Genetic polymorphisms in the locus control region and promoter of GH1 are related to serum IGF-I levels and height in patients with isolated growth hormone deficiency and healthy controls

Background/Aims: Expression of the human growth hormone (GH) gene (GH1) is regulated by a locus contro

Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution

We show that epigenome- and transcriptome-wide association studies (EWAS and TWAS) are prone to significant inflation and bias of test statistics, an unrecognized phenomenon introducing spurious findings if left unaddressed. Neither GWAS-based methodology nor state-of-the-art confounder adjustment methods completely remove bias and inflation. We propose a Bayesian method to control bias and inflation in EWAS and TWAS based on estimation of the empirical null distribution. Using simulations and real data, we demonstrate that our method maximizes power while properly controlling the false positive rate. We illustrate the utility of our method in large-scale EWAS and TWAS meta-analyses of age and smoking.</p

Telomere Length and the Risk of Alzheimer's Disease: The Rotterdam Study

There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped associa

A Large-Scale Population-Based Analysis of Common Genetic Variation in the Thyroid Hormone Receptor Alpha Locus and Bone

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DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts

Background: Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones. Results: We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R2 = 10.6%). Conclusions: This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D

Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits

Background: Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits. Results We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA;CLDND1), and BMI with six CpGs and two genes (PID1;LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression. Conclusions: Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD

Genetic Determinants of Serum Calcification Propensity and Cardiovascular Outcomes in the General Population

BACKGROUND: Serum calciprotein particle maturation time (T(50)), a measure of vascular calcification propensity, is associated with cardiovascular morbidity and mortality. We aimed to identify genetic loci associated with serum T(50) and study their association with cardiovascular disease and mortality. METHODS: We performed a genome-wide association study of serum T(50) in 2,739 individuals of European descent participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, followed by a two-sample Mendelian randomization (MR) study to examine causal effects of T(50) on cardiovascular outcomes. Finally, we examined associations between T(50) loci and cardiovascular outcomes in 8,566 community-dwelling participants in the Rotterdam study. RESULTS: We identified three independent genome-wide significant single nucleotide polymorphism (SNPs) in the AHSG gene encoding fetuin-A: rs4917 (p = 1.72 × 10(−101)), rs2077119 (p = 3.34 × 10(−18)), and rs9870756 (p = 3.10 × 10(−8)), together explaining 18.3% of variation in serum T(50). MR did not demonstrate a causal effect of T(50) on cardiovascular outcomes in the general population. Patient-level analyses revealed that the minor allele of rs9870756, which explained 9.1% of variation in T(50), was associated with a primary composite endpoint of all-cause mortality or cardiovascular disease [odds ratio (95% CI) 1.14 (1.01–1.28)] and all-cause mortality alone [1.14 (1.00–1.31)]. The other variants were not associated with clinical outcomes. In patients with type 2 diabetes or chronic kidney disease, the association between rs9870756 and the primary composite endpoint was stronger [OR 1.40 (1.06–1.84), relative excess risk due to interaction 0.54 (0.01–1.08)]. CONCLUSIONS: We identified three SNPs in the AHSG gene that explained 18.3% of variability in serum T(50) levels. Only one SNP was associated with cardiovascular outcomes, particularly in individuals with type 2 diabetes or chronic kidney disease

Somatic TARDBP variants as a cause of semantic dementia

The aetiology of late-onset neurodegenerative diseases is largely unknown. Here we investigated whether de novo somatic variants for semantic dementia can be detected, thereby arguing for a more general role of somatic variants in neurodegenerative disease. Semantic dementia is characterized by a non-familial occurrence, early onset (<65 years), focal temporal atrophy and TDP-43 pathology. To test whether somatic variants in neural progenitor cells during brain development might lead to semantic dementia, we compared deep exome sequencing data of DNA derived from brain and blood of 16 semantic dementia cases. Somatic variants observed in brain tissue and absent in blood were validated using amplicon sequencing and digital PCR. We identified two variants in exon one of the TARDBP gene (L41F and R42H) at low level (1-3%) in cortical regions and in dentate gyrus in two semantic dementia brains, respectively. The pathogenicity of both variants is supported by demonstrating impaired splicing regulation of TDP-43 and by altered subcellular localization of the mutant TDP-43 protein. These findings indicate that somatic variants may cause semantic dementia as a non-hereditary neurodegenerative disease, which might be exemplary for other late-onset neurodegenerative disorders

Multi-Omics Analysis Reveals MicroRNAs Associated With Cardiometabolic Traits

MicroRNAs (miRNAs) are non-coding RNA molecules that regulate gene expression. Extensive research has explored the role of miRNAs in the risk for type 2 diabetes (T2D) and