Two papers imply DTNB and other genes in Alzheimer’s

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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New epigenetic clock analyses in the Berlin Aging Study II

As part of the Lifebrain consortium project, LIGA has recently generated genome-wide DNA methylation (DNAm) profiles in a number of independent datasets, including those from the Berlin Aging Study II (BASE-II). These DNAm data were combined into an age estimate called the “epigenetic clock”, which allows comparisons to the traditional chronologically counted age. This approach was followed in the two studies spearheaded by our BASE-II colleagues in Berlin. In the first paper (published in Frontiers of Genetics), we compared the comparability of the genome-wide DNAm clock vs. a smaller version using just 7 DNAm markers. In the second paper (published in the Journal of Gerontology), both clocks were used to assess various aging-related functional traits. However, no evidence was found for an association between the DNAm clock estimates and any of the outcome measures suggesting that the epigenetic clock is not a strong biomarker for these functional domains. From the LIGA group both Yasmine Sommerer and Lars Bertram actively contributed to these analyses.

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First EMIF-AD genome-wide association study published

This month the first genome-wide association study (GWAS) to emerge from the EMIF-AD MBD project was published today in the journal Translational Psychiatry. The paper describes the results of genome-wide genetic association analyses on a total of 16 Alzheimer’s disease biomarker traits (most derived from cerebrospinal fluid) in 931 participants of the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD). The study was funded by the EU’s EMIF program and designed and executed by the LIGA team in conjunction with a large number of international collaborators. A preprint of the m.s. had been posted earlier on bioRxiv prior to initiating the peer-review process. The study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset and sets the stage for genome-wide analyses of other AD-relevant clinical outcomes ascertained in this unique dataset.

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Paper on genetic risk scores in Parkinson’s disease

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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First genome-wide association results in EMIF-AD now available as preprint

Together with several collaborating European research teams, our group is part of the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MDB). Specifically, the LIGA team leads the genomics and epigenomics efforts conducted in EMIF-AD MDB dataset and now completed their first genome-wide association study (GWAS) analyses on 16 traits, including 14 measures of amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, our data suggest novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels. In subsequent work, our team will utilize the genomics data generated in EMIF-AD MDB to perform GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset. The analyses of this very first GWAS in EMIF-AD MDB were spearheaded by LIGA researcher Shengjun Hong and are now available as pre-print on bioRxiv.

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Proteomics analyses hint to new diagnostic approaches in Alzheimer’s

Today, investigators behind the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MDB) project published their first large-scale proteomics study. The study used the “SOMAscan” a high-throughput technology allowing to analyze up to 5,000 proteins simultaneously. In EMIF-AD MDB this was performed in a total of 881 participants split into a discovery and replication group and discovered a panel of 44 proteins which, along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both groups.  Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization analyses. From the LIGA team, which is leading all genomics and epigenomics efforts in EMIF-AD MDB, three researchers contributed (Drs. Dobricic, Hong and Bertram) in the paper that is now published in the journal Alzheimer & Dementia.

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