scholarly journals The Complex and Diverse Genetic Architecture of Dilated Cardiomyopathy

2021 ◽  
Vol 128 (10) ◽  
pp. 1514-1532
Author(s):  
Ray E. Hershberger ◽  
Jason Cowan ◽  
Elizabeth Jordan ◽  
Daniel D. Kinnamon
Keyword(s):  
Genetic Variation ◽  
Dilated Cardiomyopathy ◽  
Genetic Architecture ◽  
Rare Variants ◽  
Low Frequency ◽  
Complex Nature ◽  
Environment Interaction ◽  
Human Heart Failure ◽  
The Impact ◽  
Insight Into

Our insight into the diverse and complex nature of dilated cardiomyopathy (DCM) genetic architecture continues to evolve rapidly. The foundations of DCM genetics rest on marked locus and allelic heterogeneity. While DCM exhibits a Mendelian, monogenic architecture in some families, preliminary data from our studies and others suggests that at least 20% to 30% of DCM may have an oligogenic basis, meaning that multiple rare variants from different, unlinked loci, determine the DCM phenotype. It is also likely that low-frequency and common genetic variation contribute to DCM complexity, but neither has been examined within a rare variant context. Other types of genetic variation are also likely relevant for DCM, along with gene-by-environment interaction, now established for alcohol- and chemotherapy-related DCM. Collectively, this suggests that the genetic architecture of DCM is broader in scope and more complex than previously understood. All of this elevates the impact of DCM genetics research, as greater insight into the causes of DCM can lead to interventions to mitigate or even prevent it and thus avoid the morbid and mortal scourge of human heart failure.

scholarly journals Focused Strategies for Defining the Genetic Architecture of Congenital Heart Defects

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 827
Author(s):  
Lisa J. Martin ◽  
D Woodrow Benson
Keyword(s):  
Genetic Variation ◽  
Congenital Heart Defects ◽  
Heart Development ◽  
Genetic Architecture ◽  
Congenital Heart ◽  
Rare Variants ◽  
Heart Defects ◽  
Genetic Origin ◽  
Genetic Studies ◽  
The Ideal

Congenital heart defects (CHD) are malformations present at birth that occur during heart development. Increasing evidence supports a genetic origin of CHD, but in the process important challenges have been identified. This review begins with information about CHD and the importance of detailed phenotyping of study subjects. To facilitate appropriate genetic study design, we review DNA structure, genetic variation in the human genome and tools to identify the genetic variation of interest. Analytic approaches powered for both common and rare variants are assessed. While the ideal outcome of genetic studies is to identify variants that have a causal role, a more realistic goal for genetic analytics is to identify variants in specific genes that influence the occurrence of a phenotype and which provide keys to open biologic doors that inform how the genetic variants modulate heart development. It has never been truer that good genetic studies start with good planning. Continued progress in unraveling the genetic underpinnings of CHD will require multidisciplinary collaboration between geneticists, quantitative scientists, clinicians, and developmental biologists.

scholarly journals Proportion of idiopathic pulmonary fibrosis risk explained by known genetic loci

2020 ◽  
Author(s):  
Olivia C Leavy ◽  
Shwu-Fan Ma ◽  
Philip L Molyneaux ◽  
Toby M Maher ◽  
Justin M Oldham ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Genetic Architecture ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Risk Variants ◽  
Genome Wide ◽  
The Impact ◽  
Insight Into

Genome-wide association studies have identified 14 genetic loci associated with susceptibility to idiopathic pulmonary fibrosis (IPF), a devastating lung disease with poor prognosis. Of these, the variant with the strongest association, rs35705950, is located in the promoter region of the MUC5B gene and has a risk allele (T) frequency of 30-35% in IPF cases. Here we present estimates of the proportion of disease liability explained by each of the 14 IPF risk variants as well as estimates of the proportion of cases that can be attributed to each variant. We estimate that rs35705950 explains 5.9-9.4% of disease liability, which is much lower than previously reported estimates. Of every 100,000 individuals with the rs35705950_GG genotype we estimate 30 will have IPF, whereas for every 100,000 individuals with the rs35705950_GT genotype 152 will have IPF. Quantifying the impact of genetic risk factors on disease liability improves our understanding of the underlying genetic architecture of IPF and provides insight into the impact of genetic factors in risk prediction modelling.

scholarly journals Punctuated loci on chromosome IV determine natural variation in Orsay virus susceptibility of Caenorhabditis elegans strains Bristol N2 and Hawaiian CB4856

2021 ◽  
Author(s):  
Mark G. Sterken ◽  
Lisa van Sluijs ◽  
Yiru A. Wang ◽  
Wannisa Ritmahan ◽  
Mitra L. Gultom ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Caenorhabditis Elegans ◽  
Virus Infection ◽  
Genetic Architecture ◽  
Recombinant Inbred Lines ◽  
Model Organism ◽  
C Elegans ◽  
Viral Susceptibility ◽  
Orsay Virus ◽  
Insight Into

Host-pathogen interactions play a major role in evolutionary selection and shape natural genetic variation. The genetically distinct Caenorhabditis elegans strains, Bristol N2 and Hawaiian CB4856, are differentially susceptible to the Orsay virus (OrV). Here we report the dissection of the genetic architecture of susceptibility to OrV infection. We compare OrV infection in the relatively resistant wild-type CB4856 strain to the more susceptible canonical N2 strain. To gain insight into the genetic architecture of viral susceptibility, 52 fully sequenced recombinant inbred lines (CB4856 x N2 RILs) were exposed to OrV. This led to the identification of two loci on chromosome IV associated with OrV resistance. To verify the two loci and gain additional insight into the genetic architecture controlling virus infection, introgression lines (ILs) that together cover chromosome IV, were exposed to OrV. Of the 27 ILs used, 17 had an CB4856 introgression in an N2 background and 10 had an N2 introgression in a CB4856 background. Infection of the ILs confirmed and fine-mapped the locus underlying variation in OrV susceptibility and we found that a single nucleotide polymorphism in cul-6 may contribute to the difference in OrV susceptibility between N2 and CB4856. An allele swap experiment showed the strain CB4856 became as susceptible as the N2 strain by having an N2 cul-6 allele, although having the CB4856 cul-6 allele did not increase resistance in N2. Additionally, we found that multiple strains with non-overlapping introgressions showed a distinct infection phenotype from the parental strain, indicating that there are punctuated locations on chromosome IV determining OrV susceptibility. Thus, our findings reveal the genetic complexity of OrV susceptibility in C. elegans and suggest that viral susceptibility is governed by multiple genes. Importance Genetic variation determines the viral susceptibility of hosts. Yet, pinpointing which genetic variants determine viral susceptibility remains challenging. Here, we have exploited the genetic tractability of the model organism C. elegans to dissect the genetic architecture of Orsay virus infection. Our results provide novel insight into natural determinants of Orsay virus infection.

scholarly journals Considering complexity in the genetic evaluation of dilated cardiomyopathy

Heart ◽  
2020 ◽  
Vol 107 (2) ◽  
pp. 106-112
Author(s):  
Elizabeth Jordan ◽  
Ray E Hershberger
Keyword(s):  
At Risk ◽  
Genetic Testing ◽  
Dilated Cardiomyopathy ◽  
Genetic Architecture ◽  
Rare Variants ◽  
Genetic Evaluation ◽  
Clinical Genetics ◽  
Mendelian Disease ◽  
Clinical Genetic ◽  
Actionable Variants

Dilated cardiomyopathy (DCM) is a cardiovascular disease of genetic aetiology that causes substantial morbidity and mortality, and presents considerable opportunity for disease mitigation and prevention in those at risk. Foundational to the process of caring for patients diagnosed with DCM is a clinical genetic evaluation, which always begins with a comprehensive family history and clinical evaluation. Genetic testing of the proband, the first patient identified in a family with DCM, within the context of genetic counselling is always indicated, regardless of whether the DCM is familial or non-familial. Clinical screening of at-risk family members is also indicated, as is cascade genetic testing for actionable variants found at genetic testing in the proband. Clinicians now have expansive panels with many genes available for DCM genetic testing, and the approaches used to evaluate rare variants to decide which are disease-causing continues to rapidly evolve. Despite these recent advances, only a minority of cases yield actionable variants, even in familial DCM where a genetic aetiology is highly likely. This underscores that our knowledge of DCM clinical genetics remains incomplete, including variant interpretation and DCM genetic architecture. Emerging data suggest that the single-variant Mendelian disease model is insufficient to explain some DCM cases, and rather that multiple variants, both common and rare, and at times key environmental factors, interact to cause DCM. A simple model illustrating the intersection of DCM genetic architecture with environmental impact is provided.

scholarly journals Documenting Diversity: The Experiences of LGBTQ+ Doctoral Researchers in the UK

10.28945/4328 ◽  
2019 ◽  
Vol 14 ◽  
pp. 403-430 ◽  
Author(s):  
Ross English ◽  
Kieran Fenby-Hulse
Keyword(s):  
Doctoral Students ◽  
Role Models ◽  
Doctoral Education ◽  
Working Environment ◽  
Critical Examination ◽  
Complex Nature ◽  
Diverse Range ◽  
The Uk ◽  
The Impact ◽  
Insight Into

Aim/Purpose: This article provides a much needed insight into the experiences of doctoral researchers in the UK that identify as Lesbian, Bisexual, Gay, Trans-, Queer, or outside of heteronormative or cis-normative identities (LGBTQ+) to address the question of what support, culture, and pedagogy might better support doctoral researchers who identify as LGBTQ+. Background: While experiences of LGBTQ+ students in UK Higher Education have been explored in recent studies, the experiences of doctoral students have not been differentiated, documented, or analyzed. Methodology: Through an online questionnaire sent to UK institutions, this study captures and reflects on the diverse experiences of doctoral education. The study took a predominantly phenomenological approach, placing the focus on understanding how individual researchers experienced their working environment. Contribution: This questionnaire offers a ‘campus climate’ study, providing a much-needed insight into the experiences of doctoral researchers in the UK in 2017. The study also highlights the importance of acknowledging the diversity of doctoral researchers and adapting supervisory and institutional support to meet the differing needs of doctoral researchers. It considers themes such as the impact of the working environment, experiences of macroaggressions and harassment, the need for researchers to work internationally, and the visibility of role models. The complex nature of the supervisor-student relationship is also considered throughout. Findings: Although many LGBTQ+ doctoral students felt they were studying in a supportive institution, the questionnaire highlights a diverse range of inclusivity issues as well as direct instances of homophobic and/or transphobic behavior. Recommendations for Practitioners: From this questionnaire, it is concluded that there is a need for a critical examination of systems and spaces in which doctoral education takes place and the implementation of systems and spaces that are inclusive. There is a need for all those involved in doctoral education to understand how identifying as a LGBTQ+ researcher can impact on your experience of doctoral education. And, finally, there is a need for better LGBTQ+ visibility, better representation, and better mentoring. Recommendation for Researchers: If doctoral education is to meet the needs of an increasingly diverse workforce, research needs to take into account the views and experiences of minority and marginalized groups that may challenge or be in tension with the views of the larger research population. Impact on Society: As the demographic of the doctoral researcher population diversifies, it is increasingly important that our approach to doctoral education and the systems and processes that underpin doctoral education are adapted to meet the needs of that diverse population. Future Research: There is potential scope for future studies to focus specifically on issues of intersectionality, disciplinary differences, health and wellbeing, representation, voice, and agency, as well as productivity, attainment, and career development of LGBTQ+ doctoral researchers.

scholarly journals Genetic architecture of four smoking behaviors using partitioned h2SNP

2020 ◽  
Author(s):  
Luke M. Evans ◽  
Seonkyeong Jang ◽  
Marissa A. Ehringer ◽  
Jacqueline M. Otto ◽  
Scott I. Vrieze ◽  
...  
Keyword(s):  
Smoking Cessation ◽  
Genetic Architecture ◽  
Genetic Variance ◽  
Rare Variants ◽  
Low Frequency ◽  
Smoking Initiation ◽  
Uk Biobank ◽  
Genome Wide ◽  
Smoking Behaviors

AbstractBackground and AimsSmoking is a leading cause of premature death. Although genome-wide association studies have identified many loci that influence smoking behaviors, much of the genetic variance in these traits remains unexplained. We sought to characterize the genetic architecture of four smoking behaviors through SNP-based heritability (h2SNP) analyses.DesignWe applied recently-developed partitioned h2SNP approaches to smoking behavior traits assessed in the UK Biobank.SettingUK Biobank.ParticipantsUK Biobank participants of European ancestry. The number of participants varied depending on the trait, from 54,792 to 323,068.MeasurementsSmoking initiation, age of initiation, cigarettes per day (CPD; count, log-transformed, binned, and dichotomized into heavy versus light), and smoking cessation. Imputed genome-wide SNPs.FindingsWe estimated h2SNP(SE)=0.18(0.01) for smoking initiation and 0.12(0.02) for smoking cessation, which were more than twice the previously reported estimates. Estimated age of initiation h2SNP=0.05(0.01) and binned CPD h2SNP=0.1(0.01) were similar to previous reports. These estimates remained substantially below published twin-based h2 of roughly 50%. CPD encoding strongly influenced estimates, with dichotomized CPD h2SNP=0.28. We found significant contributions of low-frequency variants and variants in low linkage-disequilibrium (LD) with surrounding genomic regions. Functional annotations related to LD, allele frequency, sequence conservation, and selective constraint also contributed significantly to the partitioned heritability. We found no evidence of dominance genetic variance for any trait.Conclusionh2SNP of these four specific smoking behaviors is modest overall. The patterns of partitioned h2SNP for these highly polygenic traits is consistent with negative selection. We found a predominant contribution of common variants, and our results suggest a role of low-frequency or rare variants, poorly tagged by surrounding regions. Deep sequencing of large samples and/or improved imputation will be required to fully assess the role of rare variants.

scholarly journals The impact of low-frequency and rare variants on lipid levels

2015 ◽  
Vol 47 (6) ◽  
pp. 589-597 ◽  
Author(s):  
Ida Surakka ◽  
◽  
Momoko Horikoshi ◽  
Reedik Mägi ◽  
Antti-Pekka Sarin ◽  
...  
Keyword(s):  
Rare Variants ◽  
Low Frequency ◽  
Lipid Levels ◽  
The Impact

scholarly journals Genotype × Environment Interaction for Wheat Yield Traits Suitable for Selection in Different Seed Priming Conditions

Plants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1804
Author(s):  
Vera Popović ◽  
Nataša Ljubičić ◽  
Marko Kostić ◽  
Mirjana Radulović ◽  
Dragana Blagojević ◽  
...  
Keyword(s):  
Grain Yield ◽  
Wheat Yield ◽  
Seed Priming ◽  
Triticum Aestivum L ◽  
Complex Nature ◽  
Environment Interaction ◽  
Zno Nps ◽  
Wheat Genotypes ◽  
Main Component ◽  
The Impact

Different seed priming treatments are widely used in order to improve the nutritional status of wheat, as well as to improve its grain yield and yield- related traits. The present study aimed to evaluate the impact of seed priming with zinc oxide nanoparticles (ZnO NPs) on the yield related traits, such as, field emergence, plant height, spike length and grain yield per plant of four winter wheat genotypes (Triticum aestivum L.) during two vegetation seasons of 2018/2019 and 2019/2020. The seeds of each wheat genotypes were primed with different concentrations of ZnO NPs (0 mg L−1, 10 mg L−1, 100 mg L−1 and 1000 mg L−1) for 48 h in a dark box by continuous aeration and were sown in soil pots with 60–70% moisture content until full maturity. The additive main effects and multiplicative interaction (AMMI) models were used to study the genotype environment effects. The results indicated that the plants response to ZnO nanoparticles significantly increased all of the observed traits of the wheat, while its maximum rates reduced the traits of the wheat. The AMMI analysis revealed the very complex nature of the variation observed in the trial and showed the significant effect of the G×E interaction, in which the first main component was significant for all components.

scholarly journals The impact of rare and low-frequency genetic variants in common variable immunodeficiency (CVID)

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Atil Bisgin ◽  
Ozge Sonmezler ◽  
Ibrahim Boga ◽  
Mustafa Yilmaz
Keyword(s):  
Common Variable Immunodeficiency ◽  
Genetic Variants ◽  
Disease Susceptibility ◽  
Rare Variants ◽  
Low Frequency ◽  
Blood Leukocytes ◽  
Population Frequency ◽  
Immune Deficiencies ◽  
The Impact ◽  
Common Variable

AbstractNext Generation Sequencing (NGS) has uncovered hundreds of common and rare genetic variants involved in complex and rare diseases including immune deficiencies in both an autosomal recessive and autosomal dominant pattern. These rare variants however, cannot be classified clinically, and common variants only marginally contribute to disease susceptibility. In this study, we evaluated the multi-gene panel results of Common Variable Immunodeficiency (CVID) patients and argue that rare variants located in different genes play a more prominent role in disease susceptibility and/or etiology. We performed NGS on DNA extracted from the peripheral blood leukocytes from 103 patients using a panel of 19 CVID-related genes: CARD11, CD19, CD81, ICOS, CTLA4, CXCR4, GATA2, CR2, IRF2BP2, MOGS, MS4A1, NFKB1, NFKB2, PLCG2, TNFRSF13B, TNFRSF13C, TNFSF12, TRNT1 and TTC37. Detected variants were evaluated and classified based on their impact, pathogenicity classification and population frequency as well as the frequency within our study group. NGS revealed 112 different (a total of 227) variants with under 10% population frequency in 103 patients of which 22(19.6%) were classified as benign, 29(25.9%) were classified as likely benign, 4(3.6%) were classified as likely pathogenic and 2(1.8%) were classified as pathogenic. Moreover, 55(49.1%) of the variants were classified as variants of uncertain significance. We also observed different variant frequencies when compared to population frequency databases. Case–control data is not sufficient to unravel the genetic etiology of immune deficiencies. Thus, it is important to understand the incidence of co-occurrence of two or more rare variants to aid in illuminating their potential roles in the pathogenesis of immune deficiencies.

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