Traditional and Digital Biomarkers: Two Worlds Apart?

The identification and application of biomarkers in the clinical and medical fields has an enormous impact on society. The increase of digital devices and the rise in popularity of health-related mobile apps has produced a new trove of biomarkers in large, diverse, and complex data. However, the unclear definition of digital biomarkers, population groups, and their intersection with traditional biomarkers hinders their discovery and validation.

Genetic variation is associated with PTSD risk and aversive memory: Evidence from two trauma-Exposed African samples and one healthy European sample.

The probability to develop posttraumatic stress disorder (PTSD), characterized by vivid, intrusive emotional memories of the encountered traumatic events, depends - among other factors - on the number of previous traumatic experiences (traumatic load) and individual genetic vulnerability. So far, our knowledge regarding the biological underpinnings of PTSD is relatively sparse. Genome-wide association studies (GWAS) followed by independent replication might help to discover novel, so far unknown biological mechanisms associated with the development of traumatic memories.

Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts.

The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans-membrane receptor proteins (NOTCH1-4), constitutes an evolutionarily well-conserved intercellular communication pathway (involved, e.g.

Genetic estimators of DNA methylation provide insights into the molecular basis of polygenic traits.

The large biological distance between genetic risk loci and their mechanistic consequences in the tissue of interest limits the ability to establish functionality of susceptibility variants for genetically complex traits. Such a biological gap may be reduced through the systematic study of molecular mediators of genomic action, such as epigenetic modification. Here, we report the identification of robust genetic estimators of whole-blood CpG methylation, which can serve as intermediate molecular traits amenable to association testing with other genetically complex traits.

Exhaustive search for epistatic effects on the human methylome.

Studies assessing the existence and magnitude of epistatic effects on complex human traits provide inconclusive results. The study of such effects is complicated by considerable increase in computational burden, model complexity, and model uncertainty, which in concert decrease model stability. An additional source introducing significant uncertainty with regard to the detection of robust epistasis is the biological distance between the genetic variation and the trait under study.

A peripheral epigenetic signature of immune system genes is linked to neocortical thickness and memory.

Increasing age is tightly linked to decreased thickness of the human neocortex. The biological mechanisms that mediate this effect are hitherto unknown. The DNA methylome, as part of the epigenome, contributes significantly to age-related phenotypic changes.

The NCAM1 gene set is linked to depressive symptoms and their brain structural correlates in healthy individuals.

Depressive symptoms exist on a continuum, the far end of which is found in depressive disorders. Utilizing the continuous spectrum of depressive symptoms may therefore contribute to the understanding of the biological underpinnings of depression. Gene set enrichment analysis (GSEA) is an important tool for the identification of gene groups linked to complex traits, and was applied in the present study on genome-wide association study (GWAS) data of depression scores and their brain-level structural correlates in healthy young individuals.

Common epigenetic variation in a European population of mentally healthy young adults.

DNA methylation represents an important link between structural genetic variation and complex phenotypes. The study of genome-wide CpG methylation and its relation to traits relevant to psychiatry has become increasingly important. Here, we analyzed quality metrics of 394,043 CpG sites in two samples of 568 and 319 mentally healthy young adults.

Genetic Analysis of Association Between Calcium Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic Alzheimer Disease.

Importance: Human episodic memory performance is linked to the function of specific brain regions, including the hippocampus; declines as a result of increasing age; and is markedly disturbed in Alzheimer disease (AD), an age-associated neurodegenerative disorder that primarily affects the hippocampus. Exploring the molecular underpinnings of human episodic memory is key to the understanding of hippocampus-dependent cognitive physiology and pathophysiology.

Objective: To determine whether biologically defined groups of genes are enriched in episodic memory performance across age, memory encoding-related brain activity, and AD.

Computational dissection of human episodic memory reveals mental process-specific genetic profiles.

Episodic memory performance is the result of distinct mental processes, such as learning, memory maintenance, and emotional modulation of memory strength. Such processes can be effectively dissociated using computational models. Here we performed gene set enrichment analyses of model parameters estimated from the episodic memory performance of 1,765 healthy young adults.

Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.

Background: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

Methods: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years.

Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors.

Recent evidence suggests that altered expression and epigenetic modification of the glucocorticoid receptor gene (NR3C1) are related to the risk of post-traumatic stress disorder (PTSD). The underlying mechanisms, however, remain unknown. Because glucocorticoid receptor signaling is known to regulate emotional memory processes, particularly in men, epigenetic modifications of NR3C1 might affect the strength of traumatic memories.

Genetic influences on dietary variety - results from a twin study.

The heritability of variety seeking in the food domain was estimated from a large sample (N = 5,543) of middle age to elderly monozygotic and dizygotic twins from the "Virginia 30,000" twin study. Different dietary variety scores were calculated based on a semi-quantitative food choice questionnaire that assessed consumption frequencies and quantities for a list of 99 common foods. Results indicate that up to 30% of the observed variance in dietary variety was explained through heritable influences.

Forgetting is regulated via Musashi-mediated translational control of the Arp2/3 complex.

A plastic nervous system requires the ability not only to acquire and store but also to forget. Here, we report that musashi (msi-1) is necessary for time-dependent memory loss in C. elegans.

Converging genetic and functional brain imaging evidence links neuronal excitability to working memory, psychiatric disease, and brain activity.

Working memory, the capacity of actively maintaining task-relevant information during a cognitive task, is a heritable trait. Working memory deficits are characteristic for many psychiatric disorders. We performed genome-wide gene set enrichment analyses in multiple independent data sets of young and aged cognitively healthy subjects (n = 2,824) and in a large schizophrenia case-control sample (n = 32,143).

BAIAP2 is related to emotional modulation of human memory strength.

Memory performance is the result of many distinct mental processes, such as memory encoding, forgetting, and modulation of memory strength by emotional arousal. These processes, which are subserved by partly distinct molecular profiles, are not always amenable to direct observation. Therefore, computational models can be used to make inferences about specific mental processes and to study their genetic underpinnings.

Human genome-guided identification of memory-modulating drugs.

In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information.

The role of memory-related gene WWC1 (KIBRA) in lifetime posttraumatic stress disorder: evidence from two independent samples from African conflict regions.

Background: Posttraumatic stress disorder (PTSD) results from the formation of a strong memory for the sensory-perceptual and affective representations of traumatic experiences, which is detached from the corresponding autobiographical context information. Because WWC1, the gene encoding protein KIBRA, is associated with long-term memory performance, we hypothesized that common WWC1 alleles influence the risk for a lifetime diagnosis of PTSD.

Methods: Traumatic load and diagnosis of current and lifetime PTSD were assessed in two independent African samples of survivors from conflict zones who had faced severe trauma (n = 392, Rwanda, and n = 399, Northern Uganda, respectively).

Association of KIBRA with episodic and working memory: a meta-analysis.

WWC1 was first implicated in human cognition through a genome wide association study in 2006 that reported an association of the intronic single nucleotide polymorphism (SNP) rs17070145 with episodic memory performance. WWC1 encodes the protein KIBRA, which is almost ubiquitously expressed. Together with its binding partners, KIBRA is assumed to play a role in synaptic plasticity.

PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors.

Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα (PRKCA) was associated with memory capacity--including aversive memory--in nontraumatized subjects of European descent.

A role for α-adducin (ADD-1) in nematode and human memory.

Identifying molecular mechanisms that underlie learning and memory is one of the major challenges in neuroscience. Taken the advantages of the nematode Caenorhabditis elegans, we investigated α-adducin (add-1) in aversive olfactory associative learning and memory. Loss of add-1 function selectively impaired short- and long-term memory without causing acquisition, sensory, or motor deficits.

Statistical epistasis and functional brain imaging support a role of voltage-gated potassium channels in human memory.

Despite the current progress in high-throughput, dense genome scans, a major portion of complex traits' heritability still remains unexplained, a phenomenon commonly termed "missing heritability." The negligence of analytical approaches accounting for gene-gene interaction effects, such as statistical epistasis, is probably central to this phenomenon. Here we performed a comprehensive two-way SNP interaction analysis of human episodic memory, which is a heritable complex trait, and focused on 120 genes known to show differential, memory-related expression patterns in rat hippocampus.

Microarray-based maps of copy-number variant regions in European and sub-Saharan populations.

The genetic basis of phenotypic variation can be partially explained by the presence of copy-number variations (CNVs). Currently available methods for CNV assessment include high-density single-nucleotide polymorphism (SNP) microarrays that have become an indispensable tool in genome-wide association studies (GWAS). However, insufficient concordance rates between different CNV assessment methods call for cautious interpretation of results from CNV-based genetic association studies.

Fine-mapping of the brain-derived neurotrophic factor (BDNF) gene supports an association of the Val66Met polymorphism with episodic memory.

Brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity and long-term potentiation. A valine (Val) to methionine (Met) substitution in the BDNF gene (Val66Met) has been associated with episodic memory performance. This study aimed at fine-mapping the genomic region harbouring BDNF and the adjacent gene, BDNFOS, in order to identify other possible memory-related gene variants.

Attention-deficit/hyperactivity disorder phenotype is influenced by a functional catechol-O-methyltransferase variant.

The catechol-O-methyltransferase gene (COMT) plays a crucial role in the metabolism of catecholamines in the frontal cortex. A single nucleotide polymorphism (Val(158)Met SNP, rs4680) leads to either methionine (Met) or valine (Val) at codon 158, resulting in a three- to fourfold reduction in COMT activity. The aim of the present study was to assess the COMT Val(158)Met SNP as a risk factor for attention-deficit/hyperactivity disorder (ADHD), ADHD symptom severity and co-morbid conduct disorder (CD) in 166 children with ADHD.