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 Assessing the contribution of rare-to-common protein-coding variants to circulating metabolic biomarker levels via 412,394 UK Biobank exome sequences

2021 ◽  
Author(s):  
Abhishek Nag ◽  
Lawrence Middleton ◽  
Ryan S Dhindsa ◽  
Dimitrios Vitsios ◽  
Eleanor M Wigmore ◽  
...  
Keyword(s):  
Gene Networks ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Protein Coding ◽  
The Uk ◽  
Metabolic Biomarkers ◽  
Coding Variants

Genome-wide association studies have established the contribution of common and low frequency variants to metabolic biomarkers in the UK Biobank (UKB); however, the role of rare variants remains to be assessed systematically. We evaluated rare coding variants for 198 metabolic biomarkers, including metabolites assayed by Nightingale Health, using exome sequencing in participants from four genetically diverse ancestries in the UKB (N=412,394). Gene-level collapsing analysis, that evaluated a range of genetic architectures, identified a total of 1,303 significant relationships between genes and metabolic biomarkers (p<1x10-8), encompassing 207 distinct genes. These include associations between rare non-synonymous variants in GIGYF1 and glucose and lipid biomarkers, SYT7 and creatinine, and others, which may provide insights into novel disease biology. Comparing to a previous microarray-based genotyping study in the same cohort, we observed that 40% of gene-biomarker relationships identified in the collapsing analysis were novel. Finally, we applied Gene-SCOUT, a novel tool that utilises the gene-biomarker association statistics from the collapsing analysis to identify genes having similar biomarker fingerprints and thus expand our understanding of gene networks.

scholarly journals Common and Rare Variants in Genes Associated with von Willebrand Factor Level Variation: No Accumulation of Rare Variants in Swedish von Willebrand Disease Patients

TH Open ◽  
2020 ◽  
Vol 04 (04) ◽  
pp. e322-e331
Author(s):  
Eric Manderstedt ◽  
Christina Lind-Halldén ◽  
Stefan Lethagen ◽  
Christer Halldén
Keyword(s):  
Von Willebrand Factor ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Von Willebrand Disease ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
The Common ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractGenome-wide association studies (GWASs) have identified genes that affect plasma von Willebrand factor (VWF) levels. ABO showed a strong effect, whereas smaller effects were seen for VWF, STXBP5, STAB2, SCARA5, STX2, TC2N, and CLEC4M. This study screened comprehensively for both common and rare variants in these eight genes by resequencing their coding sequences in 104 Swedish von Willebrand disease (VWD) patients. The common variants previously associated with the VWF level were all accumulated in the VWD patients compared to three control populations. The strongest effect was detected for blood group O coded for by the ABO gene (71 vs. 38% of genotypes). The other seven VWF level associated alleles were enriched in the VWD population compared to control populations, but the differences were small and not significant. The sequencing detected a total of 146 variants in the eight genes. Excluding 70 variants in VWF, 76 variants remained. Of the 76 variants, 54 had allele frequencies > 0.5% and have therefore been investigated for their association with the VWF level in previous GWAS. The remaining 22 variants with frequencies < 0.5% are less likely to have been evaluated previously. PolyPhen2 classified 3 out of the 22 variants as probably or possibly damaging (two in STAB2 and one in STX2); the others were either synonymous or benign. No accumulation of low frequency (0.05–0.5%) or rare variants (<0.05%) in the VWD population compared to the gnomAD (Genome Aggregation Database) population was detected. Thus, rare variants in these genes do not contribute to the low VWF levels observed in VWD patients.

scholarly journals Genetic architecture of nonadditive inheritance in Arabidopsis thaliana hybrids

2016 ◽  
Vol 113 (46) ◽  
pp. E7317-E7326 ◽  
Author(s):  
Danelle K. Seymour ◽  
Eunyoung Chae ◽  
Dominik G. Grimm ◽  
Carmen Martín Pizarro ◽  
Anette Habring-Müller ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Molecular Basis ◽  
Genetic Architecture ◽  
Genetic Basis ◽  
Genetic Variance ◽  
Candidate Region ◽  
Hybrid Vigor ◽  
Mads Box ◽  
Genome Wide ◽  
Half Diallel

The ubiquity of nonparental hybrid phenotypes, such as hybrid vigor and hybrid inferiority, has interested biologists for over a century and is of considerable agricultural importance. Although examples of both phenomena have been subject to intense investigation, no general model for the molecular basis of nonadditive genetic variance has emerged, and prediction of hybrid phenotypes from parental information continues to be a challenge. Here we explore the genetics of hybrid phenotype in 435 Arabidopsis thaliana individuals derived from intercrosses of 30 parents in a half diallel mating scheme. We find that nonadditive genetic effects are a major component of genetic variation in this population and that the genetic basis of hybrid phenotype can be mapped using genome-wide association (GWA) techniques. Significant loci together can explain as much as 20% of phenotypic variation in the surveyed population and include examples that have both classical dominant and overdominant effects. One candidate region inherited dominantly in the half diallel contains the gene for the MADS-box transcription factor AGAMOUS-LIKE 50 (AGL50), which we show directly to alter flowering time in the predicted manner. Our study not only illustrates the promise of GWA approaches to dissect the genetic architecture underpinning hybrid performance but also demonstrates the contribution of classical dominance to genetic variance.

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 A year of COVID-19 GWAS results from the GRASP portal reveals potential SARS-CoV-2 modifiers

2021 ◽  
Author(s):  
Florian Thibord ◽  
Melissa V Chan ◽  
Ming-Huei Chen ◽  
Andrew D Johnson
Keyword(s):  
Genetic Architecture ◽  
Association Studies ◽  
Therapeutic Strategies ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Independent Dataset ◽  
Genome Wide ◽  
Data Release ◽  
Host Genetic

Host genetic variants influence the susceptibility and severity of several infectious diseases, and the discovery of novel genetic associations with Covid-19 phenotypes could help developing new therapeutic strategies to reduce its burden. Between May 2020 and February 2021, we used Covid-19 data released periodically by UK Biobank and performed over 400 Genome-Wide Association Studies (GWAS) of Covid-19 susceptibility (N=15,738 cases), hospitalization (N=1,916), severe outcomes (N=935) and death (N=828), stratified by ancestry and sex. In coherence with previous studies, we observed 2 independent signals at the chr3p21.31 locus (rs73062389-A, OR=1.22, P=7.64E-14 and rs13092887-A, OR=1.73, P=2.38E-8, in Europeans) modulating susceptibility and severity, respectively, and a signal influencing susceptibility at the ABO locus (rs9411378-A, OR=1.10, P =7.36E-10, in Europeans), which was more significant in men than in women (P=0.01). In addition, we detected 7 genome-wide significant signals in the last data release analyzed (on February 24th 2021), of which 4 were associated with susceptibility (SCRT2, LRMDA, chr15q24.2, MIR3681HG), 2 with hospitalization (ANKS1A, chr12p13.31) and 1 for severity (ADGRE1). Finally, we identified over 300 associations which increased in significance over time, and reached at least P<10-5 in the last data release analyzed. We replicated 2 of these signals in an independent dataset: a variant downstream of CCL3 (rs2011959) associated with severity in men, and a variant located in an ATP5PO intron (rs12482569) associated with hospitalization. These results, freely available on the GRASP portal, provide new insights on the host genetic architecture of Covid-19 phenotypes.

scholarly journals HOPS: a quantitative score reveals pervasive horizontal pleiotropy in human genetic variation is driven by extreme polygenicity of human traits and diseases

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Daniel M. Jordan ◽  
Marie Verbanck ◽  
Ron Do
Keyword(s):  
Genetic Variation ◽  
Genetic Architecture ◽  
Genome Wide Association ◽  
Summary Statistics ◽  
Human Genetic Variation ◽  
Uk Biobank ◽  
Multiple Traits ◽  
Genome Wide ◽  
Quantitative Score ◽  
Independent Effects

Abstract Horizontal pleiotropy, where one variant has independent effects on multiple traits, is important for our understanding of the genetic architecture of human phenotypes. We develop a method to quantify horizontal pleiotropy using genome-wide association summary statistics and apply it to 372 heritable phenotypes measured in 361,194 UK Biobank individuals. Horizontal pleiotropy is pervasive throughout the human genome, prominent among highly polygenic phenotypes, and enriched in active regulatory regions. Our results highlight the central role horizontal pleiotropy plays in the genetic architecture of human phenotypes. The HOrizontal Pleiotropy Score (HOPS) method is available on Github at https://github.com/rondolab/HOPS.

scholarly journals The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Erna V. Ivarsdottir ◽  
Hilma Holm ◽  
Stefania Benonisdottir ◽  
Thorhildur Olafsdottir ◽  
Gardar Sveinbjornsson ◽  
...  
Keyword(s):  
Hearing Impairment ◽  
Genetic Architecture ◽  
Rare Variants ◽  
Meta Analysis ◽  
Genetic Risk Score ◽  
Missense Variant ◽  
Genome Wide Association ◽  
Age Related ◽  
Genome Wide ◽  
A Genome

AbstractAge-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P = 1.7 × 10−22 and OR = 4.2 for heterozygotes, P = 5.7 × 10−27, respectively). We constructed an ARHI genetic risk score (GRS) using common variants and showed that a common variant GRS can identify individuals at risk comparable to carriers of rare high penetrance variants. Furthermore, we found that ARHI and tinnitus share genetic causes. This study sheds a new light on the genetic architecture of ARHI, through several rare variants in both Mendelian deafness genes and genes not previously linked to hearing.

scholarly journals Latest findings in the genetic architecture of schizophrenia: The contribution of genetic studies among Afrikaners

2014 ◽  
Vol 33 (1) ◽  
Author(s):  
Johannes L. Roos
Keyword(s):  
Genetic Architecture ◽  
De Novo ◽  
Disease Risk ◽  
Association Studies ◽  
Copy Number Variants ◽  
Point Mutations ◽  
Risk Variants ◽  
Genome Wide ◽  
Long Time

A genetic component of schizophrenia has been acknowledged for a long time. The underlying architecture of the genetic risk remains a contentious issue. Early linkage and candidate association studies led to largely inconclusive results. More recently powerful technologies became available. This aspect coupled with samples of sufficient sizes, and genome-wide panels of genetic markers facilitated systematic and agnostic scans throughout the genome for either common or rare disease risk variants of small or large effect size, respectively. Although the former had limited success, the role of rare genetic events, such as copy-number variants (CNVs) or rare point mutations, has become increasingly important in gene discovery for schizophrenia. Recent research done among Afrikaner patients with schizophrenia, building upon earlier findings of de novo recurrent CNVs at the 22q11.2 locus, has highlighted a de novo mutational paradigm as a major component of the genetic architecture of schizophrenia. Recent progress in this regard will be reviewed.

scholarly journals Genetic architecture influences when and how hybridization contributes to colonization

2019 ◽  
Author(s):  
Bryan Reatini ◽  
Todd J. Vision
Keyword(s):  
Environmental Conditions ◽  
Genetic Architecture ◽  
Genetic Variance ◽  
De Novo ◽  
Dispersal Rate ◽  
Intraspecific Hybridization ◽  
Source Populations ◽  
Second Category ◽  
Do So

AbstractThe role of genetic architecture in adaptation to novel environments has received considerable attention when the source of adaptation variation is de novo mutation. Relatively less is known when the source of adaptive variation is inter- or intraspecific hybridization. We model hybridization between divergent source populations and subsequent colonization of an unoccupied novel environment using individual-based simulations in order to understand the influence of genetic architecture on the timing of colonization and the mode of adaptation. We find that two distinct categories of genetic architecture facilitate rapid colonization but that they do so in qualitatively different ways. For few and/or tightly linked loci, the mode of adaptation is via the recovery of adaptive parental genotypes. With many unlinked loci, the mode of adaptation is via the generation of novel hybrid genotypes. The first category results in the shortest colonization lag phases across the widest range of parameter space, but further adaptation is mutation limited. The second category takes longer and is more sensitive to genetic variance and dispersal rate, but can facilitate adaptation to environmental conditions which exceed the tolerance of parental populations. These findings have implications for understanding the origins of biological invasions and the success of hybrid populations.

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