Posts in Category ‘Publications

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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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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GWAS on educational attainment in more than 1 million individuals

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

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

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

The aim of this study was to identify microRNAs that show consistent differential expression across all published expression studies in Parkinson’s disease (PD). To this end, we performed a systematic literature search on microRNA expression studies in PD and meta-analyzed the extracted data. We identified several microRNAs that showed highly significant differential expression in PD blood and brain. Future studies need to assess the possible role of these miRNAs in PD pathogenesis and progression as well as the utility as biomarkers for diagnosis, progression or prediction of PD. The study was published as pre-print on bioRxiv.

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New genes identified for human longevity

Elucidating factors that influence human longevity is of great interest to a number of disciplines in medicine and biology. In this study, LIGA contributed genome-wide data from the Berlin Aging Study II to a meta-analysis using parental life span in >600000 individuals as outcome measure. We identified associations at HLA-DQA/DRB1 and LPA and found that genetic variants that increase educational attainment positively affects lifespan whereas increasing BMI showed negative effects. The study was published in the journal Nature Communications.

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Sixteen new genes for reproductive behavior in humans

This work represents the first bona-fide genome-wide association study (GWAS) assessing reproductive behavior in humans, to which LIGA contributed the data from the Berlin Aging Study II. Overall, nearly 350,000 individuals were analyzed leading to the identification of 16 independent loci that are significantly associated with ‘age at first birth’ and/or ‘number of children ever born’. These identified loci harbor genes that are likely to have a role,in human reproduction and infertility. The study was published in the journal Nature Genetics.

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GxE study on inflammation and air polution in PD

Both air pollution exposure and systemic inflammation have been linked to Parkinson’s disease (PD). In this study, led by long-time LIGA collaborator Prof. Beate Ritz at UCLA in the USA, we correlated long term traffic related air pollution measures with genetic markers for inflammation. The analyses showed suggestive evidence that a combination of traffic-related air pollution and genetic variation in the IL1B gene may contribute to risk of developing PD. The results were published in the journal Environmental Research.

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First genome-wide GxE study in PD published

The LIGA team was part of a collaborative effort where we performed the first ever genome-wide gene-environment interaction (GxE) analysis of pesticide exposure and risk of Parkinson’s disease (PD). The results of this effort suggest that the effect of pesticide exposure on PD risk may be modified by SNPs in the ERCC6L2 gene. This finding needs to be replicated in independent samples before it should be considered as established. The results were published in the journal Parkinsonism and Related Disorders.

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