scholarly journals Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

2021 ◽  
Vol 11 (11) ◽  
pp. 1233
Author(s):  
Zulfan Zazuli ◽  
Corine de de Jong ◽  
Wei Xu ◽  
Susanne J. H. Vijverberg ◽  
Rosalinde Masereeuw ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Genetic Risk ◽  
Validation Cohort ◽  
Genotype Imputation ◽  
Candidate Gene Approach ◽  
Genetic Associations ◽  
Discovery Cohort ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10−8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10−7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

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.

scholarly journals Genetic Associations with Subjective Well-Being Also Implicate Depression and Neuroticism

2015 ◽  
Author(s):  
Aysu Okbay ◽  
Bart M. L. Baselmans ◽  
Jan-Emmanuel De Neve ◽  
Patrick Turley ◽  
Michel G. Nivard ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Genome Wide Association Study ◽  
Well Being ◽  
Genome Wide Association ◽  
Subjective Well Being ◽  
Genetic Associations ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

We conducted a genome-wide association study of subjective well-being (SWB) in 298,420 individuals. We also performed auxiliary analyses of depressive symptoms ("DS";N= 161,460) and neuroticism (N= 170,910), both of which have a substantial genetic correlation with SWB (ρ≈-0.8). We identify three SNPs associated with SWB at genome-wide significance. Two of them are significantly associated with DS in an independent sample. In our auxiliary analyses, we identify 13 additional genome-wide-significant associations: two with DS and eleven with neuroticism, including two inversion polymorphisms. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are enriched. The discovery of genetic loci associated with the three phenotypes we study has proven elusive; our findings illustrate the payoffs from studying them jointly.

scholarly journals Genome-Wide Association Studies Identify 15 Genetic Markers Associated with Marmite Taste Preference

2017 ◽  
Author(s):  
Thomas R. Roos ◽  
Nikolay A. Kulemin ◽  
Ildus I. Ahmetov ◽  
Avi Lasarow ◽  
Keith Grimaldi
Keyword(s):  
Candidate Gene ◽  
Genetic Markers ◽  
Bitter Taste ◽  
Taste Preference ◽  
Genome Wide Association ◽  
Candidate Gene Approach ◽  
Genome Wide ◽  
Human Trait ◽  
Genome Wide Significance ◽  
Complex Human Trait

AbstractMarmite is a popular food eaten around the world, to which individuals have commonly considered themselves either “lovers” or “haters”. We aimed to determine whether this food preference has a genetic basis.Weperformed a genome-wide association study (GWAS) for Marmite taste preference using genotype and questionnaire data froma cohort of 261 healthy adults. We found 1 single nucleotide polymorphism (SNP) associated with Marmite taste preferencethat reached genome-wide significance (p<5x10-8) in our GWAS analyses. We found another 4 SNPsassociated with Marmite taste preference that reached genome-wide significance (p<5x10-8) in at leastoneGWAS and/or for at least one phenotype analysed. Moreover, we identified 10 additional SNPs potentially associated with Marmite taste preference through candidate gene analysis. Our results indicate that there is a genetic basis to Marmite taste preference and we have identified 15 genetic markers for this trait. Overall, we conclude that Marmite tastepreference is a complex human trait influenced by multiple genetic markers, as well as the environment.Summary of Main ResultsMarmite taste preference is a complex human trait with many factors influencing whether an individual loves or hates Marmite.The relative contribution of genetics versus environment (ie. heritability) for Marmite taste preference is unknown.The genetic contribution to Marmite taste preference involves multiple genetic markers each contributing a small amount (ie. the trait is polygenic). There is not one single Marmite gene with a large contribution like in thecase of the TAS2R38gene and bitter taste perception.We have found a total of 15 SNPs associated with Marmite taste preference: 5 SNPs by a genetic-association screen atgenome-wide significance, and 10 SNPs by a candidate gene approach at nominal significance.We did not find an association between the TAS2R38bitter taste receptor gene and Marmite taste preference.It is important to independently replicate the findings of this study in order to validate these genetic markers and get a more accurate idea of their true effect on Marmite taste preference.

scholarly journals Towards an understanding of the genetic basis behind 1080 (sodium fluoroacetate) tolerance and an investigation of the candidate gene ACO2

2013 ◽  
Vol 61 (1) ◽  
pp. 69 ◽  
Author(s):  
Janine E. Deakin ◽  
Desmond W. Cooper ◽  
Jennifer J. Sinclair ◽  
Catherine A. Herbert ◽  
Marilyn B. Renfree ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Western Australia ◽  
Genetic Basis ◽  
Tammar Wallaby ◽  
Candidate Gene Approach ◽  
Sequence Variant ◽  
Genome Wide ◽  
Mitochondrial Aconitase ◽  
A Genome ◽  
Vertebrate Pests

Sodium fluoroacetate, commonly referred to as 1080, is a pesticide heavily used to control vertebrate pests. The development of tolerance to this poison by target species is a critical concern raised by its intensive use. Tolerance to 1080 is common amongst many native vertebrates in south-west Western Australia and is thought to be the result of a long period of coevolution with plant species that produce 1080 in their seeds and flowers. Among those vertebrate species tolerant to 1080 exposure is a subspecies of the tammar wallaby (Macropus eugenii). Tammars from Western Australia are tolerant while the subspecies present on Kangaroo Island is susceptible to 1080 exposure. The availability of genetic and genomic information, combined with a distinct difference in tolerance to 1080 between subspecies, makes the tammar wallaby an ideal species in which to study the genetic basis behind 1080 resistance. To date, research in this area has focussed on a candidate gene approach. Since 1080 inhibits the action of the mitochondrial aconitase enzyme, the aconitase gene ACO2 was considered a prime candidate for involvement in 1080 tolerance. However, sequencing of the full-length ACO2 transcript failed to identify a sequence variant between the two subspecies that would result in an amino acid change in the active site of the enzyme. Future studies will need to take a genome-wide approach to identify the gene(s) responsible for 1080 tolerance.

scholarly journals Molecular genetics in psychology and personality neuroscience: On candidate genes, genome wide scans, and new research strategies

2019 ◽  
Author(s):  
Christian Montag ◽  
Richard Ebstein ◽  
Philippe Jawinski ◽  
Sebastian Markett
Keyword(s):  
Candidate Gene ◽  
Molecular Genetics ◽  
Treatment Options ◽  
Candidate Gene Approach ◽  
Genetic Associations ◽  
Research Strategies ◽  
Psychological Traits ◽  
Genome Wide ◽  
New Research ◽  
Gwas Approach

Despite the substantial heritability estimates for psychological traits, their precise genetic foundation from a molecular perspective remains elusive. We summarize findings and advances from twenty years of research into the molecular genetics of personality and other psychological traits. We describe how the candidate gene approach has – despite its appealing theoretical foundations – often (but not always) failed to point towards replicable associations between genetic polymorphism and behavioral traits. The genome wide analysis (GWAS) approach on the contrary has become more fruitful in recent years and pointed towards reliable genetic associations. GWAS results are currently leveraged to explore gene-behavior associations through genetic correlation and polygenic score prediction which are important steps towards a precision medicine where treatment options are tailored to a patient’s individual biology. The GWAS approach, however, faces its own problems when it comes to linking its extensive findings to biopsychological theory. We argue that research strategies from the candidate gene approach can be used to address these issues – given that necessary precautions are taken to avoid the problem of false-positive associations.

Evidence for a genetic role in varicose veins and chronic venous insufficiency

2012 ◽  
Vol 27 (7) ◽  
pp. 329-335 ◽  
Author(s):  
J Krysa ◽  
G T Jones ◽  
A M Van Rij
Keyword(s):  
Candidate Gene ◽  
Genome Wide Association Study ◽  
Current Knowledge ◽  
Varicose Veins ◽  
Candidate Gene Approach ◽  
Venous Disease ◽  
Genetic Associations ◽  
Ulcer Disease ◽  
A Genome ◽  
Venous Diseases

There is a strong body of circumstantial evidence which implicates genetics in the aetiology and pathology of varicose veins and venous ulcer disease. The aim of this review is to consider the current knowledge of the genetic associations and the ways in which new genetic technologies may be applied to advancing our understanding of the cause and progression of these venous diseases. A number of publications have used a candidate gene approach to identify genes implicated in venous disease. Although these studies have opened up important new insights, there has been a general failure to replicate results in an independent cohort of patients. With our limited knowledge of the biological pathways involved in the pathogenesis of venous disease we are not in a strong position to formulate truly erudite a priori candidate gene hypothesis-directed studies. A genome wide association study should therefore be considered to help further our understanding of the genetic basis of venous disease. Due to the large sample sizes required for discovery and validation, using the new generations of molecular technologies, it will be necessary to form collaborating groups in order to successfully advance the field of venous disease genetics.

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 Common genetic risk variants identified in the SPARK cohort implicate DDHD2 as a novel autism risk gene

2020 ◽  
Author(s):  
Nana Matoba ◽  
Dan Liang ◽  
Huaigu Sun ◽  
Nil Aygün ◽  
Jessica C. McAfee ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Association Study ◽  
Genetic Risk ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Risk Variants ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
Gene Regulatory

AbstractBackgroundAutism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of three common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants are expected to contribute to ASD risk given the high heritability. Here, we performed a genome-wide association study (GWAS) using the Simons Foundation Powering Autism Research for Knowledge (SPARK) dataset to identify additional common genetic risk factors and molecular mechanisms underlying risk for ASD.MethodsWe performed an association study on 6,222 case-pseudocontrol pairs from SPARK and meta-analyzed with a previous GWAS. We integrated gene regulatory annotations to map non-coding risk variants to their regulated genes. Further, we performed a massively parallel reporter assay (MPRA) to identify causal variant(s) within a novel risk locus.ResultsWe identified one novel GWS locus from the SPARK GWAS. The meta-analysis identified four significant loci, including an additional novel locus. We observed significant enrichment of ASD heritability within regulatory regions of the developing cortex, indicating that disruption of gene regulation during neurodevelopment is critical for ASD risk. The MPRA identified one variant at the novel locus with strong impacts on gene regulation (rs7001340), and expression quantitative trait loci data demonstrated an association between the risk allele and decreased expression of DDHD2 (DDHD domain containing 2) in both adult and pre-natal brains.ConclusionsBy integrating genetic association data with multi-omic gene regulatory annotations and experimental validation, we fine-mapped a causal risk variant and demonstrated that DDHD2 is a novel gene associated with ASD risk.

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