Background
The apolipoprotein E gene (APOE) is the most important single determinant of dementia risk but has also been implicated in life span. Specifically, the APOE ε4 allele is associated with ...lower odds of longevity and the APOE ε2 allele with higher odds. Other diseases that may explain the association between APOE and mortality are cardiovascular disease (CVD) and coronavirus disease 2019 (COVID‐19). The aim of this study is to examine the relative contribution of mediators by which APOE affects the risk of mortality.
Method
We conducted this study in UK Biobank, a large prospective cohort of 459,227 subjects with extensive genotypic and phenotypic data. Data on mortality and morbidities were obtained via the UK death registry and hospital record linkage up to September 2020. Cox regression was performed to determine the effect of APOE adjusting for age, sex, and lifestyle factors (body mass index, smoking status, and education).
Result
In total, 29,208 subjects died during follow‐up. APOE ε34 (Hazard Ratio (HR): 1.08 (95% Confidence Interval (CI) 1.05‐1.11) and APOE ε44 (1.38,1.29‐1.48) were significantly associated with increased mortality, while the APOE ε23 genotype was associated with a decreased risk (0.96, 0.93‐0.99). We conducted a formal mediation analysis evaluating the contribution of dementia, CVD and COVID‐19 as putative mediators of this relationship. We found that 77.8% of the association of APOE ε44 to mortality could be explained by dementia, 8.1% could be explained by CVD and 1.1% could be explained by COVID‐19. Further adjustment for dementia attenuated the mediation effect of CVD from 8.1% to a significant 4.8%. After adjustment for dementia, the observed mediation effect of COVID‐19 became non‐significant. There was no evidence of a significant association between APOE and the risk of mortality in patients with dementia.
Conclusion
Our study shows that APOE is associated with mortality by increasing the incidence of dementia and that the relative contribution of CVD and COVID‐19 is small.
The variance component tests used in genome-wide association studies (GWAS) including large sample sizes become computationally exhaustive when the number of genetic markers is over a few hundred ...thousand. We present an extremely fast variance components-based two-step method, GRAMMAR-Gamma, developed as an analytical approximation within a framework of the score test approach. Using simulated and real human GWAS data sets, we show that this method provides unbiased estimates of the SNP effect and has a power close to that of the likelihood ratio test-based method. The computational complexity of our method is close to its theoretical minimum, that is, to the complexity of the analysis that ignores genetic structure. The running time of our method linearly depends on sample size, whereas this dependency is quadratic for other existing methods. Simulations suggest that GRAMMAR-Gamma may be used for association testing in whole-genome resequencing studies of large human cohorts.
In order to meaningfully analyze common and rare genetic variants, results from genome-wide association studies (GWASs) of multiple cohorts need to be combined in a meta-analysis in order to obtain ...enough power. This requires all cohorts to have the same single-nucleotide polymorphisms (SNPs) in their GWASs. To this end, genotypes that have not been measured in a given cohort can be imputed on the basis of a set of reference haplotypes. This protocol provides guidelines for performing imputations with two widely used tools: minimac and IMPUTE2. These guidelines were developed and used by the Genome of the Netherlands (GoNL) consortium, which has created a population-specific reference panel for genetic imputations and used this reference to impute various Dutch biobanks. We also describe several factors that might influence the final imputation quality. This protocol, which has been used by the largest Dutch biobanks, should take approximately several days, depending on the sample size of the biobank and the computer resources available.
Genome-wide association studies (GWAS) have been successful in identifying loci associated with a wide range of complex human traits and diseases. Up to now, the majority of GWAS have focused on ...European populations. However, the inclusion of other ethnic groups as well as admixed populations in GWAS studies is rapidly rising following the pressing need to extrapolate findings to non-European populations and to increase statistical power. In this paper, we describe the methodological steps surrounding genetic data generation, quality control, study design and analytical procedures needed to run GWAS in the multiethnic and highly admixed Generation R Study, a large prospective birth cohort in Rotterdam, the Netherlands. Furthermore, we highlight a number of practical considerations and alternatives pertinent to the quality control and analysis of admixed GWAS data.
Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized ...that cumulative DNA damage during aging contributes to vascular dysfunction.
In mice with genomic instability resulting from the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1(d/-) and Xpd(TTD) mice), we explored age-dependent vascular function compared with that in wild-type mice. Ercc1(d/-) mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness, and elevated blood pressure at a very young age. The vasodilator dysfunction was due to decreased endothelial nitric oxide synthase levels and impaired smooth muscle cell function, which involved phosphodiesterase activity. Similar to Ercc1(d/-) mice, age-related endothelium-dependent vasodilator dysfunction in Xpd(TTD) animals was increased. To investigate the implications for human vascular disease, we explored associations between single-nucleotide polymorphisms of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium and found a significant association of a single-nucleotide polymorphism (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity.
Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans but with an accelerated progression compared with wild-type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness, which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease.
Background Although a striking proportion (25% to 45%) of patients with chronic obstructive pulmonary disease are never-smokers, most genetic susceptibility studies have not focused on this group ...exclusively. Objective The aim of this study was to identify common genetic variants associated with FEV1 and its ratio to forced vital capacity (FVC) in never-smokers. Methods Genome-wide association studies were performed in 5070 never-smokers of the identification cohort LifeLines, and results ( P < 10−5 ) were verified by using a meta-analysis of the Vlagtwedde-Vlaardingen study and the Rotterdam Study I-III (total n = 1966). Furthermore, we aimed to assess the effects of the replicated variants in more detail by performing genetic risk score, expression quantitative trait loci, and variant*ever-smoking interaction analyses. Results We identified associations between the FEV1 /FVC ratio and 5 common genetic variants in the identification cohort, and 2 of these associations were replicated. The 2 variants annotated to the genes hedgehog interacting protein (HHIP) and family with sequence similarity 13 member A (FAM13A) were shown to have an additive effect on FEV1 /FVC levels in the genetic risk score analysis; were associated with gene expression of HHIP and FAM13A in lung tissue, respectively; and were genome-wide significant in a meta-analysis including both identification and 4 verification cohorts ( P < 2.19 × 10−7 ). Finally, we did not identify significant interactions between the variants and ever smoking. Results of the FEV1 identification analysis were not replicated. Conclusion The genes HHIP and FAM13A confer a risk for airway obstruction in general that is not driven exclusively by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease.
There is a growing body of evidence highlighting there are significant changes in the gut microbiota composition and relative abundance in various neurological disorders. We performed a systematic ...review of the different microbiota altered in a wide range of neurological disorders (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis, and stroke). Fifty-two studies were included representing 5496 patients. At the genus level, the most frequently involved microbiota are Akkermansia, Faecalibacterium, and Prevotella. The overlap between the pathologies was strongest for MS and PD, sharing eight genera (Akkermansia, Butyricicoccus, Bifidobacterium, Coprococcus, Dorea, Faecalibacterium, Parabacteroides, and Prevotella) and PD and stroke, sharing six genera (Enterococcus, Faecalibacterium, Lactobacillus, Parabacteroides, Prevotella, and Roseburia). The identification signatures overlapping for AD, PD, and MS raise the question of whether these reflect a common etiology or rather common consequence of these diseases. The interpretation is hampered by the low number and low power for AD, ALS, and stroke with ample opportunity for false positive and false negative findings.
Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine ...and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.
Longevity is an extremely complex phenotype that is determined by environment, life style and genetics. Genome wide association studies (GWAS) have been a powerful tool to identify the genetic origin ...of other complex outcome with a similar heritability. In this chapter we discuss the findings all GWAS of longevity conducted to date. Various cut-off to define longevity have been used varying from 85+, 90+ and 100+ years and the impact of these difference are addressed in this chapter. The only consistent association emerging from GWAS to data is the APOE gene that has been already identified as a candidate gene. Although (GWAS) have identified biologically plausible genes and pathways, no new loci for longevity have been conclusively proven. A reason for not finding any replicated associations for longevity could be the complexity of the phenotype, although heterogeneity also underlies many other traits for which GWAS has been successful. One may argue that rare variants explain the high heritability of longevity and the segregation of the trait in families. Yet, whole genome analyses of GWAS data still suggest that over 80 % of the heritability is explained by common variants. Although findings of GWAS to date have been disappointing, there is ample opportunity to improve the statistical power of studies to find common variants with small effects. In the near future, joining of the published studies and new ones emerging may bring to surface new loci.
The volumes of subcortical brain structures are highly heritable, but genetic underpinnings of their shape remain relatively obscure. Here we determine the relative contribution of genetic factors to ...individual variation in the shape of seven bilateral subcortical structures: the nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus. In 3,686 unrelated individuals aged between 45 and 98 years, brain magnetic resonance imaging and genotyping was performed. The maximal heritability of shape varies from 32.7 to 53.3% across the subcortical structures. Genetic contributions to shape extend beyond influences on intracranial volume and the gross volume of the respective structure. The regional variance in heritability was related to the reliability of the measurements, but could not be accounted for by technical factors only. These findings could be replicated in an independent sample of 1,040 twins. Differences in genetic contributions within a single region reveal the value of refined brain maps to appreciate the genetic complexity of brain structures.
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