Rare Variants in known and Novel Candidate Genes Predisposing to Statin-Associated Myopathy

Neroldova, Magdalena; Stránecký, Viktor; Hodaňová, Kateřina; Hartmannová, Hana; Piherová, Lenka; Přistoupilová, Anna; Mrázová, Lenka; Vráblík, Michal; Adámková, Věra; Hubáček, J.; Jirsa, M; Kmoch, Stanislav

doi:10.2217/pgs-2016-0071

Cited by 18 publications

(11 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The ancestry of the cases were determined from genotype data obtained from the HumanOmni2.5 microarray and whole exome sequencing as previously described …”

Section: Methodsmentioning

confidence: 99%

“…Existence of selected CNVs was independently assessed either in exome sequence data that were available for each of the participants (DNA fragmentation, sequencing library preparation, library sequencing and CNV variant detection and annotation were performed as described) and/or validated and genotyped using a Universal Probe Library copy number assays using the LightCycler 480 Instrument (Roche Life Science, Prague, Czech Republic).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Rare copy number variation in extremely impulsively violent males

Vevera

Zarrei

Hartmannová

et al. 2018

Genes Brain and Behavior

Self Cite

View full text Add to dashboard Cite

The genetic correlates of extreme impulsive violence are poorly understood, and there have been no studies that have systematically characterized a large group of affected individuals both clinically and genetically. We performed a genome‐wide rare copy number variant (CNV) analysis in 281 males from four Czech prisons who met strict clinical criteria for extreme impulsive violence. Inclusion criteria included age ≥ 18 years, an ICD‐10 diagnosis of Dissocial Personality Disorder, and the absence of an organic brain disorder. Participants underwent a structured psychiatric assessment to diagnose extreme impulsive violence and then provided a blood sample for genetic analysis. DNA was genotyped and CNVs were identified using Illumina HumanOmni2.5 single‐nucleotide polymorphism array platform. Comparing with 10851 external population controls, we identified 828 rare CNVs (frequency ≤ 0.1% among control samples) in 264 participants. The CNVs impacted 754 genes, with 124 genes impacted more than once (2‐25 times). Many of these genes are associated with autosomal dominant or X‐linked disorders affecting adult behavior, cognition, learning, intelligence, specifically expressed in the brain and relevant to synapses, neurodevelopment, neurodegeneration, obesity and neuropsychiatric phenotypes. Specifically, we identified 31 CNVs of clinical relevance in 31 individuals, 59 likely clinically relevant CNVs in 49 individuals, and 17 recurrent CNVs in 65 individuals. Thus, 123 of 281 (44%) individuals had one to several rare CNVs that were indirectly or directly relevant to impulsive violence. Extreme impulsive violence is genetically heterogeneous and genomic analysis is likely required to identify, further research and specifically treat the causes in affected individuals.

show abstract

“…The ancestry of the cases were determined from genotype data obtained from the HumanOmni2.5 microarray and whole exome sequencing as previously described …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Rare copy number variation in extremely impulsively violent males

Vevera

Zarrei

Hartmannová

et al. 2018

Genes Brain and Behavior

Self Cite

View full text Add to dashboard Cite

show abstract

“…Attempts to discover additional common variants related to statin-related muscle injury have failed to yield replicable findings [20–22]. A recent study from the Czech Republic conducted whole-exome sequencing on 88 patients with mild statin-associated muscle toxicity, reporting an increased burden of rare variation in 24 genes [23]. We did not replicate these findings in our study, perhaps due to different phenotypes as most of our patients have more severe SRM.…”

Section: Discussionmentioning

confidence: 54%

Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing

et al. 2019

View full text Add to dashboard Cite

Aims Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. Methods and results SRM 3–5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3–5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. Conclusions In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

show abstract

“…40 For instance, researchers identified a heterozygote truncating mutation within CLCN1 gene by performing WES in patients with statin-associated myopathy and therefore, determined a novel candidate gene of this disease. 69 Additionally, it has been suggested that rare variants are likely to have appeared more recently than common variants, leading to reduced LD and making them more easily interpretable than common variants. 21 Moreover, early studies have indicated that rare and lowfrequency genetic variants may have larger effects on complex disease phenotypes and susceptibility than common variants.…”

Section: Benefits Of Identifying Rare and Low-frequency Variantsmentioning

confidence: 99%

Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus

et al. 2021

View full text Add to dashboard Cite

Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder and has enormous complexity and heterogeneity. Although its precise pathogenic mechanisms are obscure, this disease is widely acknowledged to be precipitated by environmental factors in individuals with genetic susceptibility. To date, the known susceptibility loci, which have mostly been identified by genome-wide association studies, can explain 80%–85% of the heritability of T1DM. Researchers believe that at least a part of its missing genetic component is caused by undetected rare and low-frequency variants. Most common variants have only small to modest effect sizes, which increases the difficulty of dissecting their functions and restricts their potential clinical application. Intriguingly, many studies have indicated that rare and low-frequency variants have larger effect sizes and play more significant roles in susceptibility to common diseases, including T1DM, than common variants do. Therefore, better recognition of rare and low-frequency variants is beneficial for revealing the genetic architecture of T1DM and for providing new and potent therapeutic targets for this disease. Here, we will discuss existing challenges as well as the great significance of this field and review current knowledge of the contributions of rare and low-frequency variants to T1DM.

show abstract

Rare Variants in known and Novel Candidate Genes Predisposing to Statin-Associated Myopathy

Abstract: These findings support the role of rare variants and nominate loci for follow-up studies.

Cited by 18 publications

References 36 publications

Rare copy number variation in extremely impulsively violent males

Rare copy number variation in extremely impulsively violent males

Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing

Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus

Contact Info

Product

Resources

About