Identification of rare coding variants associated with Kawasaki disease by whole exome sequencing.
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ABSTRACT:
SUBMITTER: Kim JJ
PROVIDER: S-EPMC8752980 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundKawasaki disease (KD) is an acute pediatric vasculitis affecting genetically susceptible infants and children. Although the pathogenesis of KD remains unclear, growing evidence links genetic susceptibility to the disease.MethodsTo explore the genes associated with susceptibility in KD, we applied whole-exome sequencing to KD and control subjects from Yunnan province, China. We conducted association study analysis on the two groups.ResultsIn this study, we successfully identified 11 significant rare variants in two genes (MYH14 and RBP3) through the genotype/allele frequency analysis. A heterozygous variant (c.2650G > A, p.V884M) of the RBP3 gene was identified in 12 KD cases, while eight heterozygous variants (c.566G > A, p.R189H; c.1109 C > T, p.S370L; c.3917T > G, p.L1306R; c.4301G > A, p.R1434Q; c.5026 C > T, p.R1676W; c.5329 C > T, p.R1777C; c.5393 C > A, p.A1798D and c.5476 C > T, p.R1826C) of the MYH14 gene were identified in 8 KD cases respectively.ConclusionThis study suggested that nine variants in MYH14 and RBP3 gene may be associated with KD susceptibility in the population from Yunnan province.
| S-EPMC10405421 | biostudies-literature
Project description:Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
| S-EPMC3928660 | biostudies-literature
Project description:Deep vein thrombosis and pulmonary embolism, collectively defined as venous thromboembolism (VTE), are the third leading cause of cardiovascular death in the United States. Common genetic variants conferring increased varying degrees of VTE risk have been identified by genome-wide association studies (GWAS). Rare mutations in the anticoagulant genes PROC, PROS1 and SERPINC1 result in perinatal lethal thrombosis in homozygotes and markedly increased VTE risk in heterozygotes. However, currently described VTE variants account for an insufficient portion of risk to be routinely used for clinical decision making. To identify new rare VTE risk variants, we performed a whole-exome study of 393 individuals with unprovoked VTE and 6114 controls. This study identified 4 genes harboring an excess number of rare damaging variants in patients with VTE: PROS1, STAB2, PROC, and SERPINC1. At STAB2, 7.8% of VTE cases and 2.4% of controls had a qualifying rare variant. In cell culture, VTE-associated variants of STAB2 had a reduced surface expression compared with reference STAB2. Common variants in STAB2 have been previously associated with plasma von Willebrand factor and coagulation factor VIII levels in GWAS, suggesting that haploinsufficiency of stabilin-2 may increase VTE risk through elevated levels of these procoagulants. In an independent cohort, we found higher von Willebrand factor levels and equivalent propeptide levels in individuals with rare STAB2 variants compared with controls. Taken together, this study demonstrates the utility of gene-based collapsing analyses to identify loci harboring an excess of rare variants with functional connections to a complex thrombotic disease.
| S-EPMC7393257 | biostudies-literature
Project description:Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts.
| S-EPMC9247822 | biostudies-literature
Project description:Objective:The genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer's disease, using whole-exome sequencing in 20,197 individuals. Methods:We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer's Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University. Results:We identified 19 cases carrying extremely rare SORL1 loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls (P = 2.17 × 10-8; OR: 36.2 [95% CI: 5.8-1493.0]). Age-at-onset was 7 years earlier for patients with SORL1 qualifying variant compared with noncarriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including GRID2IP,WDR76 and GRN, were among candidates for follow-up studies. Interpretation:This study implicates ultra-rare, loss-of-function variants in SORL1 as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in SORL1 and Alzheimer's disease in a large whole-exome study of unrelated cases and controls.
| S-EPMC6043775 | biostudies-literature
Project description:BackgroundGenetic factors contribute to the development of anxiety disorders, yet few risk genes have been previously identified. One genomic approach that has achieved success in identifying risk genes in related childhood neuropsychiatric conditions is investigations of de novo variants, which has yet to be leveraged in childhood anxiety disorders.MethodsWe performed whole-exome DNA sequencing in 76 parent-child trios (68 trios after quality control) recruited from a childhood anxiety disorder clinic and compared rates of rare and ultra-rare de novo variants with 790 previously sequenced control trios (783 trios after quality control). We then explored overlap with risk genes for other neuropsychiatric conditions and enrichment in biologic pathways.ResultsRare and ultra-rare de novo likely gene disrupting and predicted damaging missense genetic variants are enriched in anxiety disorder probands compared with controls (rare variant rate ratio 1.97, 95% confidence interval [CI]: 1.11-3.34, p = .03; ultra-rare variant rate ratio 2.59, 95% CI: 1.35-4.70, p = .008). These de novo damaging variants occur in individuals with a variety of childhood anxiety disorders and impact genes that have been associated with other neuropsychiatric conditions. Exploratory network analyses reveal enrichment of deleterious variants in canonical biological pathways.ConclusionsThese findings provide a path for identifying risk genes and promising biologic pathways in childhood anxiety disorders by de novo genetic variant detection. Our results suggest the discovery potential of applying this approach in larger anxiety disorder cohorts to advance our understanding of the underlying biology of these common and debilitating conditions.
| S-EPMC9246845 | biostudies-literature
Project description:ObjectiveRecently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes.MethodsWe performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics.ResultsWe identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD.ConclusionsWe confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.
| S-EPMC3653206 | biostudies-literature
Project description:Malignant transformation of extraovarian endometriosis is rare, with the carcinogenesis mechanism unclear. To clarify the actionable variants of rare-site endometriosis-associated cancer (RSEAC), we performed whole-exome sequencing for the tumor, in two patients. The intestine was affected in both cases, although the histology was that of clear cell carcinoma and undifferentiated carcinoma, respectively. Therefore, the cases were referred to as endometriosis-associated intestinal tumors (EIATs). Actionable variants (all frameshift mutations) were identified in tumor suppressor genes ARID1A, PTEN, and p53; however, no oncogenic variants were identified. Both cases were microsatellite stable. The patient with undifferentiated carcinoma exhibited hypermutator and homologous recombination deficiency phenotypes. The dominant mutation signatures were signature 30 (small subset of breast cancers) and 19 (pilocytic astrocytoma) in patient 1, and signature 5 (small subset of breast cancers) and 3 (breast, ovarian, and pancreatic cancers) in patient 2. Immunohistochemistry revealed positive CD8 and PD-1 expression in both patients; patient 1 also showed positive PDL-1 expression. Our results suggest that RSEAC is associated with variants of tumor suppressor genes as epigenetic alterations. Mutation signature-based whole-exome sequencing could be useful to select an adjuvant chemotherapy regimen. High CD8 and PD-1 expression in RSEAC suggests that immune checkpoint inhibitors are useful for treatment.
| S-EPMC7931088 | biostudies-literature
Project description:It has been hypothesized that, in aggregate, rare variants in coding regions of genes explain a substantial fraction of the heritability of common diseases. We sequenced the exomes of 1,000 Danish cases with common forms of type 2 diabetes (including body mass index > 27.5 kg/m(2) and hypertension) and 1,000 healthy controls to an average depth of 56×. Our simulations suggest that our study had the statistical power to detect at least one causal gene (a gene containing causal mutations) if the heritability of these common diseases was explained by rare variants in the coding regions of a limited number of genes. We applied a series of gene-based tests to detect such susceptibility genes. However, no gene showed a significant association with disease risk after we corrected for the number of genes analyzed. Thus, we could reject a model for the genetic architecture of type 2 diabetes where rare nonsynonymous variants clustered in a modest number of genes (fewer than 20) are responsible for the majority of disease risk.
| S-EPMC3852935 | biostudies-literature
Project description:Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, the leading cause of irreversible blindness worldwide. IOP is also the only modifiable risk factor for glaucoma. Previous genome-wide association studies have established the contribution of common genetic variants to IOP. The role of rare variants for IOP was unknown. Using whole exome sequencing data from 110,260 participants in the UK Biobank (UKB), we conducted the largest exome-wide association study of IOP to date. In addition to confirming known IOP genes, we identified 40 novel rare-variant genes for IOP, such as BOD1L1, ACAD10 and HLA-B, demonstrating the power of including and aggregating rare variants in gene discovery. About half of these IOP genes are also associated with glaucoma phenotypes in UKB and the FinnGen cohort. Six of these genes, i.e. ADRB1, PTPRB, RPL26, RPL10A, EGLN2, and MTOR, are drug targets that are either established for clinical treatment or in clinical trials. Furthermore, we constructed a rare-variant polygenic risk score and showed its significant association with glaucoma in independent participants (n = 312,825). We demonstrated the value of rare variants to enhance our understanding of the biological mechanisms regulating IOP and uncovered potential therapeutic targets for glaucoma.
| S-EPMC9712679 | biostudies-literature