Biology subjects

Bertram, L.

Publications and source records attributed to Bertram, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Genomics of Educational Attainment Across 80 Years of Social and Political Transformation in Germany

Abrupt social and political transformations in twentieth-century Germany may have shifted how polygenic indices relate to educational outcomes across birth cohorts. Following a prespecified analysis plan, we harmonized genomic, educational, and regional data from four German studies, comprising 13,049 individuals born between 1918 and 1995. Polygenic index associations with educational attainment were robust and strengthened modestly across more recent birth cohorts, with no detectable difference between East and West Germany. Associations with intergenerational educational mobility showed no evidence of such strengthening but were stronger in the East than in the West. Polygenic indices were less predictive of educational attainment and educational mobility for women than for men, with no evidence of regional variation. We discuss the methodological limitations of polygenic indices for examining gene-environment interactions, and emphasize that evaluating whether these differences represent progress towards equal educational opportunity requires a normative framework that social science genetics alone cannot supply.

genomics↗

bioRxiv2025

Context-dependent regulatory variants in Alzheimer's disease

Noncoding genetic variants underlie many complex diseases, yet identifying and interpreting their functional impacts remains challenging. Late-onset Alzheimers disease (LOAD), a polygenic neurodegenerative disorder, exemplifies this challenge. The disease is strongly associated with noncoding variation, including common variants enriched in microglial enhancers and rare variants nominated at loci implicated in neurodevelopment and synaptic function. These variants may perturb regulatory sequences by disrupting transcription factor (TF) motifs or altering local regulatory sequence context, with potential consequences for gene expression and chromatin accessibility. However, assessing their impact is complicated by the context-dependent functions of regulatory sequences, underscoring the need to systematically examine variant effects across diverse tissues, cell types, and cellular states. Here, we combined in vitro and in vivo massively parallel reporter assays (MPRAs) with interpretable machine-learning models to systematically characterize common and rare variants across myeloid and neuron-enriched neural contexts. Parallel profiling of variants in four immune states in vitro and three mouse brain regions in vivo revealed that individual variants can differentially and even oppositely modulate reporter activity across cellular contexts, while a subset showed immune-state-dependent effects. Within the assayed candidate set, the relative effect sizes of common and rare variants reversed between contexts, with common variants showing larger effects in THP-1 macrophages and rare variants in brain tissue. Interpretable sequence-to-function models prioritized context-biased variants and generated motif-level hypotheses, including predicted transcription-factor motif disruption and subtler changes in local motif context. To probe endogenous consequences at a prioritized locus, we used CRISPR interference to perturb a rare-variant-containing enhancer at the SEC63-OSTM1 locus, revealing metabolic and biosynthetic transcriptional programs resembling those induced by SEC63 promoter perturbation, together with a stimulation-specific interferon response. These findings show that LOAD-associated noncoding variants exhibit context-dependent effects on reporter activity and predicted chromatin accessibility, and provide a framework for linking genetic association to regulatory activity, sequence grammar and endogenous transcriptional state.

genomics↗

bioRxiv2025

Molecular hallmarks of excitatory and inhibitory neuronal resilience and resistance to Alzheimer's disease

BackgroundA significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimers disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals can identify therapeutic targets for AD dementia. This study aims to define molecular and cellular signatures of cognitive resilience, protection and resistance, by integrating genetics, bulk RNA, and single-nucleus RNA sequencing data across multiple brain regions from AD, resilient, and control individuals. MethodsWe analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk (n=631) and multi-regional single nucleus (n=48) RNA sequencing. Subjects were categorized into AD, resilient, and control based on {beta}-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition distribution. ResultsTranscriptomic results, supported by GWAS-derived polygenic risk scores, place cognitive resilience as an intermediate state in the AD continuum. Tissue-level analysis revealed 43 genes enriched in nucleic acid metabolism and signaling that were differentially expressed between AD and resilience. Only GFAP (upregulated) and KLF4 (downregulated) showed differential expression in resilience compared to controls. Cellular resilience involved reorganization of protein folding and degradation pathways, with downregulation of Hsp90 and selective upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. Excitatory neuronal subpopulations in the entorhinal cortex (ATP8B1+ and MEF2Chigh) exhibited unique resilience signaling through neurotrophin (modulated by LINGO1) and angiopoietin (ANGPT2/TEK) pathways. We identified MEF2C, ATP8B1, and RELN as key markers of resilient excitatory neuronal populations, characterized by selective vulnerability in AD. Protective rare variant enrichment highlighted vulnerable populations, including somatostatin (SST) inhibitory interneurons, validated through immunofluorescence showing co-expression of rare variant associated RBFOX1 and KIF26B in SST+ neurons in the dorsolateral prefrontal cortex. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. ConclusionsWe identified molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preservation of neuronal function, maintenance of excitatory/inhibitory balance, and activation of protective signaling pathways. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable SST interneurons likely provide compensation against AD-associated dysregulation. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

neuroscience↗

bioRxiv2023

Accelerated brain change in healthy adults is associated with genetic risk for Alzheimer's disease and uncovers adult lifespan memory decline

Across healthy adult life our brains undergo gradual structural change in a pattern of atrophy that resembles accelerated brain changes in Alzheimers disease (AD). Here, using four polygenic risk scores for AD (PRS-AD) in a longitudinal adult lifespan sample aged 30 to 89 years (2-7 timepoints), we show that healthy individuals who lose brain volume faster than expected for their age, have a higher genetic AD risk. We first demonstrate PRS-AD associations with change in early Braak regions, namely hippocampus, entorhinal cortex, and amygdala, and find evidence these extend beyond that predicted by APOE genotype. Next, following the hypothesis that brain changes in ageing and AD are largely shared, we performed machine learning classification on brain change trajectories conditional on age in longitudinal AD patient-control data, to obtain a list of AD-accelerated features and model change in these in adult lifespan data. We found PRS-AD was associated with a multivariate marker of accelerated change in many of these features in healthy adults, and that most individuals above [~]50 years of age are on an accelerated change trajectory in AD-accelerated brain regions. Finally, high PRS-AD individuals also high on a multivariate marker of change showed more adult lifespan memory decline, compared to high PRS-AD individuals with less brain change. Our results support a dimensional account linking normal brain ageing with AD, suggesting AD risk genes speed up the shared pattern of ageing- and AD-related neurodegeneration that starts early, occurs along a continuum, and tracks memory change in healthy adults.

neuroscience↗

bioRxiv2022

Sleep duration and brain structure - phenotypic associations and genotypic covariance

The question of how much sleep is best for the brain attracts scientific and public interest, and there is concern that insuficient sleep leads to poorer brain health. However, it is unknown how much sleep is sufficient and how much is too much. We analyzed 51,295 brain magnetic resonnance images from 47,039 participants, and calculated the self-reported sleep duration associated with the largest regional volumes and smallest ventricles relative to intracranial volume (ICV) and thickest cortex. 6.8 hours of sleep was associated with the most favorable brain outcome overall. Critical values, defined by 95% confidence intervals, were 5.7 and 7.9 hours. There was regional variation, with for instance the hippocampus showing largest volume at 6.3 hours. Moderately long sleep (> 8 hours) was more strongly associated with smaller relative volumes, thinner cortex and larger ventricles than even very short sleep (< 5 hours), but effect sizes were modest. People with larger ICV reported longer sleep (7.5 hours), so not correcting for ICV yielded longer durations associated with maximal volume. Controlling for socioeconomic status, body mass index and depression symptoms did not alter the associations. Genetic analyses showed that genes related to longer sleep in short sleepers were related to shorter sleep in long sleepers. This may indicate a genetically controlled homeostatic regulation of sleep duration. Mendelian randomization analyses did not suggest sleep duration to have a causal impact on brain structure in the analyzed datasets. The findings challenge the notion that habitual short sleep is negatively related to brain structure. Significance statementAccording to consensus recommendations, adults should sleep between 7 and 9 hours to optimize their health. We found that sleeping less than the recommended amount was associated with greater regional brain volumes relative to intracranial volume, and very short sleep was only weakly related to smaller volumes. Genetic analyses did not show causal effects of sleep duration on brain structure. Taken together, the results suggest that habitual short sleep is not an important contributor to lower brain volumes in adults on a group level, and that large individual dfferences in sleep need likely exist.

neuroscience↗

bioRxiv2022

Common signatures of differential microRNA expression in Parkinson's and Alzheimer's disease brains

BackgroundDysregulation of microRNA (miRNA)-mediated gene expression has been implicated in the pathogenesis and course of many neurodegenerative diseases including Parkinsons disease (PD). However, the functionally relevant miRNAs remain largely unknown. Previous meta-analyses on differential miRNA expression data in post-mortem PD brains have highlighted several miRNAs showing consistent and statistically significant effects. However, these meta-analyses were based on exceedingly small sample sizes. MethodsIn this study, we quantified the expression of the four most compelling PD candidate miRNAs from these meta-analyses in the superior temporal gyrus (STG) of one of the largest case-control post-mortem brain datasets available (261 samples), thereby quadruplicating previously investigated sample sizes. Furthermore, we probed for common differential miRNA expression signatures with Alzheimers disease (AD) by also analyzing these miRNAs in post-mortem STG of 190 AD patients and controls and by testing six top AD miRNAs in the PD brains. ResultsOf all ten analyzed miRNAs, PD candidate miRNA homo sapiens (hsa-) miR-132-3p showed evidence for differential expression in both PD (p=4.89E-06) and AD (p=3.20E-24), and AD miRNAs hsa-miR-132-5p (p=4.52E-06) and hsa-miR-129-5p (p=0.0379) showed evidence for differential expression in PD. Combining these novel data with previously published data substantially improved the statistical support (=3.85E-03 using Bonferroni correction) of the corresponding meta-analyses clearly and compellingly implicating these miRNAs in both PD and AD. Furthermore, hsa-miR-132-3p/-5p (but not hsa-miR-129-5p) showed association with neuropathological Braak PD staging (p=3.51E-03/p=0.0117), suggesting that these miRNAs may play a role in -synuclein aggregation beyond the early disease phase. ConclusionsOur study represents the largest independent assessment of recently highlighted candidate brain miRNAs in PD and AD post-mortem brain samples, to date. Our results implicate hsa-miR-132-3p/-5p and hsa-miR-129-5p to be differentially expressed in both PD and AD brains, potentially pinpointing shared pathogenic mechanisms across these neurodegenerative diseases.

neuroscience↗

bioRxiv2021

A correlation map of genome-wide DNA methylation patterns between paired human brain and buccal samples

Epigenome-wide association studies (EWAS) assessing the link between DNA methylation (DNAm) and phenotypes related to structural brain measures, cognitive function, and neurodegenerative diseases are becoming increasingly more popular. Due to the inaccessibility of brain tissue in humans, several studies use peripheral tissues such as blood, buccal swabs, and saliva as surrogates. To aid the functional interpretation of EWAS findings in such settings, there is a need to assess the correlation of DNAm variability across tissues in the same individuals. In this study, we performed a correlation analysis between DNAm data of a total of n=120 matched post-mortem buccal and prefrontal cortex samples. We identified nearly 25,000 (3% of approximately 730,000) cytosine-phosphate-guanine (CpG) sites showing significant (False Discovery Rate q < 0.05) correlations between buccal and PFC samples. Correlated CpG sites showed a preponderance to being located in promoter regions and showed a significant enrichment of being determined by genetic factors, i.e. methylation quantitative trait loci (mQTL), based on buccal and dorsolateral prefrontal cortex mQTL databases. Our novel buccal-brain DNAm correlation map will provide a valuable resource for future EWAS using buccal samples for studying DNAm effects on phenotypes relating to the brain. All correlation results are made freely available to the public online.

genomics↗

bioRxiv2021

Seven-CpG DNA Methylation Age determined by Single Nucleotide Primer Extension and Illumina's Infinium MethylationEPIC array provide highly comparable results

DNA methylation age (DNAm age, epigenetic clock) is a novel and promising biomarker of aging. It is calculated from the methylation fraction of specific cytosine phosphate guanine sites (CpG sites) of genomic DNA. Several groups have proposed epigenetic clock algorithms and these differ mostly regarding the number and location of the CpG sites considered and the method used to assess the methylation status. Most epigenetic clocks are based on a large number of CpGs, e.g. as measured by DNAm microarrays. We have recently evaluated an epigenetic clock based on the methylation fraction of seven CpGs that were determined by methylation-sensitive single nucleotide primer extension (MS-SNuPE). This method is more cost-effective when compared to array-based technologies as only a few CpGs need to be examined. However, there is only little data on the correspondence in epigenetic age estimation using the 7-CpG clock and other algorithms. To bridge this gap, in this study we measured the 7-CpG DNAm age using two methods, via MS-SNuPE and via the MethylationEPIC array, in a sample of 1,058 participants of the Berlin Aging Study II (BASE-II), assessed as part of the GendAge study. On average, participants were 75.6 years old (SD: 3.7, age range: 64.9 - 90.0, 52.6% female). Agreement between methods was assessed by Bland-Altman plots. DNAm age was highly correlated between methods (Pearsons r=0.9) and Bland-Altman plots showed a difference of 3.1 years. DNAm age by the 7-CpG formula was 71.2 years (SD: 6.9 years, SNuPE) and 68.1 years (SD: 6.4 years, EPIC array). The mean of difference in methylation fraction between methods for the seven individual CpG sites was between 0.7 and 13 percent. To allow direct conversion between methods we developed an adjustment formula with a randomly selected training set of 529 participants using linear regression. After conversion of the Illumina data in a second and independent validation set, the adjusted DNAm age was 71.44 years (SD: 6.1 years, n=529). In summary, we found the results of DNAm clocks to be highly comparable. Furthermore, we developed an adjustment formula that allows for direct conversion of estimates between methods and enables one singular clock to be used in studies that employ either the Illumina or the SNuPE method.

genetics↗

bioRxiv2021

Entorhinal cortex EWAS meta-analysis highlights four novel loci showing differential methylation in Alzheimer's disease

BackgroundStudies on DNA methylation (DNAm) in Alzheimers disease (AD) have recently highlighted several genomic loci showing association with disease onset and progression. MethodsHere, we conducted an epigenome-wide association study (EWAS) using DNAm profiles in entorhinal cortex (EC) from 149 AD patients and control brains and combined these with two previously published EC datasets by meta-analysis (total n=337). ResultsWe identified 12 cytosine-phosphate-guanine (CpG) sites showing epigenome-wide significant association with either case-control status or Braaks tau-staging. Four of these CpGs, located in proximity to CNFN/LIPE, TENT5A, PALD1/PRF1, and DIRAS1, represent novel findings. Integrating DNAm levels with RNA sequencing-based mRNA expression data generated in the same individuals showed significant DNAm-mRNA correlations for 6 of the 12 significant CpGs. Lastly, by calculating rates of epigenetic age acceleration using two recently proposed "epigenetic clock" estimators we found a significant association with accelerated epigenetic aging in AD patients vs. controls. ConclusionIn summary, our study represents the hitherto most comprehensive EWAS in AD using EC and highlights several novel differentially methylated loci with potential effects on gene expression.

genomics↗

bioRxiv2021

Differential microRNA expression analyses across two brain regions in Alzheimer's disease

BackgroundDysregulation of microRNAs (miRNAs) is involved in the pathogenesis of neurodegenerative diseases, including Alzheimers disease (AD). Hitherto, sample sizes from differential miRNA expression studies in AD are exceedingly small aggravating any biological inference. To overcome this limitation, we investigated six candidate miRNAs in a large collection of brain samples. MethodsBrain tissue was derived from superior temporal gyrus (STG) and entorhinal cortex (EC) from 99 AD patients and 91 controls. Expression of six miRNAs was examined by qPCR (STG) or small RNA sequencing (EC). Brain region-dependent differential miRNA expression was investigated in a transgenic AD mouse model using qPCR and FISH. Total RNA sequencing was used to assess differential expression of miRNA target genes. ResultsMiR-129-5p, miR-132-5p, and miR-138-5p were significantly downregulated in AD vs. controls both in STG and EC, while miR-125b-5p and miR-501-3p showed no evidence for differential expression in this dataset. In addition, miR-195-5p was significantly upregulated in EC but not STG in AD patients. The brain region-specific pattern of miR-195-5p expression was corroborated in vivo in transgenic AD mice. Total RNA sequencing identified several novel and functionally interesting target genes of these miRNAs involved in synaptic transmission (GABRB1), the immune-system response (HCFC2) or AD-associated differential methylation (SLC16A3). ConclusionsUsing two different methods (qPCR and small RNA-seq) in two separate brain regions in 190 individuals we more than doubled the available sample size for most miRNAs tested. Differential gene expression analyses confirm the likely involvement of miR-129-5p, miR-132-5p, miR-138-5p, and miR-195-5p in AD pathogenesis and highlight several novel potentially relevant target mRNAs. FundingThis work was supported by the Deutsche Forschungsgemeinschaft (DFG) and the National Science Foundation China (NSFC) as a Joint Sino-German research project ("MiRNet-AD", #391523883). Additional support was provided by the DFG Research Infrastructure NGS_CC (project 407495230) as part of the Next Generation Sequencing Competence Network (#423957469) and the Cure Alzheimer s Fund (CAF) as part of the CIRCUITS consortium project.

neuroscience↗

bioRxiv2021

Brain age relates to early life factors but not to accelerated brain aging

Brain age is a widely used index for quantifying individuals brain health as deviation from a normative brain aging trajectory. Higher than expected brain age is thought partially to reflect above-average rate of brain aging. We explicitly tested this assumption in two large datasets and found no association between cross-sectional brain age and steeper brain decline measured longitudinally. Rather, brain age in adulthood was associated with early-life influences indexed by birth weight and polygenic scores. The results call for nuanced interpretations of cross-sectional indices of the aging brain and question their validity as markers of ongoing within-person changes of the aging brain. Longitudinal imaging data should be preferred whenever the goal is to understand individual change trajectories of brain and cognition in aging.

neuroscience↗

bioRxiv2020

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

BackgroundNeurofilament light (NF-L), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are utilized as biomarkers for Alzheimers disease (AD), to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Here we performed genome-wide association study (GWAS) analyses using all three biomarkers as outcome. MethodsDNA and cerebrospinal fluid (CSF) samples originated from the European Medical Information Framework AD Multimodal Biomarker Discovery (EMIF-AD MBD) study. Overlapping genotype/phenotype data were available for n=671 (NF-L), 677 (YKL-40), and 672 (Ng) individuals. GWAS analyses applied linear regression models adjusting for relevant covariates. FindingsWe identify novel genome-wide significant associations with markers in TMEM106B and CSF levels of NF-L. Additional novel signals were observed with DNA variants in CPOX and CSF levels of YKL-40. Lastly, we confirmed previous work suggesting that YKL-40 levels are regulated by cis protein quantitative trait loci (pQTL) in CHI3L1. InterpretationOur study provides important new insights into the genetic architecture underlying inter-individual variation in all three tested AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

genomics↗

bioRxiv2020

Sleep Efficiency Relates to Hippocampal Integrity Decline in β-Amyloid Positive Adults

BackgroundTo test the hypothesis that worse self-reported sleep relates to memory decay and reduced hippocampal integrity as indexed by increased intra-hippocampal water diffusion, and that the relations are stronger in the presence of {beta}-amyloid (A{beta}) accumulation, a marker of Alzheimers disease (AD) pathology. MethodsTwo-hundred and forty-three cognitively healthy participants, aged 19-81 years, completed the Pittsburgh Sleep Quality Index, and 2 diffusion tensor imaging sessions, on average 3 years apart, allowing measures of decline in hippocampal microstructural integrity as indexed by increased mean diffusivity. We measured memory decay using delayed recall from the California Verbal Learning Test. 18F-Flutemetamol positron emission tomography, in 108 participants above 44 years of age, yielded 23 A{beta} positive. Genotyping enabled controlling for APOE {varepsilon}4 status, and polygenic scores for sleep efficiency and AD. ResultsWorse global sleep quality and sleep efficiency related to more rapid reduction in hippocampal microstructural integrity over time. Focusing on sleep efficiency, the relation was stronger in presence of A{beta} accumulation. Sleep efficiency related to memory decay indirectly via hippocampal integrity decline. The results were not explained by genetic risk for sleep efficiency and AD. ConclusionsPoor self-reported sleep efficiency related to decline in hippocampal integrity, especially in the presence of A{beta} accumulation. Poor sleep and hippocampal microstructural decline may partly explain memory decline in older adults with A{beta} pathology. The relationships were not explained by genetic risk. Poor self-reported sleep efficiency might constitute a risk factor for AD, although the causal mechanisms driving the of observed associations remain unknown.

neuroscience↗

bioRxiv2019

Genetic risk for Alzheimer`s disease predicts hippocampal volume through the lifespan

INTRODUCTIONIt is unknown whether genetic risk for Alzheimers disease (AD) represents a stable influence on the brain from early in life, or whether effects are age-dependent. It is critical to characterize the effects of genetic risk factors on the primary neural substrate of AD, the hippocampus, throughout life.\n\nMETHODSRelations of polygenic risk score (PGS) for AD, including variants in Apolipoprotein E (APOE) with hippocampal volume and its change were assessed in a healthy longitudinal lifespan sample (n = 1181, 4-95 years), followed for up to 11 years with a total of 2690 MRI scans.\n\nRESULTSAD-PGS showed a significant negative effect on hippocampal volume. Offset effects of AD-PGS and APOE {varepsilon}4 were present in hippocampal development, and interactions between age and genetic risk on volume change were not consistently observed. DISCUSSION: Endophenotypic manifestation of polygenic risk for AD may be seen across the lifespan in healthy persons.\n\nHighlightsO_LIGenetic risk for AD affects the hippocampus throughout the lifespan\nC_LIO_LIAPOE {varepsilon}4 carriers have smaller hippocampi in development\nC_LIO_LIDifferent effects of genetic risk at different ages were not consistently observed\nC_LIO_LIGenetic factors increasing risk for AD impact healthy persons throughout life\nC_LIO_LIA broader population and age range are relevant targets for attempts to prevent AD\nC_LI

neuroscience↗

bioRxiv2019

Exploring the space of human exploration

What drives peoples exploration in complex scenarios where they have to actively acquire information by making queries? How do people adapt their selection of queries to their environment? We explore these questions using Entropy Mastermind, a novel variant of the Mastermind code-breaking game, in which participants have to guess a secret code by making useful queries. Participants solved games more efficiently and more quickly if the entropy of the game environment was low; moreover, people adapted their initial queries to the scenario they were in. We also investigated whether it would be possible to predict participants queries within the generalized Sharma-Mittal information-theoretic framework. Although predicting individual queries is difficult, the modeling framework offered important insight on human behavior. Entropy Mastermind offers rich possibilities for modeling and behavioral research.

animal behavior and cognition↗

bioRxiv2018

Differential expression of microRNAs in Alzheimer’s disease brain, blood and cerebrospinal fluid: a systematic review and meta-analysis

INTRODUCTIONSeveral microRNAs (miRNAs) have been implicated in Alzheimers disease (AD) pathogenesis but the evidence from individual case-control-studies remains inconclusive.\n\nMETHODSA systematic literature review was performed, followed by standardised multi-stage data extraction, quality control, and meta-analyses on eligible data for brain, blood, and cerebrospinal fluid (CSF) specimens. Results were compared with miRNAs reported in the abstracts of eligible studies or recent qualitative reviews to assess novelty.\n\nRESULTSData from 147 independent datasets across 107 publications were quantitatively assessed in 461 meta-analyses. Twenty-five, five, and 32 miRNAs showed study-wide significant differential expression (<1.08x10-4) in brain, CSF, and blood-derived specimens, respectively, with 5 miRNAs showing differential expression in both brain and blood. Of these 57 miRNAs, 13 had not been reported in the abstracts of previous original or review articles.\n\nDISCUSSIONOur systematic assessment of differential miRNA expression is the first of its kind in AD and highlights miRNAs of relevance.

neuroscience↗

bioRxiv2018

Alzheimer’s disease risk SNPs show no strong effect on miRNA expression in human lymphoblastoid cell lines

The role of microRNAs (miRNAs) in the pathogenesis of Alzheimers disease (AD) is currently extensively investigated. In this study, we assessed the potential impact of AD genetic risk variants on miRNA expression by performing large-scale bioinformatic data integration. Our analysis was based on genetic variants from three AD genome-wide association studies (GWAS). Association with miRNA expression was tested by expression quantitative trait loci (eQTL) analysis using next-generation miRNA sequencing data generated in lymphoblastoid cell lines (LCL). While, overall, we did not identify a strong effect of AD GWAS variants on miRNA expression in this cell type we highlight two notable outliers, i.e. miR-29c-5p and miR-6840-5p. MiR-29c-5p was recently reported to be involved in the regulation of BACE1 and SORL1 expression. In conclusion, despite two exceptions our large-scale assessment provides only limited support for the hypothesis that AD GWAS variants act as miRNA eQTLs.

genetics↗

bioRxiv2018

Field synopsis and systematic meta-analyses of genetic association studies in isolated dystonia

Background and objectivesDystonia is a genetically complex disease with both monogenic and polygenic causes. For the latter, numerous genetic associations studies have been performed with largely inconsistent results. The aim of this study was to perform a field synopsis including systematic meta-analyses of genetic association studies in isolated dystonia\n\nMethodsFor the field synopsis we systematically screened and scrutinized the published literature using NCBIs PubMed database. For genetic variants with sufficient information in at least two independent datasets, random-effects meta-analyses were performed, including meta-analyses stratified by ethnic descent and dystonia subtypes.\n\nResultsA total of 3,575 articles were identified and scrutinized resulting in the inclusion of 42 independent publications allowing 134 meta-analyses on 45 variants across 17 genes. While our meta-analyses pinpointed several significant association signals with variants in TOR1A, DRD1, and ARSG, no single variant displayed compelling association with dystonia in the available data.\n\nConclusionsOur study provides an up-to-date summary of the status of dystonia genetic association studies. Additional large-scale studies are needed to better understand the genetic causes of isolated dystonia.

neuroscience↗