Machine learning-based somatic variant calling in cell-free DNA of metastatic breast cancer patients using large NGS panels

Next generation sequencing of cell-free DNA (cfDNA) is a promising method for treatment monitoring and therapy selection in metastatic breast cancer (MBC). However, distinguishing tumor-specific variants from sequencing artefacts and germline variation with low false discovery rate is challenging when using large targeted sequencing panels...

Polygenic Risk Score of Longevity Predicts Longer Survival across an Age Continuum

Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with...

The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity

Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in...

Genome-wide association study of frontotemporal dementia identifies a C9ORF72 haplotype with a median of 12-G4C2 repeats that predisposes to pathological repeat expansions

Genetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare variants...

Genetics Contributes to Concomitant Pathology and Clinical Presentation in Dementia with Lewy Bodies

Background: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity. Objective: We tested if genetic variants in part explain the heterogeneity in DLB. Methods: We tested the effects of variants previously associated with DLB (near APOE, GBA, and...

Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what...

Centenarian controls increase variant effect sizes by an average twofold in an extreme case–extreme control analysis of Alzheimer’s disease

The detection of genetic loci associated with Alzheimer’s disease (AD) requires large numbers of cases and controls because variant effect sizes are mostly small. We hypothesized that variant effect sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be...

Meta-analysis on blood transcriptomic studies identifies consistently coexpressed protein–protein interaction modules as robust markers of human aging

The bodily decline that occurs with advancing age strongly impacts on the prospects for future health and life expectancy. Despite the profound role of age in disease etiology, knowledge about the molecular mechanisms driving the process of aging in humans is limited. Here, we used an integrative network-based approach for combining multiple...