Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance

Acknowledgements: The computations and data handling were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, Uppsala University, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. This research has been conducted using the UK Biobank Resource under Application Number 22224. Funding: Open Access funding provided by Karolinska Institute. Open Access funding provided by Karolinska Institute. This work was financed by the Swedish Research Council (Grant 2018-02547, 2015-03255, 2019-01272, 2018-02077), the Swedish Cancer Society (Grants CAN 2016/684), the Stockholm County Council (Grant no. 20170088), the Karolinska Institutet’s Research Foundation (Grant 2018-02146), Karolinska Institutet’s Strategic Research Program in Epidemiology, King Gustaf V:s and Queen Victoria's Foundation of Freemasons, and the Åke Wibergs Foundation (M19-0294). FG was a Leopoldina Postdoctoral Fellow (Grant no. LPDS 2018-06) funded by the Academy of Sciences Leopoldina. Correction to: Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance (Human Genetics, (2020), 10.1007/s00439-020-02249-w) The data were exclusively retrieved from the UK Biobank and can be accessed upon request from the UK Biobank. The mitochondrial DNA abundance as computed in this manuscript will be reported back to the UK Biobank upon publication. The scripts to compute the weights and the weighted mtDNA abundance in the UKB dataset will be published at https://github.com/GrassmannLab/MT_UKB.Peer reviewedPublisher PD

Association between hemoglobin glycation index and the risk of cardiovascular disease in early-stage cardiovascular-kidney-metabolic syndrome: evidence from the China health and retirement longitudinal study

BackgroundCardiovascular-kidney-metabolic (CKM) syndrome reflects the interplay among metabolic risk factors, chronic kidney disease, and cardiovascular disease (CVD). While the hemoglobin glycation index (HGI) has demonstrated prognostic value for cardiovascular events, its clinical utility remains unexplored in early-stage CKM syndrome.MethodsParticipants with early-stage CKM syndrome (stage 0-3) were recruited from the China Health and Retirement Longitudinal Study (CHARLS) database. Using k-means clustering analysis, the participants were classified according to the values of HGI measured at baseline and 3 years later, respectively. The primary outcome was self-reported CVD during the follow-up of at least 3 years. Extreme gradient boosting (XGBoost) algorithm was applied, with the Shapley additive explanation (SHAP) method used to determine feature importance. Multivariable logistics proportional regression analysis the association between HGI and CVD, and restricted cubic spline (RCS) regression assessed potential nonlinear relationships.ResultsA total of 4676 eligible participants were included in the final analysis, with 944 (20.19%) progressed to CVD within 10 years. Among the baseline clinical features, HGI ranked the second for the impact on the occurrence of CVD. According to the changes of HGI values, the participants were clustered into 4 classes. Compared to the class 1 with lower level of HGI, higher risk of CVD was observed in class 3 (adjusted OR: 1.34, 95% CI: 1.06-1.69, P = 0.013) and class 4 (adjusted OR: 1.65, 95% CI: 1.01-2.45, P = 0.025) with higher and rapidly increasing level of HGI. RCS analysis showed cumulative HGI and the risk of CVD were linearly related (P for nonlinearity = 0.967). Subgroup analyses confirmed the stability of the association. Additionally, the SHAP plot revealed that HGI were the more important features than traditional risk factors such as FBG for predicting CVD.ConclusionHGI is associated with an elevated risk of CVD in participants with early-stage CKM syndrome. HGI can serve as an independent biomarker for guiding clinical decision-making and managing patient outcomes

Can frailty scores predict the incidence of cancer? : Results from two large population-based studies

While chronological age is the single biggest risk factor for cancer, it is less clear whether frailty, an age-related state of physiological decline, may also predict cancer incidence. We assessed the associations of frailty index (FI) and frailty phenotype (FP) scores with the incidence of any cancer and five common cancers (breast, prostate, lung, colorectal, melanoma) in 453,144 UK Biobank (UKB) and 36,888 Screening Across the Lifespan Twin study (SALT) participants, who aged 38–73 years and had no cancer diagnosis at baseline. During a median follow-up of 10.9 and 10.7 years, 53,049 (11.7%) and 4,362 (11.8%) incident cancers were documented in UKB and SALT, respectively. Using multivariable-adjusted Cox models, we found a higher risk of any cancer in frail vs. non-frail UKB participants, when defined by both FI (hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 1.17–1.28) and FP (HR = 1.16; 95% CI = 1.11–1.21). The FI in SALT similarly predicted risk of any cancer (HR = 1.31; 95% CI = 1.15–1.49). Moreover, frailty was predictive of lung cancer in UKB, although this association was not observed in SALT. Adding frailty scores to models including age, sex, and traditional cancer risk factors resulted in little improvement in C-statistics for most cancers. In a within-twin-pair analysis in SALT, the association between FI and any cancer was attenuated within monozygotic but not dizygotic twins, indicating that it may partly be explained by genetic factors. Our findings suggest that frailty scores are associated with the incidence of any cancer and lung cancer, although their clinical utility for predicting cancers may be limited.publishedVersionPeer reviewe

A genome-wide association study of the frailty index highlights brain pathways in ageing

Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60–70 years) and Swedish TwinGene participants (n = 10,616, 41–87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10−8). Many FI-associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on pathways in the brain

Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C-reactive protein in white British population

Background: C-reactive protein (CRP) is a sensitive biomarker of inflammation with moderate heritability. The role of rare functional genetic variants in relation to serum CRP is understudied. We aimed to examine gene mutation burden of protein-altering (PA) and loss-of-function (LOF) variants in association with serum CRP, and to further explore the clinical relevance. Methods: We included 161,430 unrelated participants of European ancestry from the UK Biobank. Of the rare (minor allele frequency <0.1%) and functional variants, 1,776,249 PA and 266,226 LOF variants were identified. Gene-based burden tests, linear regressions, and logistic regressions were performed to identify the candidate mutations at the gene and variant levels, to estimate the potential interaction effect between the identified PA mutation and obesity, and to evaluate the relative risk of 16 CRP-associated diseases. Results: At the gene level, PA mutation burdens of the CRP (β = −0.685, p = 2.87e-28) and G6PC genes (β = 0.203, p = 1.50e-06) were associated with reduced and increased serum CRP concentration, respectively. At the variant level, seven PA alleles in the CRP gene decreased serum CRP, of which the per-allele effects were approximately three to seven times greater than that of a common variant in the same locus. The effects of obesity and central obesity on serum CRP concentration were smaller among the PA mutation carriers in the CRP (pinteraction = 0.008) and G6PC gene (pinteraction = 0.034) compared to the corresponding non-carriers. Conclusion: PA mutation burdens in the CRP and G6PC genes are strongly associated with decreased serum CRP concentrations. As serum CRP and obesity are important predictors of cardiovascular risks in clinics, our observations suggest taking rare genetic factors into consideration might improve the delivery of precision medicine.Peer reviewe

DNA methylation and all-cause mortality in middle-aged and elderly Danish twins

Several studies have linked DNA methylation at individual CpG sites to aging and various diseases. Recent studies have also identified single CpGs whose methylation levels are associated with all-cause mortality. In this study, we perform an epigenome-wide study of the association between CpG methylation and mortality in a population of 435 monozygotic twin pairs from three Danish twin studies. The participants were aged 55–90 at the time of blood sampling and were followed for up to 20 years. We validated our results by comparison with results from a British and a Swedish cohort, as well as results from the literature. We identified 2806 CpG sites associated with mortality (false discovery rate ( FDR ) &lt; 0.05 ), of which 24 had an association p-value below 10 − 7 . This was confirmed by intra-pair comparison controlling for confounding effects. Eight of the 24 top sites could be validated in independent datasets or confirmed by previous studies. For all these eight sites, hypomethylation was associated with poor survival prognosis, and seven showed monozygotic correlations above 35%, indicating a potential moderate to strong heritability, but leaving room for substantial shared or unique environmental effects. We also set up a predictor for mortality using least absolute shrinkage and selection operator (LASSO) regression. The predictor showed good performance on the Danish data under cross-validation, but did not perform very well in independent samples

Epigenome-wide analysis of frailty : Results from two European twin cohorts

Epigenetics plays an important role in the aging process, but it is unclear whether epigenetic factors also influence frailty, an age-related state of physiological decline. In this study, we performed a meta-analysis of epigenome-wide association studies in four samples drawn from the Swedish Adoption/Twin Study of Aging (SATSA) and the Longitudinal Study of Aging Danish Twins (LSADT) to explore the association between DNA methylation and frailty. Frailty was defined using the frailty index (FI), and DNA methylation levels were measured in whole blood using Illumina's Infinium HumanMethylation450K and MethylationEPIC arrays. In the meta-analysis consisting of a total of 829 participants, we identified 589 CpG sites that were statistically significantly associated with either the continuous or categorical FI (false discovery rate <0.05). Many of these CpGs have previously been associated with age and age-related diseases. The identified sites were also largely directionally consistent in a longitudinal analysis using mixed-effects models in SATSA, where the participants were followed up to a maximum of 20 years. Moreover, we identified three differentially methylated regions within the MGRN1, MIR596, and TAPBP genes that have been linked to neuronal aging, tumor growth, and immune functions. Furthermore, our meta-analysis results replicated 34 of the 77 previously reported frailty-associated CpGs at p < 0.05. In conclusion, our findings demonstrate robust associations between frailty and DNA methylation levels in 589 novel CpGs, previously unidentified for frailty, and strengthen the role of neuronal/brain pathways in frailty.Peer reviewe

Unraveling the metabolic underpinnings of frailty using multicohort observational and Mendelian randomization analyses

Identifying metabolic biomarkers of frailty, an age-related state of physiological decline, is important for understanding its metabolic underpinnings and developing preventive strategies. Here, we systematically examined 168 nuclear magnetic resonance-based metabolomic biomarkers and 32 clinical biomarkers for their associations with frailty. In up to 90,573 UK Biobank participants, we identified 59 biomarkers robustly and independently associated with the frailty index (FI). Of these, 34 associations were replicated in the Swedish TwinGene study (n = 11,025) and the Finnish Health 2000 Survey (n = 6073). Using two-sample Mendelian randomization, we showed that the genetically predicted level of glycoprotein acetyls, an inflammatory marker, was statistically significantly associated with an increased FI (β per SD increase = 0.37%, 95% confidence interval: 0.12–0.61). Creatinine and several lipoprotein lipids were also associated with increased FI, yet their effects were mostly driven by kidney and cardiometabolic diseases, respectively. Our findings provide new insights into the causal effects of metabolites on frailty and highlight the role of chronic inflammation underlying frailty development.Peer reviewe