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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.

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.

Data availability: The summary statistics of the CHARGE CRP GWAS used in this study is publicly available from the IEU open GWAS project accession code ieu-b-35 (Trait: C-Reactive protein level - IEU Open GWAS project (mrcieu.ac.uk)). The derived CRP GWAS meta-analysis summary statistics generated in this study has been deposited in the GWAS catalogue under accession code GCST00186 (https://www.ebi.ac.uk/gwas/). Human genome assembly GRCh37 (hg19) from Genome Reference Consortium https://www.sanger.ac.uk/data/genome-reference-consortium/). Copyright © The Author(s) 2022. 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. UK Dementia Research Institute at Imperial College, which receives its funding from UK DRI Ltd. (funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK) and the British Heart Foundation Centre for Research Excellence at Imperial College London and the National Institute for Health Research Imperial Biomedical Research Centre, Imperial College London. S.S. received funding from the Medical Research Council – Public Health England (MRC-PHE) Centre for Environment and Health awarded studentship, of which funding is derived from the MRC Industrial Strategy Fund. I.T and F.K. have received funding from the Hellenic Foundation for Research and Innovation (HFRI) and the General Secretariat for Research and Technology (GSRT), under grant agreement No 1312. R.P. holds a fellowship supported by Rutherford Fund from Medical Research Council (MR/R0265051/1 and MR/R0265051/2). V.K. is funded by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant (721567).

Background Tobacco smoking is estimated to account for more than 1 million annual deaths in China, and the epidemic continues to increase in men. Large nationwide prospective studies linked to different health records can help to periodically assess disease burden attributed to smoking. We aimed to examine associations of smoking with incidence of and mortality from an extensive range of diseases in China. Methods We analysed data from the prospective China Kadoorie Biobank, which recruited 512 726 adults aged 30–79 years, of whom 210 201 were men and 302 525 were women. Participants who had no major disabilities were identified through local residential records in 100–150 administrative units, which were randomly selected by use of multistage cluster sampling, from each of the ten diverse study areas of China. They were invited and recruited between June 25, 2004, and July 15, 2008. Upon study entry, trained health workers administered a questionnaire assessing detailed smoking behaviours and other key characteristics (eg, sociodemographics, lifestyle, and medical history). Participants were followed up via electronic record linkages to death and disease registries and health insurance databases, from baseline to Jan 1, 2018. During a median 11-year follow-up (IQR 10–12), 285 542 (55·7%) participants were ever hospitalised, 48 869 (9·5%) died, and 5252 (1·0%) were lost to follow-up during the age-at-risk of 35–84 years. Cox regression yielded hazard ratios (HRs) associating smoking with disease incidence and mortality, adjusting for multiple testing. Findings At baseline, 74·3% of men and 3·2% of women (overall 32·4%) ever smoked regularly. During follow-up, 1 137 603 International Classification of Diseases, 10th revision (ICD-10)-coded incident events occurred, involving 476 distinct conditions and 85 causes of death, each with at least 100 cases. Compared with never-regular smokers, ever-regular smokers had significantly higher risks for nine of 18 ICD-10 chapters examined at age-at-risk of 35–84 years. For individual conditions, smokers had significantly higher risks of 56 diseases (50 for men and 24 for women) and 22 causes of death (17 for men and nine for women). Among men, ever-regular smokers had an HR of 1·09 (95% CI 1·08–1·11) for any disease incidence when compared with never-regular smokers, and significantly more episodes and longer duration of hospitalisation, particularly those due to cancer and respiratory diseases. For overall mortality, the HRs were greater in men from urban areas than in men from rural areas (1·50 [1·42–1·58] vs 1·25 [1·20–1·30]). Among men from urban areas who began smoking at younger than 18 years, the HRs were 2·06 (1·89–2·24) for overall mortality and 1·32 (1·27–1·37) for any disease incidence. In this population, 19·6% of male (24·3% of men residing in urban settings and 16·2% of men residing in rural settings) and 2·8% of female deaths were attributed to ever-regular smoking. Interpretation Among Chinese adults, smoking was associated with higher risks of morbidity and mortality from a wide range of diseases. Among men, the future smoking-attributed disease burden will increase further, highlighting a pressing need for reducing consumption through widespread cessation and uptake prevention. Funding British Heart Foundation, Cancer Research UK, Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, UK Medical Research Council, National Natural Science Foundation of China, Wellcome Trust.