Biology subjects

Bertram, L.

Publications and source records attributed to Bertram, L..

5 recordsLinked to original sources

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↗

bioRxiv2018

Evidence for a potential role of miR-1908-5p and miR-3614-5p in autoimmune disease risk using genome-wide analyses

Genome-wide association studies (GWAS) have identified a large number of genetic risk loci for autoimmune diseases. However, the functional variants underlying these disease associations remain largely unknown. There is evidence that microRNA-mediated regulation may play an important role in this context. Therefore, we assessed whether autoimmune disease loci unfold their effects via altering microRNA expression in relevant immune cells.\n\nTo this end, we performed microRNA expression quantitative trait loci (eQTL) analyses across 115 GWAS regions associated with 12 autoimmune diseases using next-generation sequencing data of 345 lymphoblastoid cell lines. Statistical analyses included the application and extension of a recently proposed framework (joint likelihood mapping), to microRNA expression data and microRNA target gene enrichment analyses of relevant GWAS data.\n\nOverall, only a minority of autoimmune disease risk loci may exert their pathophysiologic effects by altering miRNA expression based on JLIM. However, detailed functional fine-mapping revealed two independent GWAS regions harboring autoimmune disease risk SNPs with significant effects on microRNA expression. These relate to SNPs associated with Crohns disease (CD; rs102275) and rheumatoid arthritis (RA; rs968567), which affect the expression of miR-1908-5p (prs102275=1.44e-20, prs968567=2.54e-14). In addition, an independent CD risk SNP, rs3853824, was found to alter the expression of miR-3614-5p (p=5.70e-7). To support these findings, we demonstrate that GWAS signals for RA and CD were enriched in genes predicted to be targeted by both miRNAs (all with p<0.05).\n\nIn summary, our study points towards a pathophysiological role of miR-1908-5p and miR- 3614-5p in autoimmunity.

bioinformatics↗

bioRxiv2018

Systematic meta-analyses identify differentially expressed microRNAs in Parkinson’s disease

ObjectiveMicroRNA-mediated (dys)regulation of gene expression has been implicated in Parkinsons disease (PD), although results of microRNA expression studies remain inconclusive. We aimed to identify microRNAs that show consistent differential expression across all published expression studies in PD.\n\nMethodsWe performed a systematic literature search on microRNA expression studies in PD and extracted data from eligible publications. After stratification for brain, blood, and cerebrospinal fluid (CSF)-derived specimen we performed meta-analyses across microRNAs assessed in three or more independent datasets. Meta-analyses were performed using effect-size and p-value based methods, as applicable.\n\nResultsAfter screening 599 publications we identified 47 datasets eligible for meta-analysis. On these, we performed 160 meta-analyses on microRNAs quantified in brain (n=125), blood (n=31), or CSF samples (n=4). Twenty-one meta-analyses were performed using effect sizes. We identified 13 significantly (Bonferroni-adjusted =3.13x10-4) differentially expressed microRNAs in brain (n=3) and blood (n=10) with consistent effect directions across studies. The most compelling findings were with hsa-miR-132-3p (p=6.37x10-5), hsa-miR-497-5p (p=1.35x10-4), and hsa-miR-133b (p=1.90x10-4) in brain, and with hsa-miR-221-3p (p=4.49x10-35), hsa-miR-214-3p (p=2.00x10-34), and hsa-miR-29c-3p (p=3.00x10-12) in blood. No significant signals were found in CSF. Analyses of GWAS data for target genes of brain microRNAs showed significant association (=9.40x10-5) of genetic variants in nine loci.\n\nInterpretationWe identified several microRNAs that showed highly significant differential expression in PD. Future studies may assess the possible role of the identified brain miRNAs in pathogenesis and disease progression as well as the potential of the top blood microRNAs as biomarkers for diagnosis, progression or prediction of PD.

genetics↗

bioRxiv2017

Ninety-nine independent genetic loci influencing general cognitive function include genes associated with brain health and structure (N = 280,360)

General cognitive function is a prominent human trait associated with many important life outcomes1,2, including longevity3. The substantial heritability of general cognitive function is known to be polygenic, but it has had little explication in terms of the contributing genetic variants4,5,6. Here, we combined cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N=280,360; age range = 16 to 102). We found 9,714 genome-wide significant SNPs (P<5 x 10-8) in 99 independent loci. Most showed clear evidence of functional importance. Among many novel genes associated with general cognitive function were SGCZ, ATXN1, MAPT, AUTS2, and P2RY6. Within the novel genetic loci were variants associated with neurodegenerative disorders, neurodevelopmental disorders, physical and psychiatric illnesses, brain structure, and BMI. Gene-based analyses found 536 genes significantly associated with general cognitive function; many were highly expressed in the brain, and associated with neurogenesis and dendrite gene sets. Genetic association results predicted up to 4% of general cognitive function variance in independent samples. There was significant genetic overlap between general cognitive function and information processing speed, as well as many health variables including longevity.

genetics↗