scholarly journals An Integrative Co-localization (INCO) Analysis for SNV and CNV Genomic Features With an Application to Taiwan Biobank Data

2021 ◽  
Vol 12 ◽  
Author(s):  
Qi-You Yu ◽  
Tzu-Pin Lu ◽  
Tzu-Hung Hsiao ◽  
Ching-Heng Lin ◽  
Chi-Yun Wu ◽  
...  
Keyword(s):  
Rare Variants ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Copy Number Variations ◽  
Integrative Approach ◽  
Single Nucleotide Variants ◽  
Disease Etiology ◽  
Direct Union ◽  
Genomic Studies ◽  
Intersection Operation

Genomic studies have been a major approach to elucidating disease etiology and to exploring potential targets for treatments of many complex diseases. Statistical analyses in these studies often face the challenges of multiplicity, weak signals, and the nature of dependence among genetic markers. This situation becomes even more complicated when multi-omics data are available. To integrate the data from different platforms, various integrative analyses have been adopted, ranging from the direct union or intersection operation on sets derived from different single-platform analysis to complex hierarchical multi-level models. The former ignores the biological relationship between molecules while the latter can be hard to interpret. We propose in this study an integrative approach that combines both single nucleotide variants (SNVs) and copy number variations (CNVs) in the same genomic unit to co-localize the concurrent effect and to deal with the sparsity due to rare variants. This approach is illustrated with simulation studies to evaluate its performance and is applied to low-density lipoprotein cholesterol and triglyceride measurements from Taiwan Biobank. The results show that the proposed method can more effectively detect the collective effect from both SNVs and CNVs compared to traditional methods. For the biobank analysis, the identified genetic regions including the gene VNN2 could be novel and deserve further investigation.

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.

scholarly journals Rare variants in dynein heavy chain genes in two individuals with situs inversus and developmental dyslexia

2020 ◽  
Author(s):  
Andrea Bieder ◽  
Elisabet Einarsdottir ◽  
Hans Matsson ◽  
Harriet E. Nilsson ◽  
Jesper Eisfeldt ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Developmental Dyslexia ◽  
Situs Inversus ◽  
Rare Variants ◽  
Autosomal Recessive Disorder ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Dynein Arms ◽  
Left Right Asymmetry ◽  
The Brain

ABSTRACTBackgroundDevelopmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD.MethodsHere, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify single nucleotide variants or copy number variations of importance for DD and SI.ResultsIndividual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): c.7502G>C;p.(R2501P), a previously reported variant predicted to be damaging and c.12043T>G;p.(Y4015D), a novel variant predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A>G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified.ConclusionsWe identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD, but further studies into the association are warranted.

scholarly journals Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels

2006 ◽  
Vol 103 (6) ◽  
pp. 1810-1815 ◽  
Author(s):  
J. C. Cohen ◽  
A. Pertsemlidis ◽  
S. Fahmi ◽  
S. Esmail ◽  
G. L. Vega ◽  
...  
Keyword(s):  
Rare Variants ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density

scholarly journals The utility of MLPA in Familial Hypercholesterolemia diagnosis

2021 ◽  
Vol 67 (3) ◽  
pp. 162-166
Author(s):  
George Valeriu Moldovan ◽  
Adina Huțanu ◽  
Liliana Demian ◽  
Laszlo Hadadi ◽  
Bogdan Mănescu ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Familial Hypercholesterolemia ◽  
Copy Number ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Copy Number Variations ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Premature Coronary Heart Disease

Abstract Background: Familial Hypercholesterolemia (FH) is an inherited disease, associated with an increased risk of atherosclerosis, manifested clinically as premature coronary heart disease. FH is biochemically characterized by increased Cholesterol and Low-density Lipoprotein Cholesterol serum levels. The diagnosis is often made using clinical scores however, the definitive FH diagnosis should point out the underlying molecular change, which can be: a point mutation within the three major genes, a number of single nucleotide polymorphisms determining the polygenic etiology, or copy number variations in the Low-density lipoprotein receptor gene. Objective: In the present study we investigated copy number variations as a possible etiological factor for FH in a cohort of patients with documented premature coronary heart disease. Methods: The study population consisted of 150 patients with premature coronary heart disease documented by angiography, all being under lipid-lowering therapy, and 20 apparently healthy controls. Serum lipids were assessed using the Cobas Integra 400 plus and commercial reagents. Copy number variations were evaluated with the SALSA MLPA Probemix P062 LDLR kit. Results: Cholesterol, Triglycerides, Low-density Lipoprotein Cholesterol and High-density Lipoprotein Cholesterol showed no difference between patients and controls. No copy number variations were detected in the investigated regions, namely all 18 exons and the promoter region of the Low-density lipoprotein receptor gene. Conclusions: Even in the presence of negative results, the Familial Hypercholesterolemia genetic diagnosis has to be further pursued in the presence of a clinical diagnosis, as the identification of the molecular etiology may bring additional clinical and therapeutical benefits, as well as open the possibility for “cascade screening”.

scholarly journals The Utility of Echocardiography for Non-ST-Segment Elevation Myocardial Infarction: A Retrospective Study

2019 ◽  
Vol 36 (2) ◽  
pp. 121-129
Author(s):  
Edward T. Ha ◽  
Marc Cohen ◽  
Paul J. Fields ◽  
Jessie Van Daele ◽  
Theodore J. Gaeta
Keyword(s):  
Myocardial Infarction ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Primary Diagnosis ◽  
Integrative Approach ◽  
St Segment Elevation ◽  
Segment Elevation Myocardial Infarction ◽  
St Segment ◽  
Demographic Attributes ◽  
The Impact

Objective: The objectives were to assess factors associated with a higher likelihood of predicting acute coronary atherothrombosis (ACA) in non-ST-segment elevation myocardial infarction (NSTEMI), evaluate the impact of adding echocardiographic data, and develop an algorithm that would reduce overutilization of emergent angiography. Methods: Data were retrospectively analyzed on a patient cohort presenting to an emergency department of an urban community hospital with NSTEMI from October 1, 2015, to July 31, 2018. The inclusion criterion was any adult patient with a first-time, primary diagnosis of NSTEMI without high-risk features. The main outcome variables were the presence of ACA on angiography. Results: Seventy-three patients with NSTEMI were included in this study. Logistic regression analysis identified the following independent variables useful for predicting ACA: age, wall motion abnormality on echo, and levels of low-density lipoprotein. The model’s overall fit was highly significant ( P = .0012). Conclusion: An integrative approach was demonstrated for the management of patients with NSTEMI presenting to the hospital. Although the positive predictive value of echo in predicting ACA was limited, when combined with demographic attributes and risk factors, it proved to be successful in determining the need for angiography in patients with NSTEMI.

scholarly journals Genetic basis of hypercholesterolemia in adults

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Seyedmohammad Saadatagah ◽  
Merin Jose ◽  
Ozan Dikilitas ◽  
Lubna Alhabi ◽  
Alexandra A. Miller ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Population Based ◽  
Single Nucleotide Variants ◽  
Genetic Etiology ◽  
Single Nucleotide ◽  
Primary Hypercholesterolemia ◽  
Clinical Criteria ◽  
Lipid Clinic ◽  
Pathogenic Variants

AbstractWe investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8.6 years, 41.3% males) from southeast Minnesota with primary hypercholesterolemia (low-density lipoprotein cholesterol (LDL-C) ≥155 mg/dl in the absence of identifiable secondary causes). Familial hypercholesterolemia (FH) phenotype was defined as a Dutch Lipid Clinic Network (DLCN) score ≥6. Participants underwent sequencing of LDLR, APOB, and PCSK9, and genotyping of 12 LDL-C-associated single-nucleotide variants to construct a polygenic score (PGS) for LDL-C. The presence of a pathogenic/likely pathogenic variant was considered monogenic etiology and a PGS ≥90th percentile was considered polygenic etiology. The mean LDL-C level was 187.3 ± 32.3 mg/dl and phenotypic FH was present in 8.4% of the cohort. An identifiable genetic etiology was present in 17.1% individuals (monogenic in 1.5% and polygenic in 15.6%). Phenotypic and genetic FH showed poor overlap. Only 26% of those who met the clinical criteria of FH had an identifiable genetic etiology and of those with an identifiable genetic etiology only 12.9% met clinical criteria for FH. Genetic factors explained 7.4% of the variance in LDL-C. In conclusion, in adults with primary hypercholesterolemia, 17.1% had an identifiable genetic etiology and the overlap between phenotypic and genetic FH was modest.

scholarly journals Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1728
Author(s):  
Jesús Maria Martín-Campos
Keyword(s):  
Population Distribution ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Single Nucleotide Variants

Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detect genetic factors in both hyper- and hypolipidemias, but this approach only explained extreme cases in the population distribution. Subsequently, the genetic basis of the less severe and most common dyslipidemias remained unknown. In the genomic age, performing whole-exome sequencing in families with extreme plasma LDL-c values identified some new candidate genes, but it is unlikely that such genes can explain the majority of inexplicable cases. Genome-wide association studies (GWASs) have identified several single-nucleotide variants (SNVs) associated with plasma LDL-c, introducing the idea of a polygenic origin. Polygenic risk scores (PRSs), including LDL-c-raising alleles, were developed to measure the contribution of the accumulation of small-effect variants to plasma LDL-c. This paper discusses other possibilities for unexplained dyslipidemias associated with LDL-c, such as mosaicism, maternal effect, and induced epigenetic changes. Future studies should consider gene–gene and gene–environment interactions and the development of integrated information about disease-driving networks, including phenotypes, genotypes, transcription, proteins, metabolites, and epigenetics.

scholarly journals Identifying individual risk rare variants using protein structure-guided local tests (POINT)

2018 ◽  
Author(s):  
Rachel Marceau West ◽  
Wenbin Lu ◽  
Daniel M. Rotroff ◽  
Melaine Kuenemann ◽  
Sheng-Mao Chang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cardiovascular Risk ◽  
Rare Variants ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Clinical Trial Data ◽  
Trial Data ◽  
Low Density ◽  
3 Dimensional ◽  
Additional Information

AbstractRare variants are of increasing interest to genetic association studies because of their etiological contributions to human complex diseases. Due to the rarity of the mutant events, rare variants are routinely analyzed on an aggregate level. While aggregation analyses improve the detection of global-level signal, they are not able to pinpoint causal variants within a variant set. To perform inference on a localized level, additional information, e.g., biological annotation, is often needed to boost the information content of a rare variant. Following the observation that important variants are likely to cluster together on functional domains, we propose a protein structure guided local test (POINT) to provide variant-specific association information using structure-guided aggregation of signal. Constructed under a kernel machine framework, POINT performs local association testing by borrowing information from neighboring variants in the 3-dimensional protein space in a data-adaptive fashion. Besides merely providing a list of promising variants, POINT assigns each variant a p-value to permit variant ranking and prioritization. We assess the selection performance of POINT using simulations and illustrate how it can be used to prioritize individual rare variants in PCSK9 associated with low-density lipoprotein in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data.Author summaryWhile it is known that rare variants play an important role in understanding associations between genotype and complex diseases, pinpointing individual rare variants likely to be responsible for association is still a daunting task. Due to their low frequency in the population and reduced signal, localizing causal rare variants often requires additional information, such as type of DNA change or location of variant along the sequence, to be incorporated in a biologically meaningful fashion that does not overpower the genotype data. In this paper, we use the observation that important variants tend to cluster together on functional domains to propose a new approach for prioritizing rare variants: the protein structure guided local test (POINT). POINT uses a gene’s 3-dimensional protein folding structure to guide aggregation of information from neighboring variants in the protein in a robust manner. We show how POINT improves selection performance over single variant tests and sliding window approaches. We further illustrate how it can be used to prioritize individual rare variants using the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data, finding five promising variants within PCSK9 in association with low-density lipoprotein, including three new mutations near the PCSK9-LDLR binding domain.

scholarly journals Both Rare and Common Variants in PCSK9 Influence Plasma Low-Density Lipoprotein Cholesterol Level in American Indians

2015 ◽  
Vol 100 (2) ◽  
pp. E345-E349 ◽  
Author(s):  
Ching-Wei Tsai ◽  
Kari E. North ◽  
Adrienne Tin ◽  
Karin Haack ◽  
Nora Franceschini ◽  
...  
Keyword(s):  
American Indians ◽  
Genetic Architecture ◽  
Rare Variants ◽  
Meta Analysis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Common Variants ◽  
Pcsk9 Gene ◽  
Family Based ◽  
Study Participants

Abstract Context: Elevated LDL cholesterol (LDL-C) is an important risk factor for atherosclerosis and cardiovascular disease. Variants in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene have been associated not only with plasma LDL-C concentration, but also with ischemic heart disease. Little is known about the genetic architecture of PCSK9 and its influence on LDL-C in American Indians. Objective: We aimed to investigate the genetic architecture in the 1p32 region encompassing PCSK9 and its influence on LDL-C in American Indians. Design: The Strong Heart Family Study (SHFS) is a family-based genetic study. Participants: Two thousand four hundred fifty eight American Indians from Arizona, Oklahoma, North Dakota, and South Dakota, who were genotyped by Illumina MetaboChip. Results: We genotyped 486 SNPs in a 3.9 Mb region at chromosome 1p32 encompassing PCSK9 in 2458 American Indians. We examined the association between these SNPs and LDL-C. For common variants (MAF ≥ 1%), meta-analysis across the three geographic regions showed common variants in PCSK9 were significantly associated with higher LDL-C. The most significant SNP rs12067569 (MAF = 1.7 %, β = 16.9 ± 3.7, P = 5.9 × 10−6) was in complete LD (r2 = 1) with a nearby missense SNP, rs505151 (E670G) (β = 15.0 ± 3.6, P = 3.6 × 10−5). For rare variants (MAF < 1%), rs11591147 (R46L, MAF = 0.9%) was associated with lower LDL-C (β = − 31.1 ± 7.1, P = 1.4 × 10−5). The mean (SD) of LDL-C was 76.9 (7.8) and 107.4 (1.0) mg/dL for those with and without the R46L mutation, respectively. One person who was homozygous for R46L had LDL-C levels of 11 mg/dL. In one family, 6 out of 8 members carrying the R46L mutation had LDL-C levels below the lower 10% percentile of LDL-C among all study participants. Conclusions: Both rare and common variants in PCSK9 influence plasma LDL-C levels in American Indians. Follow-up studies may disclose the influence of these mutations on the risk of CVD and responses to cholesterol-lowering medications.

Intralysosomal Accumulation of Colloidal Gold-Low Density Lipoprotein Conjugates in Chloroquine-Treated Fibroblasts

1985 ◽  
Vol 43 ◽  
pp. 546-547 ◽  
Author(s):  
Dean A. Handley ◽  
Cynthia M. Arbeeny ◽  
Larry D. Witte
Keyword(s):  
Colloidal Gold ◽  
Cultured Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Coated Vesicle ◽  
Low Density ◽  
Cholesterol Esters ◽  
Cultured Fibroblasts ◽  
Surface Receptors ◽  
Ldl Particles

Low density lipoproteins (LDL) are the major cholesterol carrying particles in the blood. Using cultured cells, it has been shown that LDL particles interact with specific surface receptors and are internalized via a coated pit-coated vesicle pathway for lysosomal catabolism. This (Pathway has been visualized using LDL labeled to ferritin or colloidal gold. It is now recognized that certain lysomotropic agents, such as chloroquine, inhibit lysosomal enzymes that degrade protein and cholesterol esters. By interrupting cholesterol ester hydrolysis, chloroquine treatment results in lysosomal accumulation of cholesterol esters from internalized LDL. Using LDL conjugated to colloidal gold, we have examined the ultrastructural effects of chloroquine on lipoprotein uptake by normal cultured fibroblasts.

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