Posts in Category ‘Publications’

New GWAS paper on Alzheimer’s biomarkers

30. November 2023

In collaboration with our long-standing collaborators at VIB Center for Molecular Neurology in Antwerp, Belgium, the LIGA team published a new paper on the role of genetics on Alzheimer’s disease (AD) biomarker levels. Here, the data for six different CSF biomarkers ascertained in the EMIF-AD and ADNI datasets (n~1000) were combined using a novel multivariate approach to derive components that were deemed more informative than analyzing biomarkers individually. Using a genome-wide association study (GWAS) approach, we then searched for genetic determinants of biomarker component variation and identified five loci to show very strong (i.e. genome-wide significant) association, including two novel signals. One of the novel loci highlighted the gene GRIN2D, which is part of an important neurotransmitter receptor and plays an important role in learning and memory. A wide range of additional analyses suggested that the novel computational approach developed by our group can improve our understanding of AD genetics and may contribute to precision medicine. The study was published in the renowned journal “Genome Medicine” in October 2023. See also the press release of University of Lübeck on this paper.

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New EWAS in Alzheimer’s brains published

25. May 2023

This month a new epigenome-wide association study (EWAS) led by the LIGA team was published in the journal Alzheimer’s Research & Therapy. The study was based on generating genome-wide DNA methylation profiles in nearly 200 brain samples from patients with Alzheimer’s disease (AD) and controls with the aim to identify novel genomic regions showing differential methylation. By combining our novel DNAm data with those from two previous studies we identified 12 loci showing epigenome-wide significant association with AD. Four of these loci, near the genes 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. Our study represents the hitherto most comprehensive EWAS in AD using tissue from the entorhinal cortex and highlights several novel differentially methylated loci with potential effects on gene expression. The study was conducted with collaborators in Oxford and Kiel and represents the third publication of the doctoral thesis work of first author Yasmine Sommerer from the LIGA team.

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New LIGA paper on DNA methylation in brain and periphery

1. November 2022

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New papers on epigenetic age estimators in old age

26. September 2022

Our collaborators at Charité university hospital in Berlin, Germany, have recently extended their ongoing projects assessing the relevance of so called “epigenetic clock” estimates in advance age. To this end, the LIGA team had generated high-resolution DNA methylation profiles in participants of the Berlin Aging Study II (BASE-II). In their newest analyses, the BASE-II team – with the help of Yasmine Sommerer and Lars Bertram from LIGA – found that vitamin D supplementation (to treat vitamin D deficiency) is associated with slower epigenetic aging (Vetter et al, 2022a). In a second analysis (Vetter et al., 2022b), we investigated the role of perceived stress on epigenetic aging as measured by DNA methylation. Although a growing body of literature suggests an association between higher (=older) epigenetic age and stress or trauma during early childhood, the current study found no evidence for an association of perception of stress with DNAmAA in older people from BASE-II, suggesting that different mechanisms are at work in young vs. old people.

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Two new LIGA papers on the role of miRNAs in AD and PD

29. August 2022

In collaboration with their partners at Oxford and London, the LIGA group recently completed two projects on the role of micro-RNAs in Alzheimer’s (AD) and Parkinson’s disease (PD). This work extended earlier meta-analytic projects led by the LIGA team combining published evidence on the topic (see papers by Takousis et al, 2019 and Schulz et al. 2019). Our new work took the main results of these meta-analyses and tested them in two unique and independent collections of human brain samples contributed by our collaborators in the UK. Specifically, the first new study (published in Translational Psychiatry) revealed that micro-RNAs miR-129-5p, miR-132-5p, and miR-138-5p, and miR-195-5p are differentially expressed in Alzheimer’s. Interestingly, the second study (now in press in the journal Brain Communications) also found miR-129-5p and miR-132-5p to be differentially expressed in Parkinson’s. In addition, this latter work also implied PD candidate miR-132-3p to be associated with both disorders. Collectively, these results point to a “common micro-RNA signature” in both AD and PD, potentially pinpointing shared pathogenic mechanisms across these two neurodegenerative diseases. Both studies were spearheaded by LIGA member Valerija Dobricic who also served as first author on both papers.

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Two papers imply DTNB and other genes in Alzheimer’s

21. March 2022

Two papers with LIGA contributions implicating rare variants in the DTNB and other genes in Alzheimer’s disease. The first paper (by Neumann et al.) utilized whole-exome sequencing data in a subset of participants of the EMIF-AD MBD study and utilized a novel analysis algorithm for CSF biomarker data to arrive at DTNB, FFO1, NLRC3 and SLC22A10 as putative disease genes. The study was led by our EMIF-AD collaborators at VIB in Antwerp and utilized CSF biomarker data which was combined by principal component analysis as outcome. The second study (by Prokopenko et al.) was led by our long-standing collaborators at Harvard Medical school and used whole-genome sequencing data in several family-based and case-control Alzheimer’s datasets. By applying a novel algorithm to group rare variants into genomic regions, this study, too, independently implicated rare variants in DTNB (and DLG2) to be linked to Alzheimer’s. DTNB (encoding: beta dystobrevin) is an interesting candidate owing to its role in postsynaptic membranes of excitatory synapses in the human brain. Both papers were published in the journal Molecular Psychiatry in Februrary and March of 2022.

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GWAS links TMEMB106B and CPOX to AD biomarkers

14. May 2021

LIGA_group.webex
Virtual group photo of LIGA team members who are co-authors in the new study.
(Clockwise from top left: V. Dobricic, O. Ohlei, L. Bertram, C. Lill)

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Paper on genetic risk scores in Parkinson’s disease

1. October 2020

This month, a new paper was published assessing the genetic overlap between the occurrence of hallucinations in Parkinson’s disease and Alzheimer’s and schizophrenia. To this end, genome-wide genotyping data on two population-based cohorts was used to build so called polygenic risk scores based on previously published genome-wide association studies. Genotype data for one of these cohorts was generated by the LIGA team and contributed to this international effort led by long-standing LIGA collaborator Prof. Beate Ritz at UCLA, USA. Interestingly, the strongest genetic links were observed with markers for Alzheimer’s but less so for schizophrenia suggesting that mechanisms for hallucinations in Parkinson’s may in part be driven by the same genetic architecture that leads to cognitive decline in Alzheimer’s. The study was published in the journal Neurology Genetics with Drs. Valerija Dobricic, Lars Bertram, and Christina M. Lill as LIGA co-authors.

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GWAS on educational attainment in more than 1 million individuals

18. September 2018

A new genome-wide association study (GWAS) investigated the genetics of educational attainment in over 1 million individuals, including 2,000 from the Berlin Aging Study II (BASE-II) contributed by our group. The study represents one of the largest GWAS ever performed to date and identified nearly 1,300 independent lead SNPs to show genome-wide significant association with education. Many of the identified variants are located in genes involved in brain-development processes and neuron-to-neuron communication. Polygenic analyses suggest that up to 13% of the variance underlying inter-individual differences in educational attainment can now be explained by these data, more than explained by household income but less than by parental educational attainment. The study was published in the journal Nature Genetics.

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First ever field synopsis of genetic association studies in dystonia

27. July 2018

Researchers from LIGA together with two colleagues from the Institute of Neurogenetics this month published the first ever field synopsis for genetic association studies in dystonia. The study, led by LIGA PhD student Olena Ohlei, aimed at separating the wheat from the chaff for genetic association results in datasets of isolated dystonia. To this end, we scrutinized more than 3,500 published articles resulting in the inclusion of 42 independent publications allowing 134 meta-analyses on 45 variants across 17 genes. While subsequently performed meta-analyses pinpointed several association signals with variants in TOR1A, DRD1, and ARSG, no single variant displayed compelling association with dystonia in the available data highlighting the need for additional large-scale studies. The publication was part of an ongoing DFG-funded project led by Lars Bertram and Jeanette Erdmann at the Institute of Cardiogenetics. The Ohlei et al paper is now published in the Journal Parkinsonism and Related Disorders (after having been posted on bioRxiv prior to peer-review).

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Genome-wide study pinpoints 148 loci for cognitive function

29. May 2018

Much like many other human phenotypes, cognitive function is a highly polygenic trait. In the largest genome-wide association study (GWAS) performed to date, our colleagues Gail Davies and Ian Deary at University of Edinburgh spearheaded analyses on over 300,000 individuals (including ~2000 from the Berlin Aging Study II, co-led by LIGA investigators) identifying nearly 150 independent genetic loci associated with cognitive function, many of which had not been known previously. Within the novel genetic loci are DNA variants associated with neurodevelopmental and neurodegenerative disorders (such as Alzheimer’s and Parkinson’s diesease), physical and psychiatric illnesses, and brain structure. The results of this study shed important new light on the inborn factors contributing to cognitive (dys-)function in humans. The study was published in the journal Nature Communications.

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