scholarly journals Genome-Wide Analysis of Sex Disparities in the Genetic Architecture of Lung and Colorectal Cancers

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 686
Author(s):  
Alireza Nazarian ◽  
Alexander M. Kulminski
Keyword(s):  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Significance Level ◽  
Association Analyses ◽  
Complex Disorders ◽  
Specific Effects ◽  
Genome Wide ◽  
Genetic Mechanisms ◽  
Sex Disparities ◽  
Almost All

Almost all complex disorders have manifested epidemiological and clinical sex disparities which might partially arise from sex-specific genetic mechanisms. Addressing such differences can be important from a precision medicine perspective which aims to make medical interventions more personalized and effective. We investigated sex-specific genetic associations with colorectal (CRCa) and lung (LCa) cancers using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent datasets. The genome-wide association analyses revealed that 33 SNPs were associated with CRCa/LCa at P < 5.0 × 10−6 neither males or females. Of these, 26 SNPs had sex-specific effects as their effect sizes were statistically different between the two sexes at a Bonferroni-adjusted significance level of 0.0015. None had proxy SNPs within their ±1 Mb regions and the closest genes to 32 SNPs were not previously associated with the corresponding cancers. The pathway enrichment analyses demonstrated the associations of 35 pathways with CRCa or LCa which were mostly implicated in immune system responses, cell cycle, and chromosome stability. The significant pathways were mostly enriched in either males or females. Our findings provided novel insights into the potential sex-specific genetic heterogeneity of CRCa and LCa at SNP and pathway levels.

scholarly journals The influence of X chromosome variants on trait neuroticism

2018 ◽  
Author(s):  
Michelle Luciano ◽  
Gail Davies ◽  
Kim M Summers ◽  
W David Hill ◽  
Caroline Hayward ◽  
...  
Keyword(s):  
X Chromosome ◽  
Nucleotide Polymorphisms ◽  
Nucleic Acid Binding ◽  
Single Nucleotide ◽  
Association Analyses ◽  
Complex Disorders ◽  
Genome Wide ◽  
Intergenic Regions ◽  
Protein Classes ◽  
Sample Maximum

Autosomal variants have successfully been associated with trait neuroticism in genome-wide analysis of adequately-powered samples. But such studies have so far excluded the X chromosome from analysis. Here, we report genetic association analyses of X chromosome and XY pseudoautosomal single nucleotide polymorphisms (SNPs) and trait neuroticism using UK Biobank samples (N = 405,274). Significant association was found with neuroticism on the X chromosome for 204 markers found within three independent loci (a further 783 were suggestive). Most of these significant neuroticism-related X chromosome variants were located in intergenic regions (n = 713). Involvement of HS6ST2, which has been previously associated with sociability behaviour in the dog, was supported by single SNP and gene-based tests. We found that the amino acid and nucleotide sequences are highly conserved between dogs and humans. From the suggestive X chromosome variants, there were 19 nearby genes which could be linked to gene ontology information. Molecular function was primarily related to binding and catalytic activity; notable biological processes were cellular and metabolic, and nucleic acid binding and transcription factor protein classes were most commonly involved. X-variant heritability of neuroticism was estimated at 0.34% (SE = 0.07). A polygenic X-variant score created in an independent sample (maximum N ≈ 7300) did not predict significant variance in neuroticism, psychological distress, or depressive disorder. We conclude that the X chromosome harbours significant variants influencing neuroticism, and might prove important for other quantitative traits and complex disorders.

Abstract 17111: Genetic Influences on Human Plasma Metabolites That Determine Mortality in Heart Failure Patients

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
David E Lanfear ◽  
Hongsheng Gui ◽  
Jia Li ◽  
Ruicong She ◽  
Edward Peterson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Strong Association ◽  
Plasma Metabolites ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Association Analyses ◽  
Reduced Ejection Fraction ◽  
Genome Wide ◽  
Plasma Metabolite

Background: Heart failure with reduced ejection fraction (HFrEF) continues to be a global health burden. We recently reported a strong association of plasma metabolite profile (thirteen different metabolites) with survival among patients with HFrEF but the mechanism of this association is unclear. We studied the genetic associations of plasma metabolite to try to illuminate the disease mechanisms at work. Methods: A prospective genetic registry including 1032 HFrEF with genome-wide genotyping and imputation of single nucleotide polymorphisms (SNP; ~7 millions) and targeted metabolomics profiling. Genome-wide (GW) association analyses were performed to investigate the genetic impact of each SNP on the 13 metabolites of interest. Analyses were performed using linear models stratified by race (European Americans [N=516] and African Americans [N=516] and including the top five principal components (PC) for each population to avoid spurious associations due to population stratification. A fixed-effect meta-analysis was then used to combine results from the two populations. Threshold for GW significance was p<5E-8. As a second step, Cox proportional hazard regression models of overall survival were tested for each SNP that met GW significance. Results: We found at least one SNP reaching GW significance for 6 metabolites metabolites (a-KG, C5.Isovaleryl, Fumarate, Leucine, Succinate and X3.HBA). The most significant SNP (rs77836784, an intronic variant within PACRG) was associated with X3.HBA in African American HF patients (Beta estimate=22.82, P-value=7.14E-14). A cross-checking of SNP associations on both metabolites and HF survival identified 13 independent SNPs that may partially explain the contribution of the metabolites on HF mortality (Table 1) and seem to have biologic plausibility including for example a G-protein coupled receptor (GPR68) and protein kinase C (PRKC1). Conclusion: Genetic variants are associated with predictive plasma metabolites and survival. This may be useful to understand the underlying pathways connecting metabolites to HF progression. A complete investigation of genomic and metabolomics determinants including causal mediation and pathway analyses are on-going.

scholarly journals Age by Single Nucleotide Polymorphism Interactions on Bronchodilator Response in Asthmatics

2021 ◽  
Vol 11 (1) ◽  
pp. 59
Author(s):  
Kirsten Voorhies ◽  
Joanne E. Sordillo ◽  
Michael McGeachie ◽  
Elizabeth Ampleford ◽  
Alberta L. Wang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Significance Level ◽  
Bronchodilator Response ◽  
Genome Wide ◽  
A Genome ◽  
Β2 Agonists

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to β2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10−8. Using a suggestive significance level of 5 × 10−6, three interactions, including one for a SNP within PRAG1 (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ADRB2) [p-value = 0.009], rs10827492 (CREM) [p-value = 0.02], and rs72646209 (NCOA3) [p-value = 0.02]) had a marginally significant interaction with age on BDR (p < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma.

scholarly journals Genotyping-by-Sequencing of Gossypium hirsutum Races and Cultivars Uncovers Novel Patterns of Genetic Relationships and Domestication Footprints

2019 ◽  
Vol 15 ◽  
pp. 117693431988994
Author(s):  
Shulin Zhang ◽  
Yaling Cai ◽  
Jinggong Guo ◽  
Kun Li ◽  
Renhai Peng ◽  
...  
Keyword(s):  
Gossypium Hirsutum ◽  
Genetic Relationships ◽  
Phylogenetic Analyses ◽  
Genotyping By Sequencing ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Breeding Programs ◽  
Association Analyses ◽  
Genome Wide ◽  
Candidate Gene Locus

Determining the genetic rearrangement and domestication footprints in Gossypium hirsutum cultivars and primitive race genotypes are essential for effective gene conservation efforts and the development of advanced breeding molecular markers for marker-assisted breeding. In this study, 94 accessions representing the 7 primitive races of G hirsutum, along with 9 G hirsutum and 12 Gossypium barbadense cultivated accessions were evaluated. The genotyping-by-sequencing (GBS) approach was employed and 146 558 single nucleotide polymorphisms (SNP) were generated. Distinct SNP signatures were identified through the combination of selection scans and association analyses. Phylogenetic analyses were also conducted, and we concluded that the Latifolium, Richmondi, and Marie-Galante race accessions were more genetically related to the G hirsutum cultivars and tend to cluster together. Fifty-four outlier SNP loci were identified by selection-scan analysis, and 3 SNPs were located in genes related to the processes of plant responding to stress conditions and confirmed through further genome-wide signals of marker-phenotype association analysis, which indicate a clear selection signature for such trait. These results identified useful candidate gene locus for cotton breeding programs.

scholarly journals Detecting Genetic Associations betweenATG5and Lupus Nephritis bytrans-eQTL

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Yue-miao Zhang ◽  
Fa-juan Cheng ◽  
Xu-jie Zhou ◽  
Yuan-yuan Qi ◽  
Ping Hou ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Clinical Information ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Genetic Studies ◽  
Genome Wide ◽  
Custom Made ◽  
Regulatory Effects

Objectives. Numerous loci were identified to perturb gene expression intrans. As elevatedATG5expression was observed in systemic lupus erythematosus (SLE), the study was conducted to analyze the genome-wide genetic regulatory mechanisms associated withATG5expression in a Chinese population with lupus nephritis (LN).Methods. The online expression quantitative trait loci database was searched fortrans-expression single nucleotide polymorphisms (trans-eSNPs) ofATG5. Taggingtrans-eSNPs were genotyped by a custom-made genotyping chip in 280 patients and 199 controls. For positive findings, clinical information and bioinformation analyses were performed.Results. Fourtrans-eSNPs were observed to be associated with susceptibility to LN (P< 0.05), including ANKRD50 rs17008504, AGA rs2271100, PAK7 rs6056923, and TET2 rs1391441, while seven othertrans-eSNPs showed marginal significant associations (0.05 <P< 0.1). Correlations between thetrans-eSNPs andATG5expression and different expression levels ofATG5in SLE patients and controls were validated, and their regulatory effects were annotated. However, no significant associations were observed between different genotypes oftrans-eSNPs and severity or outcome of the patients.Conclusion. Using the new systemic genetics approach, we identified 10 loci associated with susceptibility to LN potentially, which may be complementary to future pathway based genetic studies.

Are there monogenic hereditary forms of bladder cancer or only genetic susceptibilities?

2021 ◽  
Author(s):  
Tarek Souaid ◽  
Joya-Rita Hindy ◽  
Ernest Diab ◽  
Hampig Raphael Kourie
Keyword(s):  
Bladder Cancer ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Significance Level ◽  
Dna Mismatch ◽  
Common Cancer ◽  
Genome Wide ◽  
Dna Mismatch Repair Genes ◽  
Mutyh Associated Polyposis

Bladder cancer (BC) is the most common cancer involving the urinary system and the ninth most common cancer worldwide. Tobacco smoking is the most important environmental risk factor of BC. Several single nucleotide polymorphisms have been validated by genome-wide association studies as genetic risk factors for BC. However, the identification of DNA mismatch-repair genes, including MSH2 in Lynch syndrome and MUTYH in MUTYH-associated polyposis, raises the possibility of monogenic hereditary forms of BC. Moreover, other genetic mutations may play a key role in familial and hereditary transmissions of BC. Therefore, the aim of this review is to focus on the major hereditary syndromes involved in the development of BC and to report BC genetic susceptibilities established with genome-wide significance level.

scholarly journals Summary-Based Methylome-Wide Association Analyses Suggest Potential Genetically Driven Epigenetic Heterogeneity of Alzheimer’s Disease

2020 ◽  
Vol 9 (5) ◽  
pp. 1489
Author(s):  
Alireza Nazarian ◽  
Anatoliy I. Yashin ◽  
Alexander M. Kulminski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Tissue Samples ◽  
Significance Level ◽  
Association Analyses ◽  
Functional Studies ◽  
Genome Wide ◽  
Summary Data

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Exploring the genetic and non-genetic contributors to AD pathogenesis is essential to better understand its underlying biological mechanisms, and to develop novel preventive and therapeutic strategies. We investigated potential genetically driven epigenetic heterogeneity of AD through summary data-based Mendelian randomization (SMR), which combined results from our previous genome-wide association analyses with those from two publicly available methylation quantitative trait loci studies of blood and brain tissue samples. We found that 152 probes corresponding to 113 genes were epigenetically associated with AD at a Bonferroni-adjusted significance level of 5.49E-07. Of these, 10 genes had significant probes in both brain-specific and blood-based analyses. Comparing males vs. females and hypertensive vs. non-hypertensive subjects, we found that 22 and 79 probes had group-specific associations with AD, respectively, suggesting a potential role for such epigenetic modifications in the heterogeneous nature of AD. Our analyses provided stronger evidence for possible roles of four genes (i.e., AIM2, C16orf80, DGUOK, and ST14) in AD pathogenesis as they were also transcriptionally associated with AD. The identified associations suggest a list of prioritized genes for follow-up functional studies and advance our understanding of AD pathogenesis.

Response to Intravenous Cyclophosphamide Treatment for Lupus Nephritis Associated with Polymorphisms in the FCGR2B-FCRLA Locus

2016 ◽  
Vol 43 (6) ◽  
pp. 1045-1049 ◽  
Author(s):  
Kwangwoo Kim ◽  
So-Young Bang ◽  
Young Bin Joo ◽  
Taehyeung Kim ◽  
Hye-Soon Lee ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Receptor Gene ◽  
Genotype Imputation ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Cyclophosphamide Treatment

Objective.Cyclophosphamide (CYC) is an immunosuppressant drug widely used to treat various diseases including lupus nephritis, but its efficacy highly varies from individual to individual. This pharmacogenomics association study searched for genetic variations associated with CYC efficacy.Methods.Genome-wide association scan was performed for 109 Korean patients with systemic lupus erythematosus with lupus nephritis (classes III–V) who received intravenous CYC induction therapy. Genetic differences between responders and nonresponders were examined using Cochran–Armitage trend tests, and genotype imputation was used for defining the association locus.Results.Genetic polymorphisms in the Fcγ receptor gene (FCGR) cluster at human chromosome 1q23, previously associated with lupus nephritis susceptibility, were associated with the response to CYC treatment for lupus nephritis. Significant response association was found for 3 perfectly correlated (r2 = 1) single-nucleotide polymorphisms (SNP): rs6697139, rs10917686, and rs10917688, located between the FCGR2B and FCRLA genes (p = 3.4 × 10−8). Carriage of the minor alleles in these SNP was found only in nonresponders (31%) and none in responders (0%).Conclusion.This first genome-wide association approach for CYC response yielded a robust profile of genetic associations including large-effect SNP in the FCGR2B-FCRLA locus, which may provide better insights to CYC metabolism and efficacy.

scholarly journals Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes

2015 ◽  
Vol 75 (4) ◽  
pp. 652-659 ◽  
Author(s):  
Hirotaka Matsuo ◽  
Ken Yamamoto ◽  
Hirofumi Nakaoka ◽  
Akiyoshi Nakayama ◽  
Masayuki Sakiyama ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Clinical Information ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Clinical Parameters ◽  
Nucleotide Polymorphisms ◽  
Male Population ◽  
Significance Level ◽  
Genome Wide

ObjectiveGout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only.MethodsA GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls.ResultsFive gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10−8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10−12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10−23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10−9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case–control ORs for two distinct types of gout (r=0.96 [p=4.8×10−4] for urate clearance and r=0.96 [p=5.0×10−4] for urinary urate excretion).ConclusionsOur findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.

scholarly journals Candidate gene scan for Single Nucleotide Polymorphisms involved in the determination of normal variability in human craniofacial morphology

2016 ◽  
Author(s):  
Mark Barash ◽  
Philipp E. Bayer ◽  
Angela van Daal
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Candidate Gene ◽  
Genetic Variants ◽  
Massively Parallel Sequencing ◽  
Craniofacial Morphology ◽  
Candidate Gene Approach ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Genome Wide

AbstractDespite intensive research on genetics of the craniofacial morphology using animal models and human craniofacial syndromes, the genetic variation that underpins normal human facial appearance is still largely elusive. Recent development of novel digital methods for capturing the complexity of craniofacial morphology in conjunction with high-throughput genotyping methods, show great promise for unravelling the genetic basis of such a complex trait.As a part of our efforts on detecting genomic variants affecting normal craniofacial appearance, we have implemented a candidate gene approach by selecting 1,201 single nucleotide polymorphisms (SNPs) and 4,732 tag SNPs in over 170 candidate genes and intergenic regions. We used 3-dimentional (3D) facial scans and direct cranial measurements of 587 volunteers to calculate 104 craniofacial phenotypes. Following genotyping by massively parallel sequencing, genetic associations between 2,332 genetic markers and 104 craniofacial phenotypes were tested.An application of a Bonferroni–corrected genome–wide significance threshold produced significant associations between five craniofacial traits and six SNPs. Specifically, associations of nasal width with rs8035124 (15q26.1), cephalic index with rs16830498 (2q23.3), nasal index with rs37369 (5q13.2), transverse nasal prominence angle with rs59037879 (10p11.23) and rs10512572 (17q24.3), and principal component explaining 73.3% of all the craniofacial phenotypes, with rs37369 (5p13.2) and rs390345 (14q31.3) were observed.Due to over-conservative nature of the Bonferroni correction, we also report all the associations that reached the traditional genome-wide p-value threshold (<5.00E-08) as suggestive. Based on the genome-wide threshold, 8 craniofacial phenotypes demonstrated significant associations with 34 intergenic and extragenic SNPs. The majority of associations are novel, except PAX3 and COL11A1 genes, which were previously reported to affect normal craniofacial variation.This study identified the largest number of genetic variants associated with normal variation of craniofacial morphology to date by using a candidate gene approach, including confirmation of the two previously reported genes. These results enhance our understanding of the genetics that determines normal variation in craniofacial morphology and will be of particular value in medical and forensic fields.Author SummaryThere is a remarkable variety of human facial appearances, almost exclusively the result of genetic differences, as exemplified by the striking resemblance of identical twins. However, the genes and specific genetic variants that affect the size and shape of the cranium and the soft facial tissue features are largely unknown. Numerous studies on animal models and human craniofacial disorders have identified a large number of genes, which may regulate normal craniofacial embryonic development.In this study we implemented a targeted candidate gene approach to select more than 1,200 polymorphisms in over 170 genes that are likely to be involved in craniofacial development and morphology. These markers were genotyped in 587 DNA samples using massively parallel sequencing and analysed for association with 104 traits generated from 3-dimensional facial images and direct craniofacial measurements. Genetic associations (p-values<5.00E-08) were observed between 8 craniofacial traits and 34 single nucleotide polymorphisms (SNPs), including two previously described genes and 26 novel candidate genes and intergenic regions. This comprehensive candidate gene study has uncovered the largest number of novel genetic variants affecting normal facial appearance to date. These results will appreciably extend our understanding of the normal and abnormal embryonic development and impact our ability to predict the appearance of an individual from a DNA sample in forensic criminal investigations and missing person cases.

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