Systems genomics analysis of complex cognitive traits

The study of the genetic underpinnings of human cognitive traits is deemed an important tool to increase our understanding of molecular processes related to physiological and pathological cognitive functioning. The polygenic architecture of such complex traits implies that multiple naturally occurring genetic variations, each of small effect size, are likely to influence jointly the biological processes underlying cognitive ability. Genetic association results are yet devoid of biological context, thus limiting both the identification and functional interpretation of susceptibility variants. This biological gap can be reduced by the integrative analysis of intermediate molecular traits, as mediators of genomic action. In this thesis, I present results from two such systems genomics analyses, as attempts to identify molecular patterns underlying cognitive trait variability. In the first study, we adopted a system-level approach to investigate the relationship between global age-related patterns of epigenetic variation and cortical thickness, a brain morphometric measure that is linked to cognitive functioning. The integration of both genome-wide methylomic and genetic profiles allowed the identification of a peripheral molecular signature that showed association with both cortical thickness and episodic memory performance. In the second study, we explicitly modeled the interdependencies between local genetic markers and peripherally measured epigenetic variations. We thus generated robust estimators of epigenetic regulation and showed that these estimators resulted in the identification of epigenetic underpinnings of schizophrenia, a common genetically complex disorder. These results underscore the potential of systems genomics approaches, capitalizing on the integration of high-dimensional multi-layered molecular data, for the study of brain- related 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. Here we studied CpG methylation, a genetically complex molecular trait that is particularly close to genomic variation, and performed an exhaustive search for two-locus epistatic effects on the CpG-methylation signal in two cohorts of healthy young subjects. We detected robust epistatic effects for a small number of CpGs (N = 404). Our results indicate that epistatic effects explain only a minor part of variation in DNA-CpG methylation. Interestingly, these CpGs were more likely to be associated with gene-expression of nearby genes, as also shown by their overrepresentation in DNase I hypersensitivity sites and underrepresentation in CpG islands. Finally, gene ontology analysis showed a significant enrichment of these CpGs in pathways related to HPV-infection and cancer

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. For 25% of all CpGs we observed medium to large common epigenetic variation. These CpGs were overrepresented in open sea and shore regions, as well as in intergenic regions. They also showed a strong enrichment of significant hits in association analyses. Furthermore, a significant proportion of common DNA methylation is at least partially genetically driven and thus may be observed similarly across tissues. These findings could be of particular relevance for studies of complex neuropsychiatric traits, which often rely on proxy tissues

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

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

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 Swiss Corona Stress Study: Long Covid symptoms in relation to stress and depressive symptoms

Background: An infection with SARS-CoV-2 can lead to long-term health problems known as Long Covid or Post Covid-19 condition. Whereas Long Covid symptoms may induce stress and depressive symptoms, it is also possible that stress and depressive symptoms can contribute to some of the symptoms. Importantly, stress levels and depressive symptoms have been found to be increased during the pandemic and may be also increased after infection. When investigating the prevalence of Long Covid symptoms it seems therefore important to use well-matched controls and to take stress levels and depressive symptoms into account. Methods: We conducted a survey study in over 11’000 subjects in the framework of the Swiss Corona Stress Study (4th survey, November 2021) and assessed stress levels and depressive symptoms (PHQ-9) along with physical and neurological symptoms of the past two weeks. From the 1’428 participants reporting at least one SARS-CoV-2 positive PCR test (98% non-hospitalized), we created 3 non-overlapping groups based on the date of the last reported positive test: at least 9 months before the study (n=774); between 9 and 3 months before the study (n=238); within 3 months before the study (n=416). For each group, we selected an equally sized subset of matched participants from the study pool of 9’651 subjects who didn’t report any SARS-CoV-2 positive test. Results: We found that the prevalence of several physical/neurological symptoms was significantly higher in SARS-CoV-2 positives as compared to the negative controls at all 3 time points. For participants who report having been tested positive at least 9 months ago, the top 3 symptoms as compared to negative controls were loss of smell/taste (prevalence positives: 20%, prevalence negatives: 1%, p=4.0E-20), rapid physical exhaustion (prevalence positives: 29%, prevalence negatives: 15%, p=2.3E-10) and fever (prevalence positives: 10%, prevalence negatives: 3%, p=1.9E-8). Stress levels and depressive symptoms were significantly associated with increased prevalence for most of the symptoms in both SARS-CoV-2 positives and negative controls. However, a history of SARS-CoV-2 infection was not significantly associated with heightened levels of stress or depressive symptoms at any of the investigated time intervals, and a higher prevalence of symptoms in these participants was also observed under adjustment for psychological state measures. Conclusion: The present results indicate that SARS-CoV-2 positivity is associated with higher prevalence of physical or neurological symptoms independently from stress levels or depressive symptoms

Predicting emotional arousal and emotional memory performance from an identical brain network

Encoding and retrieval of emotionally arousing stimuli depend on the activation of multiple interconnected brain regions, with people showing differences in their individual strength of emotional perception and recollection. Understanding the association between these brain regions and the behavioral outcome might therefore have important clinical implications as dysfunctional emotional memory processes are characteristic of many psychiatric disorders. Based on behavioral and fMRI data collected from healthy young adults (N = 1'385), we investigated brain activation patterns, arousal ratings and memory performance during encoding and retrieval of negative and neutral pictures. We performed multi-voxel pattern analysis (MVPA) and voxel-wise association analyses. Subjects' individual strength of perceived arousal at encoding and subjects' memory performance at recognition could be predicted from the fMRI data of the respective tasks by using a topographically identical network of brain regions. This network was mainly left lateralized including dense clusters of voxels in the occipital and parietal lobe and including the amygdala. Voxel-wise association analyses confirmed the close link between the brain activation of both tasks and their relation to the respective behavioral outcome. These results point to the importance of the here identified brain network for emotional memory processes in health and, possibly, disease

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., 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 (N1 = 924) and Rwanda (N2 = 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) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 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 (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 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.publishe