scholarly journals Adjustment for SNPs instead of demographic and clinical covariates in GWAS

2021 ◽  
Author(s):  
Fuzhong Xue ◽  
Xiaoru Sun ◽  
Hongkai Li ◽  
Yuanyuan Yu ◽  
Zhongshang Yuan ◽  
...  
Keyword(s):  
Statistical Power ◽  
Genome Wide Association Study ◽  
Smoking Status ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Causal Diagrams ◽  
Disease Trait ◽  
Clinical Covariates ◽  
Complex Relationships

Genome-wide association study (GWAS) is fundamentally designed to detect disease-causing genes. To reduce spurious associations or improve statistical power, about 80% of GWASs arbitrarily adjusted for demographic and clinical covariates. However, adjustment strategies in GWASs have not achieved consistent conclusions. Given the initial aim of GWAS that is to identify the causal association between a specific causal single-nucleotide polymorphism (SNP) and disease trait, we summarized all complex relationships of the target SNP, covariate and disease trait into 15 causal diagrams according to various roles of the covariate. Following each causal diagram, we conducted a series of theoretical justifications and statistical simulations. Our results demonstrate that it is unadvisable to adjust for any demographic or clinical covariates. We illustrate our point by applying GWASs for body mass index (BMI) and breast cancer, including adjusting and non-adjusting for age and smoking status. Genetic effects and P values might vary across different strategies. Instead, adjustments for SNPs (G') should be strongly recommended when G' are in linkage disequilibrium with the target SNP, and correlated with disease trait conditional on the target SNP. Specifically, adjustment for such G' can block all the confounding paths between the target SNP and disease trait, and avoid over-adjusting for colliders or intermediaries.

scholarly journals Consequence of adjustments for demographic or clinical covariates and a recommended solution in genome-wide association studies

2021 ◽  
Author(s):  
Xiaoru Sun ◽  
Hongkai Li ◽  
Yuanyuan Yu ◽  
Zhongshang Yuan ◽  
Chuandi Jin ◽  
...  
Keyword(s):  
Statistical Power ◽  
Genome Wide Association Study ◽  
Smoking Status ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Disease Trait ◽  
Clinical Covariates ◽  
Complex Relationships

Genome-wide association study (GWAS) is fundamentally designed to detect disease-causing genes. To reduce spurious associations or improve statistical power, about 80% of GWASs arbitrarily adjusted for demographic or clinical covariates. However, adjustment strategies in GWASs have not achieved consistent conclusions. Given the initial aim of GWAS that is to identify the causal association between a specific causal single-nucleotide polymorphism (SNP) and disease trait, we summarized all complex relationships of the target SNP, covariate and disease trait into 15 causal diagrams according to various roles of the covariate. Following each causal diagram, we conducted a series of theoretical justifications and statistical simulations. Our results demonstrate that it is unadvisable to adjust for any demographic or clinical covariates. We illustrate our point by applying GWASs for body mass index (BMI) and breast cancer, including adjusting and non-adjusting for age and smoking status. Genetic effects and P values might vary across different strategies. Instead, adjustments for SNPs (G') should be strongly recommended when G' are in linkage disequilibrium with the target SNP, and correlated with disease trait conditional on the target SNP. Specifically, adjustment for such G' can block all the confounding paths between the target SNP and disease trait, and avoid over-adjusting for colliders or intermediaries.

scholarly journals Single nucleotide polymorphism heritability and differential patterns of genetic overlap between inattention and four neurocognitive factors in youth

2020 ◽  
pp. 1-11
Author(s):  
Lauren Micalizzi ◽  
Leslie A. Brick ◽  
Marisa E. Marraccini ◽  
Chelsie E. Benca-Bachman ◽  
Rohan H.C. Palmer ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Executive Function ◽  
Social Cognition ◽  
Genome Wide Association Study ◽  
Population Sample ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Genetic Overlap ◽  
Complex Cognition

Abstract Theoretical models of attention-deficit/hyperactivity disorder implicate neurocognitive dysfunction, yet neurocognitive functioning covers a range of abilities that may not all be linked with inattention. This study (a) investigated the single nucleotide polymorphism (SNP) heritability (h2SNP) of inattention and aspects of neurocognitive efficiency (memory, social cognition, executive function, and complex cognition) based on additive genome-wide effects; (b) examined if there were shared genetic effects among inattention and each aspect of neurocognitive efficiency; and (c) conducted an exploratory genome-wide association study to identify genetic regions associated with inattention. The sample included 3,563 participants of the Philadelphia Neurodevelopmental Cohort, a general population sample aged 8–21 years who completed the Penn Neurocognitive Battery. Data on inattention was obtained with the Kiddie Schedule of Affective Disorders (adapted). Genomic relatedness matrix restricted maximum likelihood was implemented in genome-wide complex trait analysis. Analyses revealed significant h2SNP for inattention (20%, SE = 0.08), social cognition (13%, SE = 0.08), memory (17%, SE = 0.08), executive function (25%, SE = 0.08), and complex cognition (24%, SE = 0.08). There was a positive genetic correlation (0.67, SE = 0.37) and a negative residual covariance (−0.23, SE = 0.06) between inattention and social cognition. No SNPs reached genome-wide significance for inattention. Results suggest specificity in genetic overlap among inattention and different aspects of neurocognitive efficiency.

Association of the Intergenic Single-Nucleotide Polymorphism rs10865331 (2p15) with Ankylosing Spondylitis in a Spanish Population

2010 ◽  
Vol 37 (11) ◽  
pp. 2345-2347 ◽  
Author(s):  
ALEJANDRA SÁNCHEZ ◽  
MAGDALENA SZCZYPIORSKA ◽  
XAVIER JUANOLA ◽  
NEREA BARTOLOMÉ ◽  
JORDI GRATACÓS ◽  
...  
Keyword(s):  
New York ◽  
Ankylosing Spondylitis ◽  
Genome Wide Association Study ◽  
Spanish Population ◽  
Nucleotide Polymorphisms ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Healthy Donors ◽  
Independent Cohort

Objective.A recent genome-wide association study has identified 2 single-nucleotide polymorphisms (SNP) associated with ankylosing spondylitis (AS), rs10865331 (2p15) and rs2242944 (21q22). We assessed the association of these SNP with AS in a Spanish population.Methods.Four hundred fifty-six patients with AS fulfilling the modified New York Criteria and 300 healthy donors were analyzed.Result.SNP rs10865331 (allele A: p = 0.039; genotype: p = 0.016) was significantly associated with AS, while no association was found for rs2242944.Conclusion.This is the first study that replicates in an independent cohort the association of the intergenic SNP rs10865331 with susceptibility to AS.

scholarly journals Compelling Evidence Linking CD40 Gene With Graves’ Disease in the Chinese Han Population

2021 ◽  
Vol 12 ◽  
Author(s):  
He Jiang ◽  
Fei-Fei Yuan ◽  
Hai-Ning Wang ◽  
Wei Liu ◽  
Xiao-Ping Ye ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Graves Disease ◽  
Nucleotide Polymorphism ◽  
Rt Pcr ◽  
Chinese Han ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Cd40 Gene ◽  
Trait Locus ◽  
Robust Evidence

Mutations in CD40 have been widely reported to be risk factors for Graves’ disease (GD). The gene, along with its cognate ligand CD40L, may regulate pro-inflammatory and immune responses. Rs1883832, located at the -1 position of the Kozak sequence, is the most well-studied single nucleotide polymorphism (SNP) of CD40, and has been confirmed to predispose those with the alteration to GD, regardless of ethnicity. Our genome-wide association study (GWAS) indicated that several SNPs, including rs1883832 located within the vicinity of CD40 were associated with GD in the Han Chinese population. Aiming at identifying the most consequential SNP and its underlying pathogenic mechanism, we performed a two-stage refined study on 8,171 patients with GD and 7,906 controls, and found rs1883832 was the most significantly GD-associated SNP in the CD40 gene region (PCombined = 9.17×10-11, OR = 1.18). Through searching the cis-expression quantitative trait locus database and using quantitative RT-PCR, we further discovered that the rs1883832 genotype can influence CD40 gene transcription. Furthermore, we demonstrated that rs1883832 is a susceptibility locus for pTRAb+ GD patients. In conclusion, the current study provides robust evidence that rs1883832 can regulate CD40 gene expression and affect serum TRAb levels, which ultimately contributes to the development of GD.

scholarly journals The continuing evolution of community-associated MRSA ST93-IV in Australia

2020 ◽  
Author(s):  
Stanley Pang ◽  
Denise A Daley ◽  
Shafi Sahibzada ◽  
Shakeel Mowlaboccus ◽  
Marc Stegger ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genetic Traits ◽  
Genome Wide ◽  
A Genome ◽  
High Prevalence ◽  
Northern Regions ◽  
Australian Community ◽  
Gwas Approach

Abstract Background The global emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has seen the dominance of specific clones in different regions around the world with the PVL-positive ST93-IV as the predominant CA-MRSA clone in Australia. In this study we applied a genome-wide association study (GWAS) approach on a collection of Australian ST93-IV MRSA genomes to identify genetic traits that may have assisted the ongoing transmission of ST93-IV in Australia. We also compared the genomes of ST93-IV bacteraemia and non-bacteraemia isolates to identify potential virulence factors associated with bacteraemia.Results Based on single nucleotide polymorphism phylogenetics we identified two distinct ST93-IV clades circulating concurrently in Australia. One of the clades contained isolates primarily isolated in the northern regions of Australia whilst isolates in the second clade were distributed across the country. Analyses of the ST93-IV genome plasticity over a 15-year period (2002-2017) revealed an observed gain in accessory genes amongst the clone’s population. The GWAS analysis on the bacteraemia isolates identified two genes that have also previously been associated to this kind of infection. Conclusions The emergence of a ST93-IV clade containing additional virulence genes may explain the high prevalence of ST93-IV infections amongst the indigenous population living in the northern regions of Australia. In summary, this study has shown ST93-IV is evolving with multiple additional genes possibly contributing to its dominance in the Australian community.

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