Genetic analysis of over half a million people characterises C-reactive protein loci

Chronic low-grade inflammation is linked to a multitude of chronic diseases. We report the largest genome-wide association study (GWAS) on C-reactive protein (CRP), a marker of systemic inflammation, in UK Biobank participants (N = 427,367, European descent) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (total N = 575,531 European descent). We identify 266 independent loci, of which 211 are not previously reported. Gene-set analysis highlighted 42 gene sets associated with CRP levels (p ≤ 3.2 ×10−6) and tissue expression analysis indicated a strong association of CRP related genes with liver and whole blood gene expression. Phenome-wide association study identified 27 clinical outcomes associated with genetically determined CRP and subsequent Mendelian randomisation analyses supported a causal association with schizophrenia, chronic airway obstruction and prostate cancer. Our findings identified genetic loci and functional properties of chronic low-grade inflammation and provided evidence for causal associations with a range of diseases

Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases. Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease

Multi-omics approach to explore the effects of chronic low-grade inflammation marked by c-reactive protein

Chronic low-grade inflammation is linked to a multitude of chronic diseases and conditions. However, chronic low-grade inflammation has not been fully characterised, as there remains conflicting and inconclusive evidence from epidemiological studies. My thesis aimed to explore chronic inflammation using a multi-omic approach. Data from the UK Biobank and Airwave cohort was used. Within this thesis I report genome-wide association on C-reactive protein (CRP), a marker of systemic inflammation, in UK Biobank participants (N = 427,367) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (total N= 575,531). I identify 266 independent loci, of which 211 were not previously reported. Gene-set analysis highlighted 42 gene sets associated with CRP levels (p ≤ 3.2 x 10-6) and tissue expression analysis indicated a strong association of CRP related genes to the liver and whole blood gene expression. Phenome-wide association identified 27 clinical outcomes associated with genetically determined CRP, including five phenotypes of the respiratory system, nine of the circulatory system, three musculoskeletal, three sense organs, one mental disorder, five endocrine/metabolic, and lastly one genitourinary. Mendelian randomisation analyses of chronic diseases supported a causal association with several outcomes, such as schizophrenia (beta (β) = -0.074, 95%, p = 7.83 x 10-6), chronic airway obstruction (β=0.330, p=7.94 x 10-4) and breast cancer (β = 0.044, p = 2.02 x 10-5). Metabolome-wide causal association MR analyses tested CRP associated genetic variants with 123 NMR platform measured metabolites and identified five with convincing evidence, including citrate (β=-0.13, p=1.6 x 10-5) and phenylalanine (β=0.13, p=1.3 x 10-5). In combination these results provides insight into the genomic, phenotypic, metabolomic profile, and functional properties of CRP proxied systemic chronic low-grade inflammation. Results provide novel findings, which can be investigated further to understand the underlying molecular pathways of disease afflicted by systemic chronic low-grade inflammation. As CRP proxied chronic inflammation is modifiable, this may be of interest for therapeutic intervention.Open Acces

Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease

Causal association between snoring and stroke: a Mendelian randomization study in a Chinese populationResearch in context

Summary: Background: Previous observational studies established a positive relationship between snoring and stroke. We aimed to investigate the causal effect of snoring on stroke. Methods: Based on 82,339 unrelated individuals with qualified genotyping data of Asian descent from the China Kadoorie Biobank (CKB), we conducted a Mendelian randomization (MR) analysis of snoring and stroke. Genetic variants identified in the genome-wide association analysis (GWAS) of snoring in CKB and UK Biobank (UKB) were selected for constructing genetic risk scores (GRS). A two-stage method was applied to estimate the associations of the genetically predicted snoring with stroke and its subtypes. Besides, MR analysis among the non-obese group (body mass index, BMI <24.0 kg/m2), as well as multivariable MR (MVMR), were performed to control for potential pleiotropy from BMI. In addition, the inverse-variance weighted (IVW) method was applied to estimate the causal association with genetic variants identified in CKB GWAS. Findings: Positive associations were found between snoring and total stroke, hemorrhagic stroke (HS), and ischemic stroke (IS). With GRS of CKB, the corresponding HRs (95% CIs) were 1.56 (1.15, 2.12), 1.50 (0.84, 2.69), 2.02 (1.36, 3.01), and the corresponding HRs (95% CIs) using GRS of UKB were 1.78 (1.30, 2.43), 1.94 (1.07, 3.52), and 1.74 (1.16, 2.61). The associations remained stable in the MR among the non-obese group, MVMR analysis, and MR analysis using the IVW method. Interpretation: This study suggests that, among Chinese adults, genetically predicted snoring could increase the risk of total stroke, IS, and HS, and the causal effect was independent of BMI. Funding: National Natural Science Foundation of China, Kadoorie Charitable Foundation Hong Kong, UK Wellcome Trust, National Key R&D Program of China, Chinese Ministry of Science and Technology