LAVAA: a lightweight association viewer across ailments

Fauman, Eric B.; Keppo, Stella; Cerioli, Nicola; Vyas, Rupesh; Kurki, Mitja; Daly, Mark J.; Reeve, Mary Pat

doi:10.1093/bioadv/vbad018

Cited by 3 publications

(1 citation statement)

References 10 publications

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“…A detailed description of the analytical methods is available at https://github.com/FINNGEN/regenie-pipelines. Phenotype associations for variant rs1244787406-G across 2489 FinnGen core analysis endpoints were visualized using LAVAA ( 34 ). Regional association plots for the endpoint ‘dementia including primary care registry’ were generated with topr 2.0.0 package in R 4.3.2 ( 35, 36 ).…”

Section: Methodsmentioning

confidence: 99%

MonoallelicTYROBPdeletion is a novel risk factor for Alzheimer’s disease

Martiskainen,

Willman,

Heikkinen

et al. 2024

Preprint

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Biallelic loss-of-function variants inTYROBPandTREM2cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some otherTREM2variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleteriousTYROBPvariants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1-4 ofTYROBPand causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelicTYROBPdeletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelicTYROBPdeletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelicTYROBPdeletion carrier with NHD-type bone cysts. Mechanistically, monoallelicTYROBPdeletion leads to decreased levels of DAP12 protein (encoded byTYROBP) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelicTYROBPdeletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies ofTYROBP. Collectively, our findings indicateTYROBPdeletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.

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Section: Methodsmentioning

confidence: 99%

MonoallelicTYROBPdeletion is a novel risk factor for Alzheimer’s disease

Martiskainen,

Willman,

Heikkinen

et al. 2024

Preprint

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Loss ofCFHR5function reduces the risk for age-related macular degeneration

Reeve,

Loomis,

Nissilä

et al. 2024

Preprint

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Age-related macular degeneration (AMD) is a prevalent cause of vision loss in the elderly with limited therapeutic options. A single chromosomal region around the complement factor H gene (CFH) is reported to explain nearly 25% of genetic AMD risk. Here, we used association testing, statistical finemapping and conditional analyses in 12,495 AMD cases and 461,686 controls to deconvolute four major CFH haplotypes that convey protection from AMD. We show that beyond CFH, two of these are explained by Finn-enriched frameshift and missense variants in the CFH modulator CFHR5. We demonstrate through a FinnGen sample recall study that CFHR5 variant carriers exhibit dose-dependent reductions in serum levels of the CFHR5 gene product FHR-5 and two functionally related proteins at the locus. Genetic reduction in FHR-5 correlates with higher preserved activities of the classical and alternative complement pathways. Our results propose therapeutic downregulation of FHR-5 as promising to prevent or treat AMD.

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Phylogenetic diversity and interspecies competition shaped species diversity in adaptive radiated Ligustrum (Oleaceae)

Wang,

Li,

Sun

et al. 2024

J of Sytematics Evolution

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Speciation events often occur with adaptive radiation. The factors that promote these adaptive radiating species diversity patterns have intrigued biologists for more than a century. In the present study, we used the adaptive radiated genus Ligustrum to evaluate the relative contributions of the environment, species interactions, phylogenetic diversity, and diversification rates in generating extant species diversity patterns. Using complete chloroplast genome data, we reconstructed the highly supported and dated backbone phylogenetic relationships of Ligustrum. Biogeographic results indicated that Ligustrum originated in Southwest China during the Oligocene and spread to suitable areas that were warm and humid via 18 dispersal events. For the overlapping ranges of species pairs, a smaller phylogenetic distance was detected in high species overlap than in low species overlap, which is consistent with no significant difference in niche among the different species. We found that the phylogenetic diversity and interspecies competition induced by insignificant niche divergence shaped the global pattern of Ligustrum diversity.

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LAVAA: a lightweight association viewer across ailments

Cited by 3 publications

References 10 publications

MonoallelicTYROBPdeletion is a novel risk factor for Alzheimer’s disease

MonoallelicTYROBPdeletion is a novel risk factor for Alzheimer’s disease

Loss ofCFHR5function reduces the risk for age-related macular degeneration

Phylogenetic diversity and interspecies competition shaped species diversity in adaptive radiated Ligustrum (Oleaceae)

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