Stehouwer, Coen D. A.; Stumvoll, M; Sullivan, Patrick F.; Hoen, Peter A C ‘t; Thiery, Joachim; Tönjes, Anke; Dongen, Jenny van; Iterson, Maarten van; Veldink, Jan H.; Völker, Uwe; Warmerdam, Robert; Wijmenga, Cisca; Swertz, Morris A.; Andiappan, Anand Kumar; Montgomery, Grant W.; Ripatti, Samuli; Perola, Markus; Kutalik, Zoltán; Dermitzakis, Emmanouil T.; Bergmann, Sven; Frayling, Timothy M.; Meurs, Joyce van; Prokisch, Holger; Ahsan, Habibul; Pierce, Brandon L.; Lehtimäki, Terho; Boomsma, Dorret I.; Psaty, Bruce M.; Gharib, Sina A.; Awadalla, Philip; Milani, Lili; Ouwehand, Willem H.; Downes, Kate; Stegle, Oliver; Battle, Alexis; Visscher, Peter M.; Yang, Jian; Scholz, Markus; Powell, Joseph E.; Gibson, Greg; Esko, Tõnu; Franke, Lude

doi:10.1038/s41588-021-00913-z

Cited by 1,025 publications

(1,062 citation statements)

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“…It has been observed in blood that genes without a detectable cis -eQTL effect are more intolerant to loss-of-function mutations 7 . This is possibly explained by more extensive buffering of regulatory effects on these important genes 54 .…”

Section: Resultsmentioning

confidence: 99%

“…To investigate if the key genes result from trans regulation originating in the GWAS loci, we assessed if there was a correlation between the key gene scores and trans -eQTL effects from the eQTLgen consortium 7 . To do so, for each gene, we summed the squared z-scores of trans -eQTL effects from the independent top hits for each GWAS.…”

Section: Resultsmentioning

confidence: 99%

“…For instance, common variants associated to PR interval, a measurement of heart function, have been found within the MYH6 gene 5 , which is known to harbour mutations in individuals with familial dilated cardiomyopathy 6 . Moreover, eQTL studies have found examples of rare disease genes that are affected by distal common variants in trans , such as the immunodeficiency gene ISG15, which is affected by multiple systemic lupus erythematosus–associated variants 7 . These results indicate that common and rare diseases can result from damage to or altered regulation of the same genes, suggesting that the same biological pathways underlie these conditions 4 .…”

Section: Introductionmentioning

confidence: 99%

“…In blood, expression quantitative trait locus (eQTL) mapping has been successful in identifying the downstream trans regulatory consequences of GWAS- associated variants (i.e. trans -eQTLs and eQTSs, where polygenic scores are linked to expression levels) 7 . Unfortunately, large eQTL sample sizes are required to detect such effects, and such datasets are not yet available for most tissues.…”

Section: Introductionmentioning

confidence: 99%

“…-displayed significant negative correlations, which suggests the unsuitability of blood trans-eQTLs for interpreting non-blood traits, likely due to low expression of the relevant genes in blood 7 .…”

mentioning

confidence: 99%

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Linking common and rare disease genetics through gene regulatory networks

Bakker

Claringbould²,

Westra

et al. 2021

Preprint

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Genetic variants identified through genome-wide association studies (GWAS) are typically non-coding and exert small regulatory effects on downstream genes, but which downstream genes are ultimately impacted and how they confer risk remains mostly unclear. Conversely, variants that cause rare Mendelian diseases are often coding and have a more direct impact on disease development. We demonstrate that common and rare genetic diseases can be linked by studying the gene regulatory networks impacted by common disease-associated variants. We implemented this in the 'Downstreamer' method and applied it to 44 GWAS traits and find that predicted downstream "key genes" are enriched with Mendelian disease genes, e.g. key genes for height are enriched for genes that cause skeletal abnormalities and Ehlers-Danlos syndromes. We find that 82% of these key genes are located outside of GWAS loci, suggesting that they result from complex trans regulation rather than being impacted by disease-associated variants in cis. Finally, we discuss the challenges in reconstructing gene regulatory networks and provide a roadmap to improve identification of these highly connected genes for common traits and diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Linking common and rare disease genetics through gene regulatory networks

Bakker

Claringbould²,

Westra

et al. 2021

Preprint

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Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease

et al. 2022

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IMPORTANCE Cholesteryl ester transfer protein inhibition (CETP) has been shown to increase levels of high-density lipoprotein cholesterol (HDL-C) and reduce levels of low-density lipoprotein cholesterol (LDL-C). Current LDL-C target attainment is low, and novel phase 3 trials are underway to investigate whether CETP inhibitors result in reduction of cardiovascular disease risk in high-risk patients who may be treated with PCSK9-inhibiting agents.OBJECTIVE To explore the associations of combined reduction of CETP and PCSK9 concentrations with risk of coronary artery disease (CAD) and other clinical and safety outcomes.DESIGN, SETTING, AND PARTICIPANTS Two-sample 2 × 2 factorial Mendelian randomization study in a general population sample that includes data for UK Biobank participants of European ancestry.EXPOSURES Separate genetic scores were constructed for CETP and PCSK9 plasma protein concentrations, which were combined to determine the associations of combined genetically reduced CETP and PCSK9 concentrations with disease.MAIN OUTCOMES AND MEASURES Blood lipid and lipoprotein concentrations, blood pressure, CAD, age-related macular degeneration, type 2 diabetes, any stroke and ischemic stroke, Alzheimer disease, vascular dementia, heart failure, atrial fibrillation, chronic kidney disease, asthma, and multiple sclerosis.RESULTS Data for 425 354 UKB participants were included; the median (IQR) age was 59 years (51-64), and 229 399 (53.9%) were female. The associations of lower CETP and lower PCSK9 concentrations with CAD are similar when scaled per 10-mg/dL reduction in LDL-C concentrations

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Major Psychiatric Disorders, Substance Use Behaviors, and Longevity

Rosoff,

Hamandi,

Bell

et al. 2024

JAMA Psychiatry

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ImportanceObservational studies suggest that major psychiatric disorders and substance use behaviors reduce longevity, making it difficult to disentangle their relationships with aging-related outcomes.ObjectiveTo evaluate the associations between the genetic liabilities for major psychiatric disorders, substance use behaviors (smoking and alcohol consumption), and longevity.Design, Settings, and ParticipantsThis 2-sample mendelian randomization (MR) study assessed associations between psychiatric disorders, substance use behaviors, and longevity using single-variable and multivariable models. Multiomics analyses were performed elucidating transcriptomic underpinnings of the MR associations and identifying potential proteomic therapeutic targets. This study sourced summary-level genome-wide association study (GWAS) data, gene expression, and proteomic data from cohorts of European ancestry. Analyses were performed from May 2022 to November 2023.ExposuresGenetic susceptibility for major depression (n = 500 199), bipolar disorder (n = 413 466), schizophrenia (n = 127 906), problematic alcohol use (n = 435 563), weekly alcohol consumption (n = 666 978), and lifetime smoking index (n = 462 690).Main Outcomes and MeasuresThe main outcome encompassed aspects of health span, lifespan, and exceptional longevity. Additional outcomes were epigenetic age acceleration (EAA) clocks.ResultsFindings from multivariable MR models simultaneously assessing psychiatric disorders and substance use behaviorsm suggest a negative association between smoking and longevity in cohorts of European ancestry (n = 709 709; 431 503 [60.8%] female; β, −0.33; 95% CI, −0.38 to −0.28; P = 4.59 × 10−34) and with increased EAA (n = 34 449; 18 017 [52.3%] female; eg, PhenoAge: β, 1.76; 95% CI, 0.72 to 2.79; P = 8.83 × 10−4). Transcriptomic imputation and colocalization identified 249 genes associated with smoking, including 36 novel genes not captured by the original smoking GWAS. Enriched pathways included chromatin remodeling and telomere assembly and maintenance. The transcriptome-wide signature of smoking was inversely associated with longevity, and estimates of individual smoking-associated genes, eg, XRCC3 and PRMT6, aligned with the smoking-longevity MR analyses, suggesting underlying transcriptomic mediators. Cis-instrument MR prioritized brain proteins associated with smoking behavior, including LY6H (β, 0.02; 95% CI, 0.01 to 0.03; P = 2.37 × 10−6) and RIT2 (β, 0.02; 95% CI, 0.01 to 0.03; P = 1.05 × 10−5), which had favorable adverse-effect profiles across 367 traits evaluated in phenome-wide MR.ConclusionsThe findings suggest that the genetic liability of smoking, but not of psychiatric disorders, is associated with longevity. Transcriptomic associations offer insights into smoking-related pathways, and identified proteomic targets may inform therapeutic development for smoking cessation strategies.

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Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Abstract: Large-scale cis-and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Cited by 1,025 publications

References 82 publications

Linking common and rare disease genetics through gene regulatory networks

Linking common and rare disease genetics through gene regulatory networks

Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease

Major Psychiatric Disorders, Substance Use Behaviors, and Longevity

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