Genome Wide Association Studies
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2021 ◽  
Vol 17 (10) ◽  
pp. e1009992
Sarah G. Earle ◽  
Mariya Lobanovska ◽  
Hayley Lavender ◽  
Changyan Tang ◽  
Rachel M. Exley ◽  

Many invasive bacterial diseases are caused by organisms that are ordinarily harmless components of the human microbiome. Effective interventions against these microbes require an understanding of the processes whereby symbiotic or commensal relationships transition into pathology. Here, we describe bacterial genome-wide association studies (GWAS) of Neisseria meningitidis, a common commensal of the human respiratory tract that is nevertheless a leading cause of meningitis and sepsis. An initial GWAS discovered bacterial genetic variants, including single nucleotide polymorphisms (SNPs), associated with invasive meningococcal disease (IMD) versus carriage in several loci across the meningococcal genome, encoding antigens and other extracellular components, confirming the polygenic nature of the invasive phenotype. In particular, there was a significant peak of association around the fHbp locus, encoding factor H binding protein (fHbp), which promotes bacterial immune evasion of human complement by recruiting complement factor H (CFH) to the meningococcal surface. The association around fHbp with IMD was confirmed by a validation GWAS, and we found that the SNPs identified in the validation affected the 5’ region of fHbp mRNA, altering secondary RNA structures, thereby increasing fHbp expression and enhancing bacterial escape from complement-mediated killing. This finding is consistent with the known link between complement deficiencies and CFH variation with human susceptibility to IMD. These observations demonstrate the importance of human and bacterial genetic variation across the fHbp:CFH interface in determining IMD susceptibility, the transition from carriage to disease.

2021 ◽  
Jicai Jiang

Using summary statistics from genome-wide association studies (GWAS) has been widely used for fine-mapping complex traits in humans. The statistical framework was largely developed for unrelated samples. Though it is possible to apply the framework to fine-mapping with related individuals, extensive modifications are needed. Unfortunately, this has often been ignored in summary-statistics-based fine-mapping with related individuals. In this paper, we show in theory and simulation what modifications are necessary to extend the use of summary statistics to related individuals. The analysis also demonstrates that though existing summary-statistics-based fine-mapping methods can be adapted for related individuals, they appear to have no computational advantage over individual-data-based methods.

2021 ◽  
pp. 67-80
S. Priya ◽  
R. Manavalan

Complex diseases identification through Gene-Gene Interactions (GGIs) plays a significant challenge in Genome-Wide Association Studies (GWAS). A typical indicator of genetic variations in many human diseases is Single Nucleotide Polymorphisms (SNPs). SNPs are the most prevalent sort of genetic variation seen in human beings. The interactions between various SNPs are called Epistasis or genetic interactions. This research paper proposes a two-stage epistasis detection approach based on K-Means clustering and optimization techniques to detect epistasis effects responsible for complex human diseases. In the screening stage, K-Means clustering is adapted to partition the genotype dataset into various clusters. Traditional K-Means clustering algorithms have the flaw of arbitrary selection of the initial k centroid, which leads to inconsistent solutions and traps in the local optimum. We present a hybridized technique based on the K-Means algorithm and Nelder-Mead (NM) optimization (KMeans-NM) to avoid local optima, and all the genotype data falls into a unique collection of clusters for different runs. In the search stage, Salp Optimization with single objective functions (Salp-SO) and Salp Optimization with multi-objective functions (Salp-MO) are employed over the clusters obtained from the screening stage to find disease correlated SNP combinations. The performance of the various proposed algorithms is tested over the simulated datasets. Experimental findings indicated that the KMeans-NM-SalpEpi-SO and KMeans-NM-SalpEpi-MO method is superior to other techniques.

2021 ◽  
Vol 13 (1) ◽  
Marcus M. Soliai ◽  
Atsushi Kato ◽  
Britney A. Helling ◽  
Catherine T. Stanhope ◽  
James E. Norton ◽  

Abstract Background Genome-wide association studies (GWASs) have identified thousands of variants associated with asthma and other complex diseases. However, the functional effects of most of these variants are unknown. Moreover, GWASs do not provide context-specific information on cell types or environmental factors that affect specific disease risks and outcomes. To address these limitations, we used an upper airway epithelial cell (AEC) culture model to assess transcriptional and epigenetic responses to rhinovirus (RV), an asthma-promoting pathogen, and provide context-specific functional annotations to variants discovered in GWASs of asthma. Methods Genome-wide genetic, gene expression, and DNA methylation data in vehicle- and RV-treated upper AECs were collected from 104 individuals who had a diagnosis of airway disease (n=66) or were healthy participants (n=38). We mapped cis expression and methylation quantitative trait loci (cis-eQTLs and cis-meQTLs, respectively) in each treatment condition (RV and vehicle) in AECs from these individuals. A Bayesian test for colocalization between AEC molecular QTLs and adult onset asthma and childhood onset asthma GWAS SNPs, and a multi-ethnic GWAS of asthma, was used to assign the function to variants associated with asthma. We used Mendelian randomization to demonstrate DNA methylation effects on gene expression at asthma colocalized loci. Results Asthma and allergic disease-associated GWAS SNPs were specifically enriched among molecular QTLs in AECs, but not in GWASs from non-immune diseases, and in AEC eQTLs, but not among eQTLs from other tissues. Colocalization analyses of AEC QTLs with asthma GWAS variants revealed potential molecular mechanisms of asthma, including QTLs at the TSLP locus that were common to both the RV and vehicle treatments and to both childhood onset and adult onset asthma, as well as QTLs at the 17q12-21 asthma locus that were specific to RV exposure and childhood onset asthma, consistent with clinical and epidemiological studies of these loci. Conclusions This study provides evidence of functional effects for asthma risk variants in AECs and insight into RV-mediated transcriptional and epigenetic response mechanisms that modulate genetic effects in the airway and risk for asthma.

2021 ◽  
Vol 12 ◽  
Yonglan Liao ◽  
Zhicheng Wang ◽  
Leonardo S. Glória ◽  
Kai Zhang ◽  
Cuixia Zhang ◽  

Growth is a complex trait with moderate to high heritability in livestock and must be described by the longitudinal data measured over multiple time points. Therefore, the used phenotype in genome-wide association studies (GWAS) of growth traits could be either the measures at the preselected time point or the fitted parameters of whole growth trajectory. A promising alternative approach was recently proposed that combined the fitting of growth curves and estimation of single-nucleotide polymorphism (SNP) effects into single-step nonlinear mixed model (NMM). In this study, we collected the body weights at 35, 42, 49, 56, 63, 70, and 84 days of age for 401 animals in a crossbred population of meat rabbits and compared five fitting models of growth curves (Logistic, Gompertz, Brody, Von Bertalanffy, and Richards). The logistic model was preferably selected and subjected to GWAS using the approach of single-step NMM, which was based on 87,704 genome-wide SNPs. A total of 45 significant SNPs distributed on five chromosomes were found to simultaneously affect the two growth parameters of mature weight (A) and maturity rate (K). However, no SNP was found to be independently associated with either A or K. Seven positional genes, including KCNIP4, GBA3, PPARGC1A, LDB2, SHISA3, GNA13, and FGF10, were suggested to be candidates affecting growth performances in meat rabbits. To the best of our knowledge, this is the first report of GWAS based on single-step NMM for longitudinal traits in rabbits, which also revealed the genetic architecture of growth traits that are helpful in implementing genome selection.

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 7-7
Jian Cheng ◽  
Rohan Fernando ◽  
Hao Cheng ◽  
Stephen D Kachman ◽  
KyuSang Lim ◽  

Abstract Infectious diseases cause tremendous financial loss in the pork industry, emphasizing the importance of disease resilience, which is the ability of an animal to maintain performance under disease. The objective of this study was to identify quantitative trait loci (QTL) for disease resilience based on both univariate and bivariate genome-wide association studies (GWAS). Data used were late nursery and finisher growth rates and clinical disease phenotypes, including medical treatment and mortality rates, subjective health scores, feed and water intake traits and carcass traits, collected on 50 batches of 60 or 75 crossbred (LRxY) barrows under a polymicrobial natural disease challenge. Multiple QTL were detected for all traits. The major histocompatibility complex (MHC) region (22–25 Mb on chromosome 7) was found to be associated with multiple traits, including late nursery and finisher growth rates, average daily feed intake and intake rate, average daily water dispensed, water intake duration, and number of visits to the drinker. The MHC region explained ~13% of genetic variance for late nursery growth rate. Further fine mapping identified four QTL in the MHC region for late nursery growth rate that spanned the class I, II, and III regions. Gene set enrichment analyses found genomic regions associated with resilience phenotypes to be enriched for previously identified disease susceptibility and immune capacity QTL, for genes that were differentially expressed following bacterial or virus infection and immune response, and for gene ontology terms related to immune and inflammatory response. In conclusion, MHC and other QTL identified play an important role in host response to infectious diseases and can be incorporated in selection to improve disease resilience. Funded by Genome Canada, Genome Alberta, USDA-NIFA, and PigGen Canada.

2021 ◽  
Derek W Linskey ◽  
David C Linskey ◽  
Howard L McLeod ◽  
Jasmine A Luzum

The primary research approach in pharmacogenetics has been candidate gene association studies (CGAS), but pharmacogenomic genome-wide association studies (GWAS) are becoming more common. We are now at a critical juncture when the results of those two research approaches, CGAS and GWAS, can be compared in pharmacogenetics. We analyzed publicly available databases of pharmacogenetic CGAS and GWAS (i.e., the Pharmacogenomics Knowledgebase [PharmGKB®] and the NHGRI-EBI GWAS catalog) and the vast majority of variants (98%) and genes (94%) discovered in pharmacogenomic GWAS were novel (i.e., not previously studied CGAS). Therefore, pharmacogenetic researchers are not selecting the right candidate genes in the vast majority of CGAS, highlighting a need to shift pharmacogenetic research efforts from CGAS to GWAS.

2021 ◽  
Vol 22 (1) ◽  
Guomin Zhang ◽  
Rongsheng Wang ◽  
Juntao Ma ◽  
Hongru Gao ◽  
Lingwei Deng ◽  

Abstract Background Heilongjiang Province is a high-quality japonica rice cultivation area in China. One in ten bowls of Chinese rice is produced here. Increasing yield is one of the main aims of rice production in this area. However, yield is a complex quantitative trait composed of many factors. The purpose of this study was to determine how many genetic loci are associated with yield-related traits. Genome-wide association studies (GWAS) were performed on 450 accessions collected from northeast Asia, including Russia, Korea, Japan and Heilongjiang Province of China. These accessions consist of elite varieties and landraces introduced into Heilongjiang Province decade ago. Results After resequencing of the 450 accessions, 189,019 single nucleotide polymorphisms (SNPs) were used for association studies by two different models, a general linear model (GLM) and a mixed linear model (MLM), examining four traits: days to heading (DH), plant height (PH), panicle weight (PW) and tiller number (TI). Over 25 SNPs were found to be associated with each trait. Among them, 22 SNPs were selected to identify candidate genes, and 2, 8, 1 and 11 SNPs were found to be located in 3′ UTR region, intron region, coding region and intergenic region, respectively. Conclusions All SNPs detected in this research may become candidates for further fine mapping and may be used in the molecular breeding of high-latitude rice.

Clara de Jorge Martínez ◽  
Gull Rukh ◽  
Michael J. Williams ◽  
Santino Gaudio ◽  
Samantha Brooks ◽  

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