Comprehensive genotyping in dyslipidemia: mendelian dyslipidemias caused by rare variants and Mendelian randomization studies using common variants

2017 ◽  
Vol 62 (4) ◽  
pp. 453-458 ◽  
Author(s):  
Hayato Tada ◽  
Masa-aki Kawashiri ◽  
Masakazu Yamagishi
Keyword(s):  
Rare Variants ◽  
Mendelian Randomization ◽  
Common Variants

Abstract 367: Extreme High-Density Lipoprotein Cholesterol Genetics: An Assortment of Large and Small Polygenic Effects

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Jacqueline S Dron ◽  
Jian Wang ◽  
Cécile Low-Kam ◽  
Sumeet A Khetarpal ◽  
John F Robinson ◽  
...  
Keyword(s):  
Large Scale ◽  
Genetic Basis ◽  
Rare Variants ◽  
Association Studies ◽  
Density Lipoprotein ◽  
Copy Number Variations ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Targeted Next Generation Sequencing ◽  
Common Genetic Variants

Rationale: Although HDL-C levels are known to have a complex genetic basis, most studies have focused solely on identifying rare variants with large phenotypic effects to explain extreme HDL-C phenotypes. Objective: Here we concurrently evaluate the contribution of both rare and common genetic variants, as well as large-scale copy number variations (CNVs), towards extreme HDL-C concentrations. Methods: In clinically ascertained patients with low ( N =136) and high ( N =119) HDL-C profiles, we applied our targeted next-generation sequencing panel (LipidSeq TM ) to sequence genes involved in HDL metabolism, which were subsequently screened for rare variants and CNVs. We also developed a novel polygenic trait score (PTS) to assess patients’ genetic accumulations of common variants that have been shown by genome-wide association studies to associate primarily with HDL-C levels. Two additional cohorts of patients with extremely low and high HDL-C (total N =1,746 and N =1,139, respectively) were used for PTS validation. Results: In the discovery cohort, 32.4% of low HDL-C patients carried rare variants or CNVs in primary ( ABCA1 , APOA1 , LCAT ) and secondary ( LPL , LMF1 , GPD1 , APOE ) HDL-C–altering genes. Additionally, 13.4% of high HDL-C patients carried rare variants or CNVs in primary ( SCARB1 , CETP , LIPC , LIPG ) and secondary ( APOC3 , ANGPTL4 ) HDL-C–altering genes. For polygenic effects, patients with abnormal HDL-C profiles but without rare variants or CNVs were ~2-fold more likely to have an extreme PTS compared to normolipidemic individuals, indicating an increased frequency of common HDL-C–associated variants in these patients. Similar results in the two validation cohorts demonstrate that this novel PTS successfully quantifies common variant accumulation, further characterizing the polygenic basis for extreme HDL-C phenotypes. Conclusions: Patients with extreme HDL-C levels have various combinations of rare variants, common variants, or CNVs driving their phenotypes. Fully characterizing the genetic basis of HDL-C levels must extend to encompass multiple types of genetic determinants—not just rare variants—to further our understanding of this complex, controversial quantitative trait.

SMARCA2 common variant association and rare variant excess in Schizophrenia patients from an Algerian Trio Cohort

2011 ◽  
Vol 26 (S2) ◽  
pp. 1346-1346
Author(s):  
D. Benmessaoud ◽  
A.-M. Lepagnol-Bestel ◽  
M. Delepine ◽  
J. Hager ◽  
J.-M. Moalic ◽  
...  
Keyword(s):  
Rare Variants ◽  
Association Studies ◽  
Common Variant ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Fisher Test ◽  
Coding Regions ◽  
Genome Wide ◽  
Whole Exome ◽  
Positive Evolution

Genome wide association studies (GWAS) of Schizophrenia (SZ) patients have identified common variants in ten genes including SMARCA2 (Koga et al., HMG, 2009). We found that the SZ-GWAS genes are part of an interacting network centered on SMARCA2 (Loe-Mie et al., HMG, 2010). Furthermore, SMARCA2 was found disrupted in SZ (Walsh et al., Science, 2008). SMARCA2 encodes the ATPase (BRM) of the SWI/SNF chromatin remodeling complex that is at the interface of genome and environmental adaptation.Taking advantage of an Algerian trio cohort of one hundred SZ patients (Benmessaoud et al., BMC Psychiatry, 2008), we replicated the association of SNP rs2296212 localized in exon 33, already shown associated in Koga study and resulting in D1546E amino acid change in the SMARCA2 protein. We studied SMARCA2 codons and found that exon 33 displays a signature of positive evolution in the primate lineage.Our working hypothesis is that the coding regions displaying positive selection are target of novel rare variants. To address this question, we sequenced two exons displaying positive evolution and one exon without evidence of positive evolution.We found (i) that rare variants are significantly in excess in SZ-patients compared to their parents (p = 0.038, Fisher test) and (ii) a higher proportion of rare variants in the primate-accelerated exons compared with the non-evolutionary exon in SZ-patients (p = 0.032, Fisher test).SMARCA2 exon sequencing and whole exome sequencing from patients harboring SNP rs2296212 common variant are under progress. Altogether, these results are expected to give new insights into the genetic architecture of SZ.

scholarly journals Variants in the Niemann-Pick type C gene NPC1 are not associated with Parkinson’s disease

2020 ◽  
Author(s):  
Bouchra Ouled Amar Bencheikh ◽  
Konstantin Senkevich ◽  
Uladzislau Rudakou ◽  
Eric Yu ◽  
Kheireddin Mufti ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rare Variants ◽  
Transmembrane Protein ◽  
Alpha Synuclein ◽  
Common Variants ◽  
Optimal Sequence ◽  
Lewy Pathology ◽  
Type C ◽  
Niemann Pick

AbstractBiallelic variants in NPC1, a lysosomal gene coding for a transmembrane protein involved in cholesterol trafficking, may cause Niemann-Pick disease type C (NPC). A few cases of NPC1 mutation carriers have been reported with a Parkinson’s disease (PD) presentation. In addition, pathological studies demonstrated phosphorylated alpha-synuclein and Lewy pathology in brains of NPC patients. Therefore, we aimed to examine whether NPC1 genetic variants may be associated with PD. Full sequencing of NPC1 was performed in 2,657 PD patients and 3,647 controls from three cohorts, using targeted sequencing with molecular inversion probes. A total of 9 common variants and 126 rare variants were identified across the three cohorts. To examine association with PD, regression models adjusted for age, sex and origin were performed for common variants, and optimal sequence Kernel association test (SKAT-O) was performed for rare variants. After correction for multiple comparisons, common and rare NPC1 variants were not associated with PD. Our results do not support a link between heterozygous variants in NPC1 and PD.

Association of novel rare coding variants with juvenile idiopathic arthritis

2021 ◽  
pp. annrheumdis-2020-218359
Author(s):  
Xinyi Meng ◽  
Xiaoyuan Hou ◽  
Ping Wang ◽  
Joseph T Glessner ◽  
Hui-Qi Qu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Juvenile Idiopathic Arthritis ◽  
Autoimmune Diseases ◽  
Rare Variants ◽  
Variant Calling ◽  
Rna Seq ◽  
Common Variants ◽  
Association Analyses ◽  
Coding Variants ◽  
The Impact

ObjectiveJuvenile idiopathic arthritis (JIA) is the most common type of arthritis among children, but a few studies have investigated the contribution of rare variants to JIA. In this study, we aimed to identify rare coding variants associated with JIA for the genome-wide landscape.MethodsWe established a rare variant calling and filtering pipeline and performed rare coding variant and gene-based association analyses on three RNA-seq datasets composed of 228 JIA patients in the Gene Expression Omnibus against different sets of controls, and further conducted replication in our whole-exome sequencing (WES) data of 56 JIA patients. Then we conducted differential gene expression analysis and assessed the impact of recurrent functional coding variants on gene expression and signalling pathway.ResultsBy the RNA-seq data, we identified variants in two genes reported in literature as JIA causal variants, as well as additional 63 recurrent rare coding variants seen only in JIA patients. Among the 44 recurrent rare variants found in polyarticular patients, 10 were replicated by our WES of patients with the same JIA subtype. Several genes with recurrent functional rare coding variants have also common variants associated with autoimmune diseases. We observed immune pathways enriched for the genes with rare coding variants and differentially expressed genes.ConclusionThis study elucidated a novel landscape of recurrent rare coding variants in JIA patients and uncovered significant associations with JIA at the gene pathway level. The convergence of common variants and rare variants for autoimmune diseases is also highlighted in this study.

scholarly journals A Novel Approach for the Simultaneous Analysis of Common and Rare Variants in Complex Traits

2012 ◽  
Vol 6 ◽  
pp. BBI.S8852 ◽  
Author(s):  
Ao Yuan ◽  
Guanjie Chen ◽  
Yanxun Zhou ◽  
Amy Bentley ◽  
Charles Rotimi
Keyword(s):  
Complex Traits ◽  
Rare Variants ◽  
Sequence Data ◽  
Association Studies ◽  
Simultaneous Analysis ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Disease Etiology ◽  
Novel Approach ◽  
Common Genetic Variants

Genome-wide association studies (GWAS) have been successful in detecting common genetic variants underlying common traits and diseases. Despite the GWAS success stories, the percent trait variance explained by GWAS signals, the so called “missing heritability” has been, at best, modest. Also, the predictive power of common variants identified by GWAS has not been encouraging. Given these observations along with the fact that the effects of rare variants are often, by design, unaccounted for by GWAS and the availability of sequence data, there is a growing need for robust analytic approaches to evaluate the contribution of rare variants to common complex diseases. Here we propose a new method that enables the simultaneous analysis of the association between rare and common variants in disease etiology. We refer to this method as SCARVA (simultaneous common and rare variants analysis). SCARVA is simple to use and is efficient. We used SCARVA to analyze two independent real datasets to identify rare and common variants underlying variation in obesity among participants in the Africa America Diabetes Mellitus (AADM) study and plasma triglyceride levels in the Dallas Heart Study (DHS). We found common and rare variants associated with both traits, consistent with published results.

Association of ApoCIII common variants with risk of coronary artery disease: A Mendelian randomization study

2021 ◽  
Vol 331 ◽  
pp. e10-e11
Author(s):  
S. Goyal ◽  
Y. Tanigawa ◽  
W. Zhang ◽  
C. Jin-Fang ◽  
M. Almeida ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Mendelian Randomization ◽  
Common Variants ◽  
Artery Disease

scholarly journals Deep genotype imputation captures virtually all heritability of autoimmune vitiligo

2020 ◽  
Vol 29 (5) ◽  
pp. 859-863 ◽  
Author(s):  
Genevieve H L Roberts ◽  
Stephanie A Santorico ◽  
Richard A Spritz
Keyword(s):  
Complex Disease ◽  
Rare Variants ◽  
Association Studies ◽  
Genotype Imputation ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Genome Wide ◽  
Autoimmune Vitiligo ◽  
Family Based ◽  
Project Data

Abstract Autoimmune vitiligo is a complex disease involving polygenic risk from at least 50 loci previously identified by genome-wide association studies. The objectives of this study were to estimate and compare vitiligo heritability in European-derived patients using both family-based and ‘deep imputation’ genotype-based approaches. We estimated family-based heritability (h2FAM) by vitiligo recurrence among a total 8034 first-degree relatives (3776 siblings, 4258 parents or offspring) of 2122 unrelated vitiligo probands. We estimated genotype-based heritability (h2SNP) by deep imputation to Haplotype Reference Consortium and the 1000 Genomes Project data in unrelated 2812 vitiligo cases and 37 079 controls genotyped genome wide, achieving high-quality imputation from markers with minor allele frequency (MAF) as low as 0.0001. Heritability estimated by both approaches was exceedingly high; h2FAM = 0.75–0.83 and h2SNP = 0.78. These estimates are statistically identical, indicating there is essentially no remaining ‘missing heritability’ for vitiligo. Overall, ~70% of h2SNP is represented by common variants (MAF > 0.01) and 30% by rare variants. These results demonstrate that essentially all vitiligo heritable risk is captured by array-based genotyping and deep imputation. These findings suggest that vitiligo may provide a particularly tractable model for investigation of complex disease genetic architecture and predictive aspects of personalized medicine.

scholarly journals Common and Rare Variants in the Exons and Regulatory Regions of Osteoporosis-Related Genes Improve Osteoporotic Fracture Risk Prediction

2014 ◽  
Vol 99 (11) ◽  
pp. E2400-E2411 ◽  
Author(s):  
Seung Hun Lee ◽  
Moo Il Kang ◽  
Seong Hee Ahn ◽  
Kyeong-Hye Lim ◽  
Gun Eui Lee ◽  
...  
Keyword(s):  
Fracture Risk ◽  
Osteoporotic Fracture ◽  
Rare Variants ◽  
Association Studies ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Regulatory Regions ◽  
Genetic Profiling ◽  
Functional Variants

Context: Osteoporotic fracture risk is highly heritable, but genome-wide association studies have explained only a small proportion of the heritability to date. Genetic data may improve prediction of fracture risk in osteopenic subjects and assist early intervention and management. Objective: To detect common and rare variants in coding and regulatory regions related to osteoporosis-related traits, and to investigate whether genetic profiling improves the prediction of fracture risk. Design and Setting: This cross-sectional study was conducted in three clinical units in Korea. Participants: Postmenopausal women with extreme phenotypes (n = 982) were used for the discovery set, and 3895 participants were used for the replication set. Main Outcome Measure: We performed targeted resequencing of 198 genes. Genetic risk scores from common variants (GRS-C) and from common and rare variants (GRS-T) were calculated. Results: Nineteen common variants in 17 genes (of the discovered 34 functional variants in 26 genes) and 31 rare variants in five genes (of the discovered 87 functional variants in 15 genes) were associated with one or more osteoporosis-related traits. Accuracy of fracture risk classification was improved in the osteopenic patients by adding GRS-C to fracture risk assessment models (6.8%; P < .001) and was further improved by adding GRS-T (9.6%; P < .001). GRS-C improved classification accuracy for vertebral and nonvertebral fractures by 7.3% (P = .005) and 3.0% (P = .091), and GRS-T further improved accuracy by 10.2% (P < .001) and 4.9% (P = .008), respectively. Conclusions: Our results suggest that both common and rare functional variants may contribute to osteoporotic fracture and that adding genetic profiling data to current models could improve the prediction of fracture risk in an osteopenic individual.

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