Imperial College London

ProfessorAbbasDehghan

Faculty of MedicineSchool of Public Health

Professor in Molecular Epidemiology
 
 
 
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Contact

 

+44 (0)20 7594 3347a.dehghan CV

 
 
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Location

 

Building E - Sir Michael UrenWhite City Campus

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Summary

 

Publications

Publication Type
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403 results found

Al-Jafar R, Pinto RC, Elliott P, Tsilidis KK, Dehghan Aet al., 2024, Metabolomics of Ramadan fasting and associated risk of chronic diseases., Am J Clin Nutr

BACKGROUND: The dramatic change in lifestyle associated with Ramadan fasting raises questions about its effect on metabolism and health. Metabolites, as the end product of metabolism, are excellent candidates to be studied in this regard. OBJECTIVE: This study aims to investigate the effect of Ramadan fasting on the metabolic profile and risk of chronic diseases. METHODS: The London Ramadan study (LORANS) is an observational study in which 2 blood samples were collected from 72 participants a few days before and after the fasting month of Ramadan. We conducted metabolomic profiling using nuclear magnetic resonance spectroscopy to assess the change in individual metabolites from before to after Ramadan. Also, we generated metabolic scores (scaled from 0 to 100) for 7 chronic diseases in the UK Biobank and assessed the association of Ramadan fasting with these scores in LORANS. RESULTS: Of the 72 participants, 35 were male (48.6%); the mean (± standard deviation) age was 45.7 (±16) y. Ramadan fasting was associated with changes in 14 metabolites (1 inflammation marker, 1 amino acid, 2 glycolysis-related metabolites, 2 ketone bodies, 2 triglyceride, and 6 lipoprotein subclasses), independent of changes in body composition. Using data from 117,981 participants in the UK Biobank, we generated metabolic scores for diabetes, hypertension, coronary artery disease, renal failure, colorectal cancer, breast cancer, and lung cancer. The metabolic scores for lung cancer, colorectal cancer, and breast cancer were lower after Ramadan in LORANS (-4.74, 9.6%, 95% confidence interval -6.56, -2.91, P < 0.001), (-1.09, -2.4%, -1.69, -0. 50, P < 0.001), and (-0.48, -1.1%, -0. 81, -0.15, P = 0.006), respectively. CONCLUSIONS: Ramadan fasting is associated with short-term favorable changes in the metabolic profile concerning risk of some chronic diseases. These findings should be further investigated in future, larger studies of longer follow-up with clinical outcomes.

Journal article

Zagkos L, Dib M-J, Cronjé HT, Elliott P, Dehghan A, Tzoulaki I, Gill D, Daghlas Iet al., 2024, Cerebrospinal fluid C1-esterase inhibitor and tie-1 levels affect cognitive performance: evidence from proteome-wide mendelian randomization., Genes, Vol: 15, ISSN: 2073-4425

OBJECTIVE: The association of cerebrospinal fluid (CSF) protein levels with cognitive function in the general population remains largely unexplored. We performed Mendelian randomization (MR) analyses to query which CSF proteins may have potential causal effects on cognitive performance. METHODS AND ANALYSIS: Genetic associations with CSF proteins were obtained from a genome-wide association study conducted in up to 835 European-ancestry individuals and for cognitive performance from a meta-analysis of GWAS including 257,841 European-ancestry individuals. We performed Mendelian randomization (MR) analyses to test the effect of randomly allocated variation in 154 genetically predicted CSF protein levels on cognitive performance. Findings were validated by performing colocalization analyses and considering cognition-related phenotypes. RESULTS: Genetically predicted C1-esterase inhibitor levels in the CSF were associated with a better cognitive performance (SD units of cognitive performance per 1 log-relative fluorescence unit (RFU): 0.23, 95% confidence interval: 0.12 to 0.35, p = 7.91 × 10-5), while tyrosine-protein kinase receptor Tie-1 (sTie-1) levels were associated with a worse cognitive performance (-0.43, -0.62 to -0.23, p = 2.08 × 10-5). These findings were supported by colocalization analyses and by concordant effects on distinct cognition-related and brain-volume measures. CONCLUSIONS: Human genetics supports a role for the C1-esterase inhibitor and sTie-1 in cognitive performance.

Journal article

Wang N, Mustafa R, Zuber V, Rodgers A, Dehghan Aet al., 2023, Association between systolic blood pressure and low-density lipoprotein cholesterol with coronary heart disease according to age, PLoS One, Vol: 18, ISSN: 1932-6203

BACKGROUND: The impact of elevated systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) at different stages of life is unclear. We aimed to investigate whether genetically mediated SBP/LDL-C is associated with the risk of CHD throughout life. METHODS AND FINDINGS: We conducted a three-sample Mendelian randomization analysis using data from the UK Biobank including 136,648 participants for LDL-C, 135,431 participants for SBP, and 24,052 cases for CHD to assess the effect of duration of exposure to the risk factors on risk of CHD. Analyses were stratified by age at enrolment. In univariable analyses, there was a consistent association between exposure to higher LDL-C and SBP with increased odds of incident CHD in individuals aged ≤55 years, ≤60 years, and ≤65 years (p-value for heterogeneity = 1.00 for LDL-C and 0.67 for SBP, respectively). In multivariable Mendelian randomization analyses, exposure to elevated LDL-C/SBP early in life (age ≤55 years) was associated with a higher risk of CHD independent of later life levels (age >55 years) (odds ratio 1.68, 95% CI 1.20-2.34 per 1 mmol/L LDL-C, and odds ratio 1.33, 95% CI 1.18-1.51 per 10 mmHg SBP). CONCLUSIONS: Genetically predicted SBP and LDL-C increase the risk of CHD independent of age. Elevated SBP and LDL-C in early to middle life is associated with increased CHD risk independent of later-life SBP and LDL-C levels. These findings support the importance of lifelong risk factor control in young individuals, whose risk of CHD accumulates throughout life.

Journal article

Gallego-Fabrega C, Temprano-Sagrera G, Cárcel-Márquez J, Muiño E, Cullell N, Lledós M, Llucià-Carol L, Martin-Campos JM, Sobrino T, Castillo J, Millán M, Muñoz-Narbona L, López-Cancio E, Ribó M, Alvarez-Sabin J, Jiménez-Conde J, Roquer J, Tur S, Obach V, Arenillas JF, Segura T, Serrano-Heras G, Marti-Fabregas J, Freijo-Guerrero M, Moniche F, Castellanos MDM, Morrison AC, Smith NL, de Vries PS, Fernández-Cadenas I, Sabater-Lleal M, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, Spanish Stroke Genetic Consortiumet al., 2023, A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment, Journal of Thrombosis and Haemostasis, ISSN: 1538-7836

BACKGROUND: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis. OBJECTIVES: To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment. METHODS: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. RESULTS: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10-11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10-10; rs1421067 (CHD9), P = 1.81 × 10-14; and rs34780449, near ROBO1 gene, P = 1.64 × 10-8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10-14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05). CONCLUSION: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Fur

Journal article

Mustafa R, Ghanbari M, Karhunen V, Evangelou M, Dehghan Aet al., 2023, Phenome-wide association study on miRNA-related sequence variants: the UK Biobank, Human Genomics, Vol: 17, ISSN: 1479-7364

Background:Genetic variants in the coding region could directly affect the structure and expression levels of genes and proteins. However, the importance of variants in the non-coding region, such as microRNAs (miRNAs), remain to be elucidated. Genetic variants in miRNA-related sequences could affect their biogenesis or functionality and ultimately affect disease risk. Yet, their implications and pleiotropic effects on many clinical conditions remain unknown.Methods:Here, we utilised genotyping and hospital records data in the UK Biobank (N = 423,419) to investigate associations between 346 genetic variants in miRNA-related sequences and a wide range of clinical diagnoses through phenome-wide association studies. Further, we tested whether changes in blood miRNA expression levels could affect disease risk through colocalisation and Mendelian randomisation analysis.Results:We identified 122 associations for six variants in the seed region of miRNAs, nine variants in the mature region of miRNAs, and 27 variants in the precursor miRNAs. These included associations with hypertension, dyslipidaemia, immune-related disorders, and others. Nineteen miRNAs were associated with multiple diagnoses, with six of them associated with multiple disease categories. The strongest association was reported between rs4285314 in the precursor of miR-3135b and celiac disease risk (odds ratio (OR) per effect allele increase = 0.37, P = 1.8 × 10–162). Colocalisation and Mendelian randomisation analysis highlighted potential causal role of miR-6891-3p in dyslipidaemia.Conclusions:Our study demonstrates the pleiotropic effect of miRNAs and offers insights to their possible clinical importance.

Journal article

O'Farrell F, Aleyakpo B, Mustafa R, Jiang X, Pinto RC, Elliott P, Tzoulaki I, Dehghan A, Loh SHY, Barclay JW, Martins LM, Pazoki Ret al., 2023, Evidence for involvement of the alcohol consumption WDPCP gene in lipid metabolism, and liver cirrhosis, Scientific Reports, Vol: 13, ISSN: 2045-2322

Biological pathways between alcohol consumption and alcohol liver disease (ALD) are not fully understood. We selected genes with known effect on (1) alcohol consumption, (2) liver function, and (3) gene expression. Expression of the orthologs of these genes in Caenorhabditis elegans and Drosophila melanogaster was suppressed using mutations and/or RNA interference (RNAi). In humans, association analysis, pathway analysis, and Mendelian randomization analysis were performed to identify metabolic changes due to alcohol consumption. In C. elegans, we found a reduction in locomotion rate after exposure to ethanol for RNAi knockdown of ACTR1B and MAPT. In Drosophila, we observed (1) a change in sedative effect of ethanol for RNAi knockdown of WDPCP, TENM2, GPN1, ARPC1B, and SCN8A, (2) a reduction in ethanol consumption for RNAi knockdown of TENM2, (3) a reduction in triradylglycerols (TAG) levels for RNAi knockdown of WDPCP, TENM2, and GPN1. In human, we observed (1) a link between alcohol consumption and several metabolites including TAG, (2) an enrichment of the candidate (alcohol-associated) metabolites within the linoleic acid (LNA) and alpha-linolenic acid (ALA) metabolism pathways, (3) a causal link between gene expression of WDPCP to liver fibrosis and liver cirrhosis. Our results imply that WDPCP might be involved in ALD.

Journal article

Li JH, Brenner LN, Kaur V, Figueroa K, Schroeder P, Huerta-Chagoya A, MAGIC Investigators, Diabetes Prevention Program DPP Research Group, Udler MS, Leong A, Mercader JM, Florez JCet al., 2023, Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH., Diabetologia, Vol: 66, Pages: 1260-1272

AIMS/HYPOTHESIS: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes. METHODS: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals. RESULTS: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAFAfr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10-9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAFAfr=0.0536), was associated with a reduced response to metformin (p=2.4×10-8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increa

Journal article

Huffman JE, Nicolas J, Hahn J, Heath AS, Raffield LM, Yanek LR, Brody JA, Thibord F, Almasy L, Bartz TM, Bielak LF, Bowler RP, Carrasquilla GD, Chasman DI, Chen M-H, Emmert DB, Ghanbari M, Haessle J, Hottenga J-J, Kleber ME, Le N-Q, Lee J, Lewis JP, Li-Gao R, Luan J, Malmberg A, Mangino M, Marioni RE, Martinez-Perez A, Pankratz N, Polasek O, Richmond A, Rodriguez BA, Rotter JI, Steri M, Suchon P, Trompet S, Weiss S, Zare M, Auer P, Cho MH, Christofidou P, Davies G, de Geus E, Deleuze J-F, Delgado GE, Ekunwe L, Faraday N, Gögele M, Greinacher A, He G, Howard T, Joshi PK, Kilpeläinen TO, Lahti J, Linneberg A, Naitza S, Noordam R, Paüls-Vergés F, Rich SS, Rosendaal FR, Rudan I, Ryan KA, Souto JC, van Rooij FJ, Wang H, Zhao W, Becker LC, Beswick A, Brown MR, Cade BE, Campbell H, Cho K, Crapo JD, Curran JE, de Maat MP, Doyle M, Elliott P, Floyd JS, Fuchsberger C, Grarup N, Guo X, Harris SE, Hou L, Kolcic I, Kooperberg C, Menni C, Nauck M, O'Connell JR, Orrù V, Psaty BM, Räikkönen K, Smith JA, Soria JM, Stott DJ, van Hylckama Vlieg A, Watkins H, Willemsen G, Wilson P, Ben-Shlomo Y, Blangero J, Boomsma D, Cox SR, Dehghan A, Eriksson JG, Fiorillo E, Fornage M, Hansen T, Hayward C, Ikram MA, Jukema JW, Kardia SL, Lange LA, März W, Mathias RA, Mitchell BD, Mook-Kanamori DO, Morange P-E, Pedersen O, Pramstaller PP, Redline S, Reiner A, Ridker PM, Silverman EK, Spector TD, Völker U, Wareham N, Wilson JF, Yao J, VA Million Veteran Program, NHLBI Trans-Omics for Precision Medicine TOPMed Consortium, Trégouët D-A, Johnson AD, Wolberg AS, de Vries PS, Sabater-Lleal M, Morrison AC, Smith NLet al., 2023, Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles., medRxiv

UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( SERPINA1, ZFP36L2 , and TLR10) signals contain predicted deleterious missense variants. Two loci, SOCS3 and HPN , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( FGG;FGB;FGA ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation. KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Suff

Journal article

Hahn J, Bressler J, Domingo-Relloso A, Chen M-H, McCartney DL, Teumer A, van Dongen J, Kleber ME, Aissi D, Swenson BR, Yao J, Zhao W, Huang J, Xia Y, Brown MR, Costeira R, de Geus EJC, Delgado GE, Dobson DA, Elliott P, Grabe HJ, Guo X, Harris SE, Huffman JE, Kardia SLR, Liu Y, Lorkowski S, Marioni RE, Nauck M, Ratliff SM, Sabater-Lleal M, Spector TD, Suchon P, Taylor KD, Thibord F, Tregouet D-A, Wiggins KL, Willemsen G, Bell JT, Boomsma DI, Cole SA, Cox SR, Dehghan A, Greinacher A, Haack K, Marz W, Morange P-E, Rotter JI, Sotoodehnia N, Tellez-Plaza M, Navas-Acien A, Smith JA, Johnson AD, Fornage M, Smith NL, Wolberg AS, Morrison AC, de Vries PSet al., 2023, DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 21, Pages: 1135-1147, ISSN: 1538-7933

Journal article

Nazarzadeh M, Bidel Z, Mohseni H, Canoy D, Pinho-Gomes A-C, Hassaine A, Dehghan A, Tregouet D-A, Smith NL, Rahimi Ket al., 2023, Blood pressure and risk of venous thromboembolism: a cohort analysis of 5.5 million UK adults and Mendelian randomization studies, Cardiovascular Research, Vol: 119, Pages: 835-842, ISSN: 0008-6363

AimsEvidence for the effect of elevated blood pressure (BP) on the risk of venous thromboembolism (VTE) has been conflicting. We sought to assess the association between systolic BP and the risk of VTE.Methods and resultsThree complementary studies comprising an observational cohort analysis, a one-sample and two-sample Mendelian randomization were conducted using data from 5 588 280 patients registered in the Clinical Practice Research Datalink (CPRD) dataset and 432 173 UK Biobank participants with valid genetic data. Summary statistics of International Network on Venous Thrombosis genome-wide association meta-analysis was used for two-sample Mendelian randomization. The primary outcome was the first occurrence of VTE event, identified from hospital discharge reports, death registers, and/or primary care records. In the CPRD cohort, 104 017(1.9%) patients had a first diagnosis of VTE during the 9.6-year follow-up. Each 20 mmHg increase in systolic BP was associated with a 7% lower risk of VTE [hazard ratio: 0.93, 95% confidence interval (CI): (0.92–0.94)]. Statistically significant interactions were found for sex and body mass index, but not for age and subtype of VTE (pulmonary embolism and deep venous thrombosis). Mendelian randomization studies provided strong evidence for the association between systolic BP and VTE, both in the one-sample [odds ratio (OR): 0.69, (95% CI: 0.57–0.83)] and two-sample analyses [OR: 0.80, 95% CI: (0.70–0.92)].ConclusionWe found an increased risk of VTE with lower BP, and this association was independently confirmed in two Mendelian randomization analyses. The benefits of BP reduction are likely to outweigh the harms in most patient groups, but in people with predisposing factors for VTE, further BP reduction should be made cautiously.

Journal article

Dehghan A, Huang J, Hesbani N, Romuald P, Zare M, Franceschini N, de Vries P, Tzoulaki I, Meena Det al., 2023, Genome Wide Association Study and Multi-Ancestry MetaAnalysis Identify Common Variants Associated With Carotid Artery Intima Media Thickness, CIRCULATION, Vol: 147, ISSN: 0009-7322

Journal article

Dib M-J, Zagkos L, Elliott P, Dehghan A, Tzoulaki Iet al., 2023, Associations of Genetically Determined Favourable and Unfavourable Adiposity Across the Phenome, American Heart Association's Epidemiology and Prevention/Lifestyle and Cardiometabolic Health Scientific Sessions, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Meena D, Huang J, Dehghan A, Tzoulaki Iet al., 2023, Age at Menarche, Adulthood Body Mass Index and Risk of Subclinical Atherosclerosis: A Mendelian Randomization Study, American Heart Association's Epidemiology and Prevention/Lifestyle and Cardiometabolic Health Scientific Sessions, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Dib M-J, Meena D, Zagkos L, Dipender G, Elliott P, Dehghan A, Tzoulaki Iet al., 2023, Sex-Specific Genetic Interrogation of Cardiovascular Disease Drug Targets, American Heart Association's Epidemiology and Prevention/Lifestyle and Cardiometabolic Health Scientific Sessions, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Huang J, Gill D, Zuber V, Matthews PAUL, Elliott PAUL, Tzoulaki I, Dehghan ABBASet al., 2023, Circulatory proteins relate cardiovascular disease to cognitive performance: a Mendelian randomisation study, Frontiers in Genetics, Vol: 14, Pages: 1-11, ISSN: 1664-8021

Background and objectives: Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment.Methods: We applied Mendelian randomisation (MR) and colocalization analysis to investigate the causal relationships of 90 CVD-related proteins measured by the Olink CVD I panel with cognitive traits. Genetic instruments for circulatory protein concentrations were obtained using a meta-analysis of genome-wide association studies (GWAS) from the SCALLOP consortium (N = 17,747) based on three sets of criteria: 1) protein quantitative trait loci (pQTL); 2) cis-pQTL (pQTL within ±500 kb from the coding gene); and 3) brain-specific cis-expression QTL (cis-eQTL) which accounts for coding gene expression based on GTEx8. Genetic associations of cognitive performance were obtained from GWAS for either: 1) general cognitive function constructed using Principal Component Analysis (N = 300,486); or, 2) g Factor constructed using genomic structural equation modelling (N = 11,263–331,679). Findings for candidate causal proteins were replicated using a separate protein GWAS in Icelanders (N = 35,559).Results: A higher concentration of genetically predicted circulatory myeloperoxidase (MPO) was nominally associated with better cognitive performance (p < 0.05) using different selection criteria for genetic instruments. Particularly, brain-specific cis-eQTL predicted MPO, which accounts for protein-coding gene expression in brain tissues, was associated with general cognitive function (βWald = 0.22, PWald = 2.4 × 10−4). The posterior probability for colocalization (PP.H4) of MPO pQTL with the g Factor was 0.577. Findings for MPO were replicated using the Icelandic GWAS. Although we did not find evidence for colocalization, we found that higher gene

Journal article

Kojouri M, Pinto R, Mustafa R, Huang J, He G, Elliott P, Tzoulaki I, Dehghan Aet al., 2023, Metabolome-wide association study on physical activity, Scientific Reports, Vol: 13, Pages: 1-9, ISSN: 2045-2322

The underlying mechanisms linking physical activity to better health are not fully understood. Here we examined the associations between physical activity and small circulatory molecules, the metabolome, to highlight relevant biological pathways. We examined plasma metabolites associated with self-reported physical activity among 2217 participants from the Airwave Health Monitoring Study. Metabolic profiling was conducted using the mass spectrometry-based Metabolon platform (LC/GC–MS), measuring 828 known metabolites. We replicated our findings in an independent subset of the study (n = 2971) using untargeted LC–MS. Mendelian randomisation was carried out to investigate potential causal associations between physical activity, body mass index, and metabolites. Higher vigorous physical activity was associated (P < 0.05/828 = 6.03 × 10–5) with circulatory levels of 28 metabolites adjusted for age, sex and body mass index. The association was inverse for glutamate and diacylglycerol lipids, and direct for 3–4-hydroxyphenyllactate, phenyl lactate (PLA), alpha-hydroxy isovalerate, tiglylcarnitine, alpha-hydroxyisocaproate, 2-hydroxy-3-methylvalerate, isobutyrylcarnitine, imidazole lactate, methionine sulfone, indole lactate, plasmalogen lipids, pristanate and fumarate. In the replication panel, we found 23 untargeted LC–MS features annotated to the identified metabolites, for which we found nominal associations with the same direction of effect for three features annotated to 1-(1-enyl-palmitoyl)-2-oleoyl-GPC (P-16:0/18:1), 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2), 1-stearoyl-2-dihomo-linolenoyl-GPC (18:0/20:3n3 or 6). Using Mendelian randomisation, we showed a potential causal relationship between body mass index and three identified metabolites. Circulatory metabolites are associated with physical activity and may play a role in mediating its health effects.

Journal article

Huang J, Su B, Karhunen V, Gill D, Zuber V, Ahola-Olli A, Palaniswamy S, Auvinen J, Herzig K-H, Keinänen-Kiukaanniemi S, Salmi M, Jalkanen S, Lehtimäki T, Salomaa V, Raitakari OT, Matthews PM, Elliott P, Tsilidis KK, Jarvelin M-R, Tzoulaki I, Dehghan Aet al., 2023, Inflammatory diseases, inflammatory biomarkers, and Alzheimer disease: an observational analysis and mendelian randomization, Neurology, Vol: 100, Pages: e568-e581, ISSN: 0028-3878

OBJECTIVES: Whether chronic autoimmune inflammatory diseases causally affect the risk of AD is controversial. We characterised the relationship between inflammatory diseases and the risk of AD and explore the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD. METHODS: We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large scale genome-wide association study (GWAS) datasets, we performed two-sample Mendelian randomisation (MR) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD. RESULTS: Cox regression models using CPRD data showed that overall incidence of AD was higher among patients with inflammatory bowel disease (IBD) (hazard ratio (HR)=1.17; 95%CI 1.15 to 1.19; P-value=2.1×10-4), other inflammatory polyarthropathies & systematic connective tissue disorders (OID) (HR=1.13; 95%CI 1.12 to 1.14; P-value=8.6×10-5), psoriasis (HR=1.13; 95%CI 1.10 to 1.16; P-value=2.6×10-4), rheumatoid arthritis (RA) (HR=1.08; 95%CI 1.06 to 1.11; P-value=4.0×10-4), and multiple sclerosis (MS) (HR=1.06; 95%CI 1.04 to 1.07; P-value=2.8×10-4) compared to the age (± 5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted (ORIVW)=1.23; 95%CI 1.06 to 1.42; PIVW=0.007), and lower risk of Crohn's disease (ORIVW=0.73; 95%CI -0.62, 0.86; PIVW=1.3×10

Journal article

Al-Jafar R, Wahyuni NS, Belhaj K, Ersi MH, Boroghani Z, Alreshidi A, Alkhalaf Z, Elliott P, Tsilidis KK, Dehghan A, Al Jafar Ret al., 2023, The impact of Ramadan fasting on anthropometric measurements and body composition: evidence from London Ramadan Study and a meta-analysis, Frontiers in Nutrition, Vol: 10, Pages: 1-24, ISSN: 2296-861X

Background: Although the effect of Ramadan intermittent fasting (RIF) on anthropometry and body composition has been questioned, none of the previous studies tried to explain the reported changes in these parameters. Also, systematic reviews that investigated the topic were limited to healthy individuals or a specific disease group.Methods: The London Ramadan Study (LORANS) is an observational study on health effects of RIF. We measured weight, waist circumference (WC), hip circumference (HC), body mass index (BMI), waist-to-hip ratio (WHR), basal metabolic rate (BMR), fat percentage (FP), free-fat mass (FFM), extremities predicted muscle mass, total body water (TBW), trunk FM, trunk FFM and trunk predicted muscle mass before and immediately after Ramadan. Using mixed-effects regression models, we investigated the effect of RIF with adjustment for potential confounders. We also conducted a meta-analysis of the results of LORANS with other studies that investigated the effect of RIF on anthropometry and body composition. The review protocol is registered with PROSPERO registry (CRD42020186532).Results: We recruited 146 participants (Mean ± SD age = 43.3 ± 15 years). Immediately after Ramadan, compared with before Ramadan, the mean difference was−1.6 kg (P<0.01) in weight,−1.95cm (P<0.01) in WC,−2.86cm (P <0.01) in HC, −0.60 kg/m2 (P < 0.01) in BMI and −1.24 kg (P < 0.01) in FM. In the systematic review and meta-analysis, after screening 2,150 titles and abstracts, 66 studies comprising 7,611 participants were included. In the general population, RIF was followed by a reduction of 1.12 Kg in body weight (−1.89– −0.36, I2 = 0), 0.74 kg/m2 reduction in BMI (−0.96– −0.53, I2 = 0), 1.54cm reduction in WC (−2.37– −0.71, I2 = 0) and 1.76cm reduction in HC (−2.69– −0.83, I2 = 0). The effect of fasting on anthropometric and body composition parame

Journal article

Garcia-Segura ME, Durainayagam BR, Liggi S, Graça G, Jimenez B, Dehghan A, Tzoulaki I, Karaman I, Elliott P, Griffin JLet al., 2023, Pathway-based integration of multi-omics data reveals lipidomics alterations validated in an Alzheimer´s Disease mouse model and risk loci carriers, Journal of Neurochemistry, Vol: 164, Pages: 57-76, ISSN: 0022-3042

Alzheimer´s Disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of the importance of metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these datasets using gene ontology, transcription factor, pathway, and cell-type enrichment analyses. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic dataset derived from cortical tissue of ABCA-7 null mice, a mouse model of one of the genes associated with late onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and genes associated with AD risk. We found 203 DE transcripts, 164 DE proteins and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetics metabolic pathways were significantly over-represented across the AD multi-omics datasets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modelled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms (SNP)-metabolite associations, of which 70% corresponded to lipid classes. These results support the importance of lipid metabolism dysregulation in AD and highlight the suitability of mapping AD multi-omics data into GSMNs to identify metabol

Journal article

Zagkos L, Dib M-J, Pinto R, Gill D, Koskeridis F, Drenos F, Markozannes G, Elliott P, Zuber V, Tsilidis K, Dehghan A, Tzoulaki Iet al., 2022, Associations of genetically predicted fatty acid levels across the phenome: a mendelian randomisation study, PLoS Medicine, Vol: 19, ISSN: 1549-1277

BACKGROUND: Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes. METHODS AND FINDINGS: The UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.

Journal article

Lumbers RT, Shah S, Lin H, Czuba T, Henry A, Swerdlow DI, Malarstig A, Andersson C, Verweij N, Holmes MV, Arnlov J, Svensson P, Hemingway H, Sallah N, Almgren P, Aragam KG, Asselin G, Backman JD, Biggs ML, Bloom HL, Boersma E, Brandimarto J, Brown MR, Brunner-La Rocca H-P, Carey DJ, Chaffin MD, Chasman DI, Chazara O, Chen X, Chen X, Chung JH, Chutkow W, Cleland JGF, Cook JP, de Denus S, Dehghan A, Delgado GE, Denaxas S, Doney AS, Doerr M, Dudley SC, Engstrom G, Esko T, Fatemifar G, Felix SB, Finan C, Ford I, Fougerousse F, Fouodjio R, Ghanbari M, Ghasemi S, Giedraitis V, Giulianini F, Gottdiener JS, Gross S, Guobjartsson DF, Gui H, Gutmann R, Haggerty CM, van der Harst P, Hedman AK, Helgadottir A, Hillege H, Hyde CL, Jacob J, Jukema JW, Kamanu F, Kardys I, Kavousi M, Khaw K-T, Kleber ME, Kober L, Koekemoer A, Kraus B, Kuchenbaecker K, Langenberg C, Lind L, Lindgren CM, London B, Lotta LA, Lovering RC, Luan J, Magnusson P, Mahajan A, Mann D, Margulies KB, Marston NA, Maerz W, McMurray JJV, Melander O, Melloni G, Mordi IR, Morley MP, Morris AD, Morris AP, Morrison AC, Nagle MW, Nelson CP, Newton-Cheh C, Niessner A, Niiranen T, Nowak C, O'Donoghue ML, Owens AT, Palmer CNA, Pare G, Perola M, Perreault L-PL, Portilla-Fernandez E, Psaty BM, Rice KM, Ridker PM, Romaine SPR, Roselli C, Rotter JI, Ruff CT, Sabatine MS, Salo P, Salomaa V, van Setten J, Shalaby AA, Smelser DT, Smith NL, Stefansson K, Stender S, Stott DJ, Sveinbjornsson G, Tammesoo M-L, Tardif J-C, Taylor KD, Teder-Laving M, Teumer A, Thorgeirsson G, Thorsteinsdottir U, Torp-Pedersen C, Trompet S, Tuckwell D, Tyl B, Uitterlinden AG, Vaura F, Veluchamy A, Visscher PM, Voelker U, Voors AA, Wang X, Wareham NJ, Weeke PE, Weiss R, White HD, Wiggins KL, Xing H, Yang J, Yang Y, Yerges-Armstrong LM, Yu B, Zannad F, Zhao F, Wilk JB, Holm H, Sattar N, Lubitz SA, Lanfear DE, Shah S, Dunn ME, Wells QS, Asselbergs FW, Hingorani AD, Dube M-P, Samani NJ, Lang CC, Cappola TP, Ellinor PT, Vasan RS, Smith JGet al., 2022, The genomics of heart failure: design and rationale of the HERMES consortium, ESC HEART FAILURE, Vol: 8, Pages: 5531-5541, ISSN: 2055-5822

Journal article

Dib M-J, Ahmadi KR, Zagkos L, Gill D, Morris B, Elliott P, Dehghan A, Tzoulaki Iet al., 2022, Associations of genetically predicted vitamin B12 status across the pohenome, Nutrients, Vol: 14, ISSN: 2072-6643

Variation in vitamin B12 levels has been associated with a range of diseases across the life-course, the causal nature of which remains elusive. We aimed to interrogate genetically predicted vitamin B12 status in relation to a plethora of clinical outcomes available in the UK Biobank. Genome-wide association study (GWAS) summary data obtained from a Danish and Icelandic cohort of 45,576 individuals were used to identify 8 genetic variants associated with vitamin B12 levels, serving as genetic instruments for vitamin B12 status in subsequent analyses. We conducted a Mendelian randomisation (MR)-phenome-wide association study (PheWAS) of vitamin B12 status with 945 distinct phenotypes in 439,738 individuals from the UK Biobank using these 8 genetic instruments to proxy alterations in vitamin B12 status. We used external GWAS summary statistics for replication of significant findings. Correction for multiple testing was taken into consideration using a 5% false discovery rate (FDR) threshold. MR analysis identified an association between higher genetically predicted vitamin B12 status and lower risk of vitamin B deficiency (including all B vitamin deficiencies), serving as a positive control outcome. We further identified associations between higher genetically predicted vitamin B12 status and a reduced risk of megaloblastic anaemia (OR = 0.35, 95% CI: 0.20–0.50) and pernicious anaemia (0.29, 0.19–0.45), which was supported in replication analyses. Our study highlights that higher genetically predicted vitamin B12 status is potentially protective of risk of vitamin B12 deficiency associated with pernicious anaemia diagnosis, and reduces risk of megaloblastic anaemia. The potential use of genetically predicted vitamin B12 status in disease diagnosis, progression and management remains to be investigated.

Journal article

Koskeridis F, Evangelou E, Said S, Boyle J, Elliott P, Dehghan A, Tzoulaki Iet al., 2022, Pleiotropic genetic architecture and novel loci for C-reactive protein levels, Nature Communications, Vol: 13, ISSN: 2041-1723

C-reactive protein is involved in a plethora of pathophysiological conditions. Many genetic loci associated with C-reactive protein are annotated to lipid and glucose metabolism genes supporting common biological pathways between inflammation and metabolic traits. To identify novel pleiotropic loci, we perform multi-trait analysis of genome-wide association studies on C-reactive protein levels along with cardiometabolic traits, followed by a series of in silico analyses including colocalization, phenome-wide association studies and Mendelian randomization. We find 41 novel loci and 19 gene sets associated with C-reactive protein with various pleiotropic effects. Additionally, 41 variants colocalize between C-reactive protein and cardiometabolic risk factors and 12 of them display unexpected discordant effects between the shared traits which are translated into discordant associations with clinical outcomes in subsequent phenome-wide association studies. Our findings provide insights into shared mechanisms underlying inflammation and lipid metabolism, representing potential preventive and therapeutic targets.

Journal article

Ghanbari M, Mustafa R, Mens M, Hilten AV, Huang J, Roshchupkin G, Huan T, Broer L, Elliott P, Levy D, Ikram MA, Evangelou M, Dehghan Aet al., 2022, An atlas of genetic regulation and disease associations of microRNAs

<jats:title>Abstract</jats:title> <jats:p>MicroRNAs (miRNAs) are small non<jats:italic>-</jats:italic>coding RNAs that post-transcriptionally regulate gene expression. Identification of genetic variants influencing the transcription of miRNAs can provide an understanding of their genetic regulation and implication in human disease. Here we present genome-wide association studies of 2,083 plasma circulating miRNAs measured by next-generation sequencing in 2,178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We report 4,310 cis- and trans-miR-eQTLs for 64 miRNAs that have been replicated across independent studies. Many of these miR-eQTLs overlap with gene expression, protein, and metabolite-QTLs and with disease-associated variants. The consequences of perturbation in miRNA transcription on a wide range of clinical conditions are systematically investigated in phenome-wide association studies, with their causality tested using Mendelian randomization. Integration of genomics and miRNAs enables interrogation of the genetic architecture of miRNAs, revealing their clinical importance, and providing valuable resources for future studies of miRNAs in human disease.</jats:p>

Journal article

Mustafa R, Mens MMJ, van Hilten A, Huang J, Roshchupkin G, Huan T, Broer L, Elliott P, Levy D, Ikram MA, Evangelou M, Dehghan A, Ghanbari Met al., 2022, An atlas of genetic regulation and disease associations of microRNAs

<jats:title>Abstract</jats:title><jats:p>MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Identification of genetic variants influencing the transcription of miRNAs can provide an understanding of their genetic regulation and implication in human disease. Here we present genome-wide association studies of 2,083 plasma circulating miRNAs measured by next-generation sequencing in 2,178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We report 4,310 cis- and trans-miR-eQTLs for 64 miRNAs that have been replicated across independent studies. Many of these miR-eQTLs overlap with gene expression, protein, and metabolite-QTLs and with disease-associated variants. The consequences of perturbation in miRNA transcription on a wide range of clinical conditions are systematically investigated in phenome-wide association studies, with their causality tested using Mendelian randomization. Integration of genomics and miRNAs enables interrogation of the genetic architecture of miRNAs, revealing their clinical importance, and providing valuable resources for future studies of miRNAs in human disease.</jats:p>

Journal article

Dehghan A, Pinto RC, Karaman I, Huang J, Durainayagam BR, Ghanbari M, Nazeer A, Zhong Q, Liggi S, Whiley L, Mustafa R, Kivipelto M, Solomon A, Ngandu T, Kanekiyo T, Aikawa T, Radulescu CI, Barnes SJ, Graça G, Chekmeneva E, Camuzeaux S, Lewis MR, Kaluarachchi MR, Ikram MA, Holmes E, Tzoulaki I, Matthews PM, Griffin JL, Elliott Pet al., 2022, Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease., Proceedings of the National Academy of Sciences of USA, Vol: 119, Pages: 1-12, ISSN: 0027-8424

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049-1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.

Journal article

Portilla-Fernandez E, Klarin D, Hwang S-J, Biggs ML, Bis JC, Weiss S, Rospleszcz S, Natarajan P, Hoffmann U, Rogers IS, Truong QA, Völker U, Dörr M, Bülow R, Criqui MH, Allison M, Ganesh SK, Yao J, Waldenberger M, Bamberg F, Rice KM, Essers J, Kapteijn DMC, van der Laan SW, de Knegt RJ, Ghanbari M, Felix JF, Ikram MA, Kavousi M, Uitterlinden AG, Roks AJM, Danser AHJ, Tsao PS, Damrauer SM, Guo X, Rotter JI, Psaty BM, Kathiresan S, Völzke H, Peters A, Johnson C, Strauch K, Meitinger T, O'Donnell CJ, Dehghan A, VA Million Veteran Programet al., 2022, Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study, Human Molecular Genetics, Vol: 31, Pages: 3566-3579, ISSN: 0964-6906

Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of Abdominal Aortic Aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in ten cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects (PBIO) as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In GWAS on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, p-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (p-value = 8.19 × 10-4). In exome-array single-variant analysis (p-value threshold = 9 × 10-7), the lowest p-value was found for rs239259 located in SLC22A20 (beta = 0.007, p-value =1.2 × 10-5). In the gene-based analysis (p-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (p-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, p-value = 0.02), triglycerides (beta = -0.16, p-value = 0.008) and height (beta = 0.03, p-value<0.0001), known risk factors for AAA, consistent with a

Journal article

Yarmolinsky J, Robinson J, Tsilidis KK, Dehghan A, Johansson M, Mariosa D, Gunter MJ, Kiemeney LA, Smith GD, Martin RMet al., 2022, Using Human Genetics to Evaluate the Causal Role of Circulating Inflammatory Markers in Risk of Adult Cancer, Publisher: WILEY, Pages: 547-547, ISSN: 0741-0395

Conference paper

Pankratz N, Wei P, Brody JA, Chen M-H, Vries PS, Huffman JE, Stimson MR, Auer PL, Boerwinkle E, Cushman M, Maat MPM, Folsom AR, Franco OH, Gibbs RA, Haagenson KK, Hofman A, Johnsen JM, Kovar CL, Kraaij R, McKnight B, Metcalf GA, Muzny D, Psaty BM, Tang W, Uitterlinden AG, Rooij JGJ, Dehghan A, O'Donnell CJ, Reiner AP, Morrison AC, Smith NLet al., 2022, Whole-exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors, HUMAN MOLECULAR GENETICS, Vol: 31, Pages: 3120-3132, ISSN: 0964-6906

Journal article

Nazarzadeh M, Bidel Z, Canoy D, Copland E, Bennett DA, Dehghan A, Davey Smith G, Holman RR, Woodward M, Gupta A, Adler AI, Wamil M, Sattar N, Cushman WC, McManus RJ, Teo K, Davis BR, Chalmers J, Pepine CJ, Rahimi K, Blood Pressure Lowering Treatment Trialists' Collaborationet al., 2022, Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: an individual participant-level data meta-analysis, The Lancet Diabetes and Endocrinology, Vol: 10, Pages: 645-654, ISSN: 2213-8595

BACKGROUND: Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure. METHODS: We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg). To estimate absolute risk reductions, we used a Poisson regression model over the follow-up duration. The effect of each of the five major blood pressure-lowering drug classes, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, calcium channel blockers, and th

Journal article

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