Using regulatory variants to detect gene–gene interactions identifies networks of genes linked to cell immortalisation

Wragg, David; Liu, Qian; Zeng, Lin; Riggio, Valentina; Pugh, Carys; Beveridge, Allan; Brown, Helen; Hume, David; Harris, Sarah E.; Deary, Ian J.; Tenesa, Albert; Prendergast, James

doi:10.1038/s41467-019-13762-6

Cited by 8 publications

(8 citation statements)

References 57 publications

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“…Sample sequencing, variant calling and quality control methods for each dataset are broadly comparable. These are described elsewhere for Project MinE (Project MinE ALS Sequencing Consortium, 2018) and the LBC (Wragg et al, 2020). Information for SARM1 variants in the Answer ALS project was obtained using ANNOVAR (Wang et al, 2010) annotation on GRCh38 positions, after read mapping with Burrows-Wheeler Alignment tool (BWA) (Li & Durbin, 2010), variant calling with GATK (McKenna et al, 2010), and joint-genotype using Sentieon (Freed et al, 2017).…”

Section: Methodsmentioning

confidence: 99%

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Gilley

Jackson

Pipis

et al. 2021

Preprint

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SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We describe eight rare missense or in-frame microdeletion human SARM1 variant alleles, in patients with amyotrophic lateral sclerosis (ALS), hereditary spastic paraparesis (HSP), or other motor nerve disorders, that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activities of six of the variants are at least as high as that of SARM1 lacking the entire ARM domain and greatly exceed the basal activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful mild stress. Importantly, we provide evidence that these gain-of-function alleles are enriched in ALS and HSP patients compared to matched individuals without these conditions within ALS and other motor nerve disorder databases. Together, these data suggest these are risk alleles for ALS and other motor nerve disorders. The broad phenotypic heterogeneity and variable age-of-onset in patients with these alleles raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.

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Section: Methodsmentioning

confidence: 99%

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Gilley

Jackson

Pipis

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

Section: Database Resourcesmentioning

confidence: 99%

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Gilley

Jackson

Pipis

et al. 2021

eLife

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SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.

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“…3 B, Additional file 5 : Table S4). The common methQTLs included well established methQTLs and eQTLs, such as the ones present in the PON1 [ 40 ], LGR6 [ 41 ], and RIBC2 [ 42 ] loci (Fig. 3 C).…”

Section: Resultsmentioning

confidence: 99%

Identification of tissue-specific and common methylation quantitative trait loci in healthy individuals using MAGAR

Scherer

Gasparoni

Rahmouni

et al. 2021

Epigenetics & Chromatin

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Background Understanding the influence of genetic variants on DNA methylation is fundamental for the interpretation of epigenomic data in the context of disease. There is a need for systematic approaches not only for determining methylation quantitative trait loci (methQTL), but also for discriminating general from cell type-specific effects. Results Here, we present a two-step computational framework MAGAR (https://bioconductor.org/packages/MAGAR), which fully supports the identification of methQTLs from matched genotyping and DNA methylation data, and additionally allows for illuminating cell type-specific methQTL effects. In a pilot analysis, we apply MAGAR on data in four tissues (ileum, rectum, T cells, B cells) from healthy individuals and demonstrate the discrimination of common from cell type-specific methQTLs. We experimentally validate both types of methQTLs in an independent data set comprising additional cell types and tissues. Finally, we validate selected methQTLs located in the PON1, ZNF155, and NRG2 genes by ultra-deep local sequencing. In line with previous reports, we find cell type-specific methQTLs to be preferentially located in enhancer elements. Conclusions Our analysis demonstrates that a systematic analysis of methQTLs provides important new insights on the influences of genetic variants to cell type-specific epigenomic variation.

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Using regulatory variants to detect gene–gene interactions identifies networks of genes linked to cell immortalisation

Cited by 8 publications

References 57 publications

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Identification of tissue-specific and common methylation quantitative trait loci in healthy individuals using MAGAR

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