scholarly journals Host Genetic Variants Potentially Associated with SARS-Cov-2: A Multi-Population Analysis

2020 ◽  
Author(s):  
Maria K. Smatti ◽  
Yasser Al-Sarraj ◽  
Omar Albagha ◽  
Hadi M. Yassine
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Population Analysis ◽  
Fold Change ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Risk Alleles ◽  
Risk Variants ◽  
Genome Wide ◽  
Ifn Γ

Background: Clinical outcomes of Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) showed enormous inter-individual and interpopulation differences, possibly due to host genetics differences. Earlier studies identified single nucleotide polymorphisms (SNPs) associated with SARS-CoV-1 in Eastern Asian (EAS) populations. In this report, we aimed at exploring the frequency of a set of genetic polymorphisms that could affect SARS-CoV-2 susceptibility or severity, including those that were previously associated with SARS-CoV-1. Methods: We extracted the list of SNPs that could potentially modulate SARS-CoV-2 from the genome wide association studies (GWAS) on SARS-CoV-1 and other viruses. We also collected the expression data of these SNPs from the expression quantitative trait loci (eQTLs) databases. Sequences from Qatar Genome Programme (QGP, n=6,054) and 1000Genome project were used to calculate and compare allelic frequencies (AF). Results: A total of 74 SNPs, located in 10 genes: ICAM3, IFN-γ, CCL2, CCL5, AHSG, MBL, Furin, TMPRSS2, IL4, and CD209 promoter, were identified. Analysis of Qatari genomes revealed significantly lower AF of risk variants linked to SARS-CoV-1 severity (CCL2, MBL, CCL5, AHSG, and IL4) compared to that of 1000Genome and/or the EAS population (up to 25-fold change). Conversely, SNPs in TMPRSS2, IFN-γ, ICAM3, and Furin were more common among Qataris (average 2-fold change). Inter-population analysis showed that the distribution of risk alleles among Europeans differs substantially from Africans and EASs. Remarkably, Africans seem to carry extremely lower frequencies of SARS-CoV-1 susceptibility alleles, reaching to 32-fold decrease compared to other populations. Conclusion: Multiple genetic variants, which could potentially modulate SARS-CoV-2 infection, are significantly variable between populations, with the lowest frequency observed among Africans. Our results highlight the importance of exploring population genetics to understand and predict COVID-19 outcomes. Indeed, further studies are needed to validate these findings as well as to identify new genetic determinants linked to SARS-CoV-2.

scholarly journals Atrial fibrillation associated common risk variants in SYNE2 lead to lower expression of nesprin-2α1 and increased nuclear stiffness

2019 ◽  
Author(s):  
Nana Liu ◽  
Jeffrey Hsu ◽  
Gautam Mahajan ◽  
Han Sun ◽  
John Barnard ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Association Studies ◽  
Dominant Negative ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Enhancer Activity ◽  
Risk Alleles ◽  
Risk Variants ◽  
Lower Expression

ABSTRACTRationaleAtrial fibrillation (AF) genome-wide association studies (GWAS) identified significant associations for rs1152591 and linked variants in the SYNE2 gene encoding the nesprin-2 protein that connects the nuclear membrane with the cytoskeletonObjectiveDetermine the effects of the AF-associated rs1152591 and rs1152595, two linked intronic single nucleotide polymorphisms (SNPs), on SYNE2 expression and investigate the mechanisms for their association with AF.Methods and ResultsRNA sequencing of human left atrial appendage (LAA) tissues indicated that rs1152591 and rs1152595 were significantly associated with the expressions of SYNE2α1, a short mRNA isoform, without an effect on the expression of the full-length SYNE2 mRNA. SYNE2α1 mRNA uses an alternative transcription start site and encodes an N-terminal deleted 62 kDa nesprin-2α1 isoform, which can act as a dominant-negative on nuclear-cytoskeleton connectivity. Western blot and qPCR assays confirmed that AF risk alleles of both SNPs were associated with lower expression of nesprin-2α1 in human LAA tissues. Reporter gene transfections demonstrated that the risk vs. reference alleles of rs1152591 and rs1152595 had decreased enhancer activity. SYNE2 siRNA knockdown (KD) or nesprin-2α1 overexpression studies in human stem cell-derived induced cardiomyocytes (iCMs) resulted in ~12.5 % increases in the nuclear area compared to controls (p<0.001). Atomic force microscopy demonstrated that SYNE2 KD or nesprin-2α1 overexpression led to 57.5% or 33.2% decreases, respectively, in nuclear stiffness compared to controls (p< 0.0001).ConclusionsAF-associated SNPs rs1152591 and rs1152595 downregulate the expression of SYNE2α1, increasing nuclear-cytoskeletal connectivity and nuclear stiffness. The resulting increase in mechanical stress may play a role in the development of AF.

scholarly journals Polygenic risk score based on weight gain trajectories is predictive of childhood obesity

2019 ◽  
Author(s):  
Sarah J. C. Craig ◽  
Ana M. Kenney ◽  
Junli Lin ◽  
Ian M. Paul ◽  
Leann L. Birch ◽  
...  
Keyword(s):  
Weight Gain ◽  
Childhood Obesity ◽  
Risk Score ◽  
Genetic Variants ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide

AbstractObesity is highly heritable, yet only a small fraction of its heritability has been attributed to specific genetic variants. These variants are traditionally ascertained from genome-wide association studies (GWAS), which utilize samples with tens or hundreds of thousands of individuals for whom a single summary measurement (e.g., BMI) is collected. An alternative approach is to focus on a smaller, more deeply characterized sample in conjunction with advanced statistical models that leverage detailed phenotypes. Here we use novel functional data analysis (FDA) techniques to capitalize on longitudinal growth information and construct a polygenic risk score (PRS) for obesity in children followed from birth to three years of age. This score, comprised of 24 single nucleotide polymorphisms (SNPs), is significantly higher in children with (vs. without) rapid infant weight gain—a predictor of obesity later in life. Using two independent cohorts, we show that genetic variants identified in early childhood are also informative in older children and in adults, consistent with early childhood obesity being predictive of obesity later in life. In contrast, PRSs based on SNPs identified by adult obesity GWAS are not predictive of weight gain in our cohort of children. Our research provides an example of a successful application of FDA to GWAS. We demonstrate that a deep, statistically sophisticated characterization of a longitudinal phenotype can provide increased statistical power to studies with relatively small sample sizes. This study shows how FDA approaches can be used as an alternative to the traditional GWAS.Author SummaryFinding genetic variants that confer an increased risk of developing a particular disease has long been a focus of modern genetics. Genome wide association studies (GWAS) have catalogued single nucleotide polymorphisms (SNPs) associated with a variety of complex diseases in humans, including obesity, but by and large have done so using increasingly large samples-- tens or even hundreds of thousands of individuals, whose phenotypes are thus often only superficially characterized. This, in turn, may hide the intricacies of the genetic influence on disease. GWAS findings are also usually study-population dependent. We found that genetic risk scores based on SNPs from large adult obesity studies are not predictive of the propensity to gain weight in very young children. However, using a small cohort of a few hundred children deeply characterized with growth trajectories between birth and two years, and leveraging such trajectories through novel functional data analysis (FDA) techniques, we were able to produce a strong childhood obesity genetic risk score.

scholarly journals Cascading epigenomic analysis for identifying disease genes from the regulatory landscape of GWAS variants

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009918
Author(s):  
Bernard Ng ◽  
William Casazza ◽  
Nam Hee Kim ◽  
Chendi Wang ◽  
Farnush Farhadi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Target Genes ◽  
Association Studies ◽  
Disease Genes ◽  
Genome Wide Association Studies ◽  
Cascading Effects ◽  
Risk Alleles ◽  
Gene Sets ◽  
Genome Wide ◽  
Regulatory Landscape

The majority of genetic variants detected in genome wide association studies (GWAS) exert their effects on phenotypes through gene regulation. Motivated by this observation, we propose a multi-omic integration method that models the cascading effects of genetic variants from epigenome to transcriptome and eventually to the phenome in identifying target genes influenced by risk alleles. This cascading epigenomic analysis for GWAS, which we refer to as CEWAS, comprises two types of models: one for linking cis genetic effects to epigenomic variation and another for linking cis epigenomic variation to gene expression. Applying these models in cascade to GWAS summary statistics generates gene level statistics that reflect genetically-driven epigenomic effects. We show on sixteen brain-related GWAS that CEWAS provides higher gene detection rate than related methods, and finds disease relevant genes and gene sets that point toward less explored biological processes. CEWAS thus presents a novel means for exploring the regulatory landscape of GWAS variants in uncovering disease mechanisms.

scholarly journals A Genome-Wide Association Study of Novel Genetic Variants Associated With Anthropometric Traits in Koreans

2021 ◽  
Vol 12 ◽  
Author(s):  
Hye-Won Cho ◽  
Hyun-Seok Jin ◽  
Yong-Bin Eom
Keyword(s):  
Genetic Variants ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Fat Distribution ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
A Genome

Most previous genome-wide association studies (GWAS) have identified genetic variants associated with anthropometric traits. However, most of the evidence were reported in European populations. Anthropometric traits such as height and body fat distribution are significantly affected by gender and genetic factors. Here we performed GWAS involving 64,193 Koreans to identify the genetic factors associated with anthropometric phenotypes including height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip ratio. We found nine novel single-nucleotide polymorphisms (SNPs) and 59 independent genetic signals in genomic regions that were reported previously. Of the 19 SNPs reported previously, eight genetic variants at RP11-513I15.6 and one genetic variant at the RP11-977G19.10 region and six Asian-specific genetic variants were newly found. We compared our findings with those of previous studies in other populations. Five overlapping genetic regions (PAN2, ANKRD52, RNF41, HGMA1, and C6orf106) had been reported previously but none of the SNPs were independently identified in the current study. Seven of the nine newly found novel loci associated with height in women revealed a statistically significant skeletal expression of quantitative trait loci. Our study provides additional insight into the genetic effects of anthropometric phenotypes in East Asians.

scholarly journals The Role of 39 Psoriasis Risk Variants on Age of Psoriasis Onset

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Yingchang Lu ◽  
Sinae Kane ◽  
Haoyan Chen ◽  
Argentina Leon ◽  
Ethan Levin ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
False Discovery ◽  
Risk Variants ◽  
Genome Wide ◽  
Independent Cohort

Recent genome-wide association studies (GWAS) have identified multiple genetic risk factors for psoriasis, but data on their association with age of onset have been marginally explored. The goal of this study was to evaluate known risk alleles of psoriasis for association with age of psoriasis onset in three well-defined case-only cohorts totaling 1,498 psoriasis patients. We selected 39 genetic variants from psoriasis GWAS and tested these variants for association with age of psoriasis onset in a meta-analysis. We found that rs10484554 and rs12191877 near HLA-C and rs17716942 near IFIH1 were associated with age of psoriasis onset with false discovery rate < 0.05. The association between rs17716942 and age of onset was not replicated in a fourth independent cohort of 489 patients (). The imputed HLA-C*06:02 allele demonstrated a much stronger association with age of psoriasis onset than rs10484554 and rs12191877. We conclude that despite the discovery of numerous psoriasis risk alleles, HLA-C*06:02 still plays the most important role in determining the age of onset of psoriasis. Larger studies are needed to evaluate the contribution of other risk alleles, including IFIH1, to age of psoriasis onset.

scholarly journals Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureus

2021 ◽  
Vol 12 ◽  
Author(s):  
Robert E. Weber ◽  
Stephan Fuchs ◽  
Franziska Layer ◽  
Anna Sommer ◽  
Jennifer K. Bender ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Genetic Variants ◽  
Association Studies ◽  
Rapid Development ◽  
Genome Wide Association ◽  
Resistant Isolate ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Resistance Traits

BackgroundAs next generation sequencing (NGS) technologies have experienced a rapid development over the last decade, the investigation of the bacterial genetic architecture reveals a high potential to dissect causal loci of antibiotic resistance phenotypes. Although genome-wide association studies (GWAS) have been successfully applied for investigating the basis of resistance traits, complex resistance phenotypes have been omitted so far. For S. aureus this especially refers to antibiotics of last resort like daptomycin and ceftaroline. Therefore, we aimed to perform GWAS for the identification of genetic variants associated with DAP and CPT resistance in clinical S. aureus isolates.Materials/methodsTo conduct microbial GWAS, we selected cases and controls according to their clonal background, date of isolation, and geographical origin. Association testing was performed with PLINK and SEER analysis. By using in silico analysis, we also searched for rare genetic variants in candidate loci that have previously been described to be involved in the development of corresponding resistance phenotypes.ResultsGWAS revealed MprF P314L and L826F to be significantly associated with DAP resistance. These mutations were found to be homogenously distributed among clonal lineages suggesting convergent evolution. Additionally, rare and yet undescribed single nucleotide polymorphisms could be identified within mprF and putative candidate genes. Finally, we could show that each DAP resistant isolate exhibited at least one amino acid substitution within the open reading frame of mprF. Due to the presence of strong population stratification, no genetic variants could be associated with CPT resistance. However, the investigation of the staphylococcal cassette chromosome mec (SCCmec) revealed various mecA SNPs to be putatively linked with CPT resistance. Additionally, some CPT resistant isolates revealed no mecA mutations, supporting the hypothesis that further and still unknown resistance determinants are crucial for the development of CPT resistance in S. aureus.ConclusionWe hereby confirmed the potential of GWAS to identify genetic variants that are associated with antibiotic resistance traits in S. aureus. However, precautions need to be taken to prevent the detection of spurious associations. In addition, the implementation of different approaches is still essential to detect multiple forms of variations and mutations that occur with a low frequency.

scholarly journals Combining multivariate genomic approaches to elucidate the comorbidity between ASD and ADHD

2020 ◽  
Author(s):  
Hugo Peyre ◽  
Tabea Schoeler ◽  
Chaoyu Liu ◽  
Camille Michèle Williams ◽  
Nicolas Hoertel ◽  
...  
Keyword(s):  
Structural Equation ◽  
Association Studies ◽  
Autism Spectrum ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Hyperactivity Disorder ◽  
Risk Variants ◽  
Genome Wide ◽  
Summary Data ◽  
Shared Genetic

ABSTRACTBackgroundSeveral lines of evidence point toward the presence of shared genetic factors underlying Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). However, Genome-Wide Association Studies (GWAS) have yet to identify risk variants (i.e. Single-Nucleotide Polymorphisms, SNPs) shared by ADHD and ASD.MethodsTwo complementary multivariate analyses – genomic structural equation modelling (SEM) and colocalization analysis – were exploited to identify the shared SNPs for ASD and ADHD, using summary data from two independent GWAS of ASD (N=46,350) and ADHD individuals (N=55,374).ResultsGenomic SEM identified 7 novel SNPs shared between ASD and ADHD (pgenome-wide<5e-8), including three SNPs that were not identified in any of the original univariate GWAS of ASD and ADHD (rs227378, rs2391769 and rs325506). We also mapped 4 novel genes (MANBA, DPYD, INSM1, and PAX1) to SNPs shared by ASD and ADHD, as well as 4 genes that had already been mapped to SNPs identified in either ASD or ADHD GWAS (SORCS3, XRN2, PTBP2 and NKX2-4). All the shared genes between ADHD and ASD were more prominently expressed in the brain than the genes mapped to SNPs specific to ASD or ADHD. Colocalization analyses revealed that 44% percent of the SNPs associated with ASD (p<1e-6) colocalized with ADHD SNPs and 26% of the SNPs associated with ADHD (p<1e-6) colocalized with ASD SNPs.ConclusionsUsing multivariate genomic analyses, the present study reveals the shared genetic pathways that underlie ASD and ADHD. Further investigation of these pathways may help identify new targets for treatment of these disorders.

scholarly journals Finding genetic variants in plants without complete genomes

2019 ◽  
Author(s):  
Yoav Voichek ◽  
Detlef Weigel
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Structural Variants ◽  
Sequencing Data ◽  
New Associations ◽  
Maize Populations ◽  
Genome Wide ◽  
Genomic Regions

AbstractStructural variants and presence/absence polymorphisms are common in plant genomes, yet they are routinely overlooked in genome-wide association studies (GWAS). Here, we expand the genetic variants detected in GWAS to include major deletions, insertions, and rearrangements. We first use raw sequencing data directly to derive short sequences, k-mers, that mark a broad range of polymorphisms independently of a reference genome. We then link k-mers associated with phenotypes to specific genomic regions. Using this approach, we re-analyzed 2,000 traits measured in Arabidopsis thaliana, tomato, and maize populations. Associations identified with k-mers recapitulate those found with single-nucleotide polymorphisms (SNPs), however, with stronger statistical support. Moreover, we identified new associations with structural variants and with regions missing from reference genomes. Our results demonstrate the power of performing GWAS before linking sequence reads to specific genomic regions, which allow detection of a wider range of genetic variants responsible for phenotypic variation.

Association of CACNA1C polymorphisms with serum BDNF levels in bipolar disorder

2019 ◽  
pp. 1-3
Author(s):  
Erik Smedler ◽  
Erik Pålsson ◽  
Kenji Hashimoto ◽  
Mikael Landén
Keyword(s):  
Bipolar Disorder ◽  
Genetic Variants ◽  
Association Studies ◽  
Serum Levels ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Voltage Gated Calcium Channels ◽  
Genome Wide ◽  
Tissue Plasminogen ◽  
Serum Bdnf

Variation in the CACNA1C gene has been associated with bipolar disorder in several genome-wide association studies. This gene encodes the alpha 1C subunit of L-type voltage-gated calcium channels, which play an essential role in neurons. We analysed 39 biomarkers in either cerebrospinal fluid or serum in relation to six different CACNA1C variants in 282 patients with bipolar disorder and 90 controls. We report associations of CACNA1C risk alleles with serum levels of BDNF as well as tissue plasminogen activator, which converts pro-BDNF to mature BDNF. This sheds light on links between CACNA1C genetic variants and pathophysiological mechanisms in bipolar disorder.Declaration of interestNone.

scholarly journals STAT4Gene Polymorphisms Are Associated with Susceptibility and ANA Status in Primary Biliary Cirrhosis

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Satoru Joshita ◽  
Takeji Umemura ◽  
Minoru Nakamura ◽  
Yoshihiko Katsuyama ◽  
Soichiro Shibata ◽  
...  
Keyword(s):  
Primary Biliary Cirrhosis ◽  
Genetic Factors ◽  
Association Studies ◽  
Biliary Cirrhosis ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Risk Alleles ◽  
Genome Wide ◽  
Mitochondrial Antibody

Recent genome-wide association studies suggest that genetic factors contribute to primary biliary cirrhosis (PBC) susceptibility. Although several reports have demonstrated that the interleukin (IL) 12 signaling pathway is involved in PBC pathogenesis, its precise genetic factors have not been fully clarified. Here, we performed an association analysis betweenIL12A,IL12RB, andsignal transducer and activator of transcription 4 (STAT4)genetic variations and susceptibility to PBC. Single nucleotide polymorphisms (SNPs) were genotyped in 395 PBC patients and 458 healthy subjects of Japanese ethnicity and evaluated for associations with PBC susceptibility, anti-nuclear antibody (ANA) status, and anti-mitochondrial antibody (AMA) status. We detected significant associations with PBC susceptibility for severalSTAT4SNPs (rs10168266;P=9.4×10-3, rs11889341;P=1.2×10-3, rs7574865;P=4.0×10-4, rs8179673;P=2.0×10-4, and rs10181656;P=4.2×10-5). Three risk alleles (rs7574865;P=0.040, rs8179673;P=0.032, and rs10181656;P=0.031) were associated with ANA status, but not with AMA positivity. Our findings confirm thatSTAT4is involved in PBC susceptibility and may play a role in ANA status in the Japanese population.

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