Exautomate: A user-friendly tool for region-based rare variant association analysis (RVAA)

Bd, Davis; Dron, Jacqueline S.; Robinson, Joshua F.; Hegele, Robert A.; Dj, Lizotte

doi:10.1101/649368

Cited by 2 publications

(2 citation statements)

References 52 publications

(51 reference statements)

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“…Variants that were located on the sex chromosomes or within the MAPT gene were excluded, due to potential influence from the cohort's sex distribution and a common haplotype variation found across the gene, respectively. The filtered merged VCF was processed with a bash-based tool that contains a collection of scripts necessary to run region-based RVAA, 'Exautomate' 43 , to produce PLINK compatible MAP and PED files. SNP & Variation Suite v8.8.3 (SVS; Golden Helix Inc.) was used to perform linkage disequilibrium (LD) pruning (threshold = 0.5) and a principal component analysis (PCA) was performed to identify the genetic ancestry.…”

Section: Ancestry Matching and Estimationmentioning

confidence: 99%

“…A gene-based RVAA, SKAT-O, was also performed using the script package 'Exautomate' 43 . This method identified specific genes covered by ONDRISeq with an increased frequency of nonsynonymous, rare variants (MAF < 0.01, ExAC) in the disease cohorts compared to controls, and in the disease cohorts compared to each other.…”

Section: Rare Variant Association Analysismentioning

confidence: 99%

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Contribution of rare variant associations to neurodegenerative disease presentation

et al. 2021

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Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.

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Section: Ancestry Matching and Estimationmentioning

confidence: 99%

Section: Rare Variant Association Analysismentioning

confidence: 99%

Contribution of rare variant associations to neurodegenerative disease presentation

et al. 2021

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Loss-of-Function CREB3L3 Variants in Patients With Severe Hypertriglyceridemia

Dron

Dilliott

Lawson

et al. 2020

ATVB

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Objective: Genetic determinants of severe hypertriglyceridemia include both common variants with small effects (assessed using polygenic risk scores) plus heterozygous and homozygous rare variants in canonical genes directly affecting triglyceride metabolism. Here, we broadened our scope to detect associations with rare loss-of-function variants in genes affecting noncanonical pathways, including those known to affect triglyceride metabolism indirectly. Approach and Results: From targeted next-generation sequencing of 69 metabolism-related genes in 265 patients of European descent with severe hypertriglyceridemia (≥10 mmol/L or ≥885 mg/dL) and 477 normolipidemic controls, we focused on the association of rare heterozygous loss-of-function variants in individual genes. We observed that compared with controls, severe hypertriglyceridemia patients were 20.2× (95% CI, 1.11–366.1; P =0.03) more likely than controls to carry a rare loss-of-function variant in CREB3L3 , which encodes a transcription factor that regulates several target genes with roles in triglyceride metabolism. Conclusions: Our findings indicate that rare variants in a noncanonical gene for triglyceride metabolism, namely CREB3L3 , contribute significantly to severe hypertriglyceridemia. Secondary genes and pathways should be considered when evaluating the genetic architecture of this complex trait.

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Exautomate: A user-friendly tool for region-based rare variant association analysis (RVAA)

Cited by 2 publications

References 52 publications

Contribution of rare variant associations to neurodegenerative disease presentation

Contribution of rare variant associations to neurodegenerative disease presentation

Loss-of-Function CREB3L3 Variants in Patients With Severe Hypertriglyceridemia

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