Virginie Freytag

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. Here, we identify an epigenetic signature that is associated with cortical thickness (P=3.86 × 10−8) and memory performance in 533 healthy young adults. The epigenetic effect on cortical thickness was replicated in a sample comprising 596 participants with major depressive disorder and healthy controls. The epigenetic signature mediates partially the effect of age on cortical thickness (P<0.001). A multilocus genetic score reflecting genetic variability of this signature is associated with memory performance (P=0.0003) in 3,346 young and elderly healthy adults. The genomic location of the contributing methylation sites points to the involvement of specific immune system genes. The decomposition of blood methylome-wide patterns bears considerable potential for the study of brain-related traits.

The association of the BDNF Val66Met polymorphism and the hippocampal volumes in healthy humans: A joint meta-analysis of published and new data

BACKGROUND The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (refSNP Cluster Report: rs6265) is a common and functionally relevant single nucleotide polymorphism (SNP). The gene itself, as well as the SNP rs6265, have been implicated in hippocampal learning and memory. However, imaging genetic studies have produced controversial results about the impact of this SNP on hippocampal volumes in healthy subjects. METHODS We examined the association between the rs6265 polymorphism and hippocampal volume in 643 healthy young subjects using automatic segmentation and subsequently included these data in a meta-analysis based on published studies with 5298 healthy subjects in total. RESULTS We found no significant association between SNP rs6265 and hippocampal volumes in our sample (g=0.05, p=0.58). The meta-analysis revealed a small, albeit significant difference in hippocampal volumes between genotype groups, such that Met-carriers had slightly smaller hippocampal volumes than Val/Val homozygotes (g=0.09, p=0.04), an association that was only evident when manual (g=0.22, p=0.01) but not automatic tracing approaches (g=0.04, p=0.38) were used. Studies using manual tracing showed evidence for publication bias and a significant decrease in effect size over the years with increasing sample sizes. CONCLUSIONS This study does not support the association between SNP rs6265 and hippocampal volume in healthy individuals. The weakly significant effect observed in the meta-analysis is mainly driven by studies with small sample sizes. In contrast, our original data and the meta-analysis of automatically segmented hippocampal volumes, which was based on studies with large samples sizes, revealed no significant genotype effect. Thus, meta-analyses of the association between rs6265 and hippocampal volumes should consider possible biases related to measuring technique and sample size.

Substantial SNP-based heritability estimates for working memory performance.

Working memory (WM) is an important endophenotype in neuropsychiatric research and its use in genetic association studies is thought to be a promising approach to increase our understanding of psychiatric disease. As for any genetically complex trait, demonstration of sufficient heritability within the specific study context is a prerequisite for conducting genetic studies of that trait. Recently developed methods allow estimating trait heritability using sets of common genetic markers from genome-wide association study (GWAS) data in samples of unrelated individuals. Here we present single-nucleotide polymorphism (SNP)-based heritability estimates (h2SNP) for a WM phenotype. A Caucasian sample comprising a total of N=2298 healthy and young individuals was subjected to an N-back WM task. We calculated the genetic relationship between all individuals on the basis of genome-wide SNP data and performed restricted maximum likelihood analyses for variance component estimation to derive the h2SNP estimates. Heritability estimates for three 2-back derived WM performance measures based on all autosomal chromosomes ranged between 31 and 41%, indicating a substantial SNP-based heritability for WM traits. These results indicate that common genetic factors account for a prominent part of the phenotypic variation in WM performance. Hence, the application of GWAS on WM phenotypes is a valid method to identify the molecular underpinnings of WM.

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. DESIGN, SETTING, AND PARTICIPANTS In this multicenter collaborative study, which began in August 2008 and is ongoing, gene set enrichment analysis was done by using primary and meta-analysis data from 57 968 participants. The Swiss cohorts consisted of 3043 healthy young adults assessed for episodic memory performance. In a subgroup (n = 1119) of one of these cohorts, functional magnetic resonance imaging was used to identify gene set-dependent differences in brain activity related to episodic memory. The German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort consisted of 763 elderly participants without dementia who were assessed for episodic memory performance. The International Genomics of Alzheimers Project case-control sample consisted of 54 162 participants (17 008 patients with sporadic AD and 37 154 control participants). Analyses were conducted between January 2014 and June 2015. Gene set enrichment analysis in all samples was done using genome-wide single-nucleotide polymorphism data. MAIN OUTCOMES AND MEASURES Episodic memory performance in the Swiss cohort and German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort was quantified by picture and verbal delayed free recall tasks. In the functional magnetic resonance imaging experiment, activation of the hippocampus during encoding of pictures served as the phenotype of interest. In the International Genomics of Alzheimers Project sample, diagnosis of sporadic AD served as the phenotype of interest. RESULTS In the discovery sample, we detected significant enrichment for genes constituting the calcium signaling pathway, especially those related to the elevation of cytosolic calcium (P = 2 × 10-4). This enrichment was replicated in 2 additional samples of healthy young individuals (P = .02 and .04, respectively) and a sample of healthy elderly participants (P = .004). Hippocampal activation (P = 4 × 10-4) and the risk for sporadic AD (P = .01) were also significantly enriched for genes related to the elevation of cytosolic calcium. CONCLUSIONS AND RELEVANCE By detecting consistent significant enrichment in independent cohorts of young and elderly participants, this study identified that calcium signaling plays a central role in hippocampus-dependent human memory processes in cognitive health and disease, contributing to the understanding and potential treatment of hippocampus-dependent cognitive pathology.

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

Significance Human memory is a highly heritable and complex trait that is the outcome of several neurobiologically distinct mental processes, such as learning, memory maintenance, and emotional modulation of memory strength. Such processes, which are not always amenable to direct observation, can be dissociated using computational models. Here we provide converging evidence linking computational model parameters and related behavioral and neuroimaging phenotypes to sets of biologically related genes in several populations of healthy young and elderly adults. Our findings suggest that distinct genetic profiles underlie specific mental processes of human episodic memory. Understanding the genetic and neural bases of such processes is essential for the development of novel therapeutic approaches that could lead to a better treatment of neuropsychiatric disorders. 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. We report robust and replicated associations of the amine compound SLC (solute-carrier) transporters gene set with the learning rate, of the collagen formation and transmembrane receptor protein tyrosine kinase activity gene sets with the modulation of memory strength by negative emotional arousal, and of the L1 cell adhesion molecule (L1CAM) interactions gene set with the repetition-based memory improvement. Furthermore, in a large functional MRI sample of 795 subjects we found that the association between L1CAM interactions and memory maintenance revealed large clusters of differences in brain activity in frontal cortical areas. Our findings provide converging evidence that distinct genetic profiles underlie specific mental processes of human episodic memory. They also provide empirical support to previous theoretical and neurobiological studies linking specific neuromodulators to the learning rate and linking neural cell adhesion molecules to memory maintenance. Furthermore, our study suggests additional memory-related genetic pathways, which may contribute to a better understanding of the neurobiology of human memory.

A common NTRK2 variant is associated with emotional arousal and brain white-matter integrity in healthy young subjects

Dysregulation of emotional arousal is observed in many psychiatric diseases such as schizophrenia, mood and anxiety disorders. The neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) has been associated with these disorders. Here we investigated the relation between genetic variability of NTRK2 and emotional arousal in healthy young subjects in two independent samples (n1=1171; n2=707). In addition, diffusion tensor imaging (DTI) data in a subgroup of 342 participants were used to identify NTRK2-related white-matter structure differences. After correction for multiple testing, we identified a NTRK2 single nucleotide polymorphism associated with emotional arousal in both samples (n1: Pnominal=0.0003, Pcorrected=0.048; n2: Pnominal=0.0141, Pcorrected=0.036). DTI revealed significant, whole-brain corrected correlations between emotional arousal and brain white-matter mean diffusivity (MD), as well as significant, whole-brain corrected NTRK2 genotype-related differences in MD (PFWE<0.05). Our study demonstrates that genetic variability of NTRK2, a susceptibility gene for psychiatric disorders, is related to emotional arousal and—independently—to brain white-matter properties in healthy individuals.

Genome-Wide Temporal Expression Profiling in Caenorhabditis elegans Identifies a Core Gene Set Related to Long-Term Memory

The identification of genes related to encoding, storage, and retrieval of memories is a major interest in neuroscience. In the current study, we analyzed the temporal gene expression changes in a neuronal mRNA pool during an olfactory long-term associative memory (LTAM) in Caenorhabditis elegans hermaphrodites. Here, we identified a core set of 712 (538 upregulated and 174 downregulated) genes that follows three distinct temporal peaks demonstrating multiple gene regulation waves in LTAM. Compared with the previously published positive LTAM gene set (Lakhina et al., 2015), 50% of the identified upregulated genes here overlap with the previous dataset, possibly representing stimulus-independent memory-related genes. On the other hand, the remaining genes were not previously identified in positive associative memory and may specifically regulate aversive LTAM. Our results suggest a multistep gene activation process during the formation and retrieval of long-term memory and define general memory-implicated genes as well as conditioning-type-dependent gene sets. SIGNIFICANCE STATEMENT The identification of genes regulating different steps of memory is of major interest in neuroscience. Identification of common memory genes across different learning paradigms and the temporal activation of the genes are poorly studied. Here, we investigated the temporal aspects of Caenorhabditis elegans gene expression changes using aversive olfactory associative long-term memory (LTAM) and identified three major gene activation waves. Like in previous studies, aversive LTAM is also CREB dependent, and CREB activity is necessary immediately after training. Finally, we define a list of memory paradigm-independent core gene sets as well as conditioning-dependent genes.

Identification of Two Distinct Working Memory-Related Brain Networks in Healthy Young Adults

Abstract Working memory (WM) is an important cognitive domain for everyday life functioning and is often disturbed in neuropsychiatric disorders. Functional magnetic resonance imaging (fMRI) studies in humans show that distributed brain areas typically described as fronto-parietal regions are implicated in WM tasks. Based on data from a large sample of healthy young adults (N = 1369), we applied independent component analysis (ICA) to the WM-fMRI signal and identified two distinct networks that were relevant for differences in individual WM task performance. A parietally-centered network was particularly relevant for individual differences in task measures related to WM performance (“WM dependent”) and a frontally-centered network was relevant for differences in attention-dependent task performance. Importantly, frontal areas that are typically considered as key regions for WM were either involved in both WM-dependent and attention-dependent performance, or in attention-dependent performance only. The networks identified here are provided as publicly available datasets. These networks can be applied in future studies to derive a low-dimensional representation of the overall WM brain activation.

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. We describe the relationship between these estimators and gene expression, demonstrate their genome-wide applicability to association testing even in the absence of individual genotypic data, and show that these estimators powerfully identify methylation-related genomic loci associated with polygenic traits and common diseases, such as schizophrenia. The use of genetic estimators for blood DNA methylation, which are made publically available, can serve as a valuable tool for the identification of epigenetic underpinnings of complex traits.

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

Abstract 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., in cell–cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1–4 (investigated by microarray) and genomic methylation of saliva‐derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N 1 = 924) and Rwanda (N 2 = 371), and investigated whether NOTCH‐related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (p uncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (p uncorrected = 0.05) in Rwandans. Yet, none of the (epi‐)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (p corrected = 0.003) and NOTCH receptor processing (p corrected = 0.01). The environmental factor trauma load was significant in all analyses (all p < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies.