scholarly journals Functional genomic characterization of the FTO locus in African Americans

2019 ◽  
Vol 51 (11) ◽  
pp. 517-528 ◽  
Author(s):  
Richard Gill ◽  
George Stratigopoulos ◽  
Joseph H. Lee ◽  
Rudolph L. Leibel
Keyword(s):  
Fine Mapping ◽  
Association Studies ◽  
Haplotype Diversity ◽  
Genome Wide Association Studies ◽  
Functional Genomic ◽  
Nucleotide Polymorphisms ◽  
Atherosclerosis Risk In Communities ◽  
Individual Level ◽  
Genome Wide ◽  
High Level

Background: SNPs in the first intron of the fat mass and obesity-associated ( FTO) gene represent the strongest genome-wide associations with adiposity [body mass index (BMI)]; the molecular basis for these associations is under intense investigation. In European populations, the focus of most genome-wide association studies conducted to date, the single nucleotide polymorphisms (SNPs) have indistinguishable associations due to the high level of linkage disequilibrium (LD). However, in African American (AA) individuals, reduced LD and increased haplotype diversity permit finer distinctions among obesity-associated SNPs. Such distinctions are important to mechanistic inferences and for selection of disease SNPs relevant to specific populations. Methods: To identify specific FTO SNP(s) directly related to adiposity, we performed: 1) haplotype analyses of individual-level data in 3,335 AAs from the Atherosclerosis Risk in Communities Cohort (ARIC) study; as well as 2) statistical fine-mapping using summary statistics from a study of FTO in over 20 000 AAs and over 1000 functional genomic annotations. Results: Our haplotype analyses suggest that in AAs at least two distinct signals underlie the intron 1 FTO-adiposity signal. Fine mapping showed that two SNPs have the highest posterior probability of association (PPA) with BMI: rs9927317 (PPA = 0.94) and rs62033405 (PPA = 0.99). These variants overlap possible enhancer sites and the 5′-regions of transcribed genes in the substantia nigra, chondrocytes, and white adipocytes. Conclusions: We found two SNPs in FTO with the highest probability of direct association with BMI in AAs, as well as tissue-specific mechanisms by which these variants may contribute to the pathogenesis of obesity.

scholarly journals Secure large-scale genome-wide association studies using homomorphic encryption

2020 ◽  
Vol 117 (21) ◽  
pp. 11608-11613 ◽  
Author(s):  
Marcelo Blatt ◽  
Alexander Gusev ◽  
Yuriy Polyakov ◽  
Shafi Goldwasser
Keyword(s):  
Large Scale ◽  
Homomorphic Encryption ◽  
Association Studies ◽  
Genome Wide Association ◽  
Single Server ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
User Interactions ◽  
Individual Level ◽  
Genome Wide

Genome-wide association studies (GWASs) seek to identify genetic variants associated with a trait, and have been a powerful approach for understanding complex diseases. A critical challenge for GWASs has been the dependence on individual-level data that typically have strict privacy requirements, creating an urgent need for methods that preserve the individual-level privacy of participants. Here, we present a privacy-preserving framework based on several advances in homomorphic encryption and demonstrate that it can perform an accurate GWAS analysis for a real dataset of more than 25,000 individuals, keeping all individual data encrypted and requiring no user interactions. Our extrapolations show that it can evaluate GWASs of 100,000 individuals and 500,000 single-nucleotide polymorphisms (SNPs) in 5.6 h on a single server node (or in 11 min on 31 server nodes running in parallel). Our performance results are more than one order of magnitude faster than prior state-of-the-art results using secure multiparty computation, which requires continuous user interactions, with the accuracy of both solutions being similar. Our homomorphic encryption advances can also be applied to other domains where large-scale statistical analyses over encrypted data are needed.

scholarly journals Pharmacogenomics of Lithium Response in Bipolar Disorder

2021 ◽  
Vol 14 (4) ◽  
pp. 287
Author(s):  
Courtney M. Vecera ◽  
Gabriel R. Fries ◽  
Lokesh R. Shahani ◽  
Jair C. Soares ◽  
Rodrigo Machado-Vieira
Keyword(s):  
Bipolar Disorder ◽  
Association Studies ◽  
Mood Stabilizer ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Lithium Response ◽  
Genetic Loading ◽  
Long Non Coding Rna

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium’s therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium’s exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

scholarly journals Transcriptional Regulation of RUNX1: An Informatics Analysis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1175
Author(s):  
Amarni L. Thomas ◽  
Judith Marsman ◽  
Jisha Antony ◽  
William Schierding ◽  
Justin M. O’Sullivan ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Runx1 Gene ◽  
Gene Regulatory Elements ◽  
Important Regulator ◽  
Aml1 Gene ◽  
Regulatory Landscape

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.

scholarly journals Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

2021 ◽  
Author(s):  
Robin N Beaumont ◽  
Isabelle K Mayne ◽  
Rachel M Freathy ◽  
Caroline F Wright
Keyword(s):  
Birth Weight ◽  
Statistical Power ◽  
Developmental Disorders ◽  
Association Studies ◽  
Later Life ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Causal Genes

Abstract Birth weight is an important factor in newborn survival; both low and high birth weights are associated with adverse later-life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with maternal or fetal effects on birth weight. Knowledge of the underlying causal genes is crucial to understand how these loci influence birth weight and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme ends of the distribution. Genes implicated in those syndromes may provide valuable information to prioritize candidate genes at the GWAS loci. We examined the proximity of genes implicated in developmental disorders (DDs) to birth weight GWAS loci using simulations to test whether they fall disproportionately close to the GWAS loci. We found birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected both when the DD gene is the nearest gene to the birth weight SNP and also when examining all genes within 258 kb of the SNP. This enrichment was driven by genes causing monogenic DDs with dominant modes of inheritance. We found examples of SNPs in the intron of one gene marking plausible effects via different nearby genes, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight, which has helped identify GWAS loci likely to have direct fetal effects on birth weight, which could not previously be classified as fetal or maternal owing to insufficient statistical power.

scholarly journals CAUSALdb: a database for disease/trait causal variants identified using summary statistics of genome-wide association studies

2019 ◽  
Author(s):  
Jianhua Wang ◽  
Dandan Huang ◽  
Yao Zhou ◽  
Hongcheng Yao ◽  
Huanhuan Liu ◽  
...  
Keyword(s):  
Fine Mapping ◽  
Genetic Variants ◽  
Association Studies ◽  
Complex Trait ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Genome Wide ◽  
Credible Sets ◽  
Causal Variants

Abstract Genome-wide association studies (GWASs) have revolutionized the field of complex trait genetics over the past decade, yet for most of the significant genotype-phenotype associations the true causal variants remain unknown. Identifying and interpreting how causal genetic variants confer disease susceptibility is still a big challenge. Herein we introduce a new database, CAUSALdb, to integrate the most comprehensive GWAS summary statistics to date and identify credible sets of potential causal variants using uniformly processed fine-mapping. The database has six major features: it (i) curates 3052 high-quality, fine-mappable GWAS summary statistics across five human super-populations and 2629 unique traits; (ii) estimates causal probabilities of all genetic variants in GWAS significant loci using three state-of-the-art fine-mapping tools; (iii) maps the reported traits to a powerful ontology MeSH, making it simple for users to browse studies on the trait tree; (iv) incorporates highly interactive Manhattan and LocusZoom-like plots to allow visualization of credible sets in a single web page more efficiently; (v) enables online comparison of causal relations on variant-, gene- and trait-levels among studies with different sample sizes or populations and (vi) offers comprehensive variant annotations by integrating massive base-wise and allele-specific functional annotations. CAUSALdb is freely available at http://mulinlab.org/causaldb.

scholarly journals Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

2016 ◽  
Vol 283 (1835) ◽  
pp. 20160569 ◽  
Author(s):  
M. E. Goddard ◽  
K. E. Kemper ◽  
I. M. MacLeod ◽  
A. J. Chamberlain ◽  
B. J. Hayes
Keyword(s):  
Complex Traits ◽  
Genetic Architecture ◽  
Quantitative Traits ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Crop Breeding ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Phenotype Identification

Complex or quantitative traits are important in medicine, agriculture and evolution, yet, until recently, few of the polymorphisms that cause variation in these traits were known. Genome-wide association studies (GWAS), based on the ability to assay thousands of single nucleotide polymorphisms (SNPs), have revolutionized our understanding of the genetics of complex traits. We advocate the analysis of GWAS data by a statistical method that fits all SNP effects simultaneously, assuming that these effects are drawn from a prior distribution. We illustrate how this method can be used to predict future phenotypes, to map and identify the causal mutations, and to study the genetic architecture of complex traits. The genetic architecture of complex traits is even more complex than previously thought: in almost every trait studied there are thousands of polymorphisms that explain genetic variation. Methods of predicting future phenotypes, collectively known as genomic selection or genomic prediction, have been widely adopted in livestock and crop breeding, leading to increased rates of genetic improvement.

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 Cigarette smoking and personality: interrogating causality using Mendelian randomisation

2018 ◽  
Vol 49 (13) ◽  
pp. 2197-2205 ◽  
Author(s):  
Hannah M. Sallis ◽  
George Davey Smith ◽  
Marcus R. Munafò
Keyword(s):  
Personality Traits ◽  
Association Studies ◽  
Smoking Initiation ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Individual Level ◽  
Causal Pathways ◽  
Genome Wide ◽  
Level Data ◽  
Causal Nature

AbstractBackgroundDespite the well-documented association between smoking and personality traits such as neuroticism and extraversion, little is known about the potential causal nature of these findings. If it were possible to unpick the association between personality and smoking, it may be possible to develop tailored smoking interventions that could lead to both improved uptake and efficacy.MethodsRecent genome-wide association studies (GWAS) have identified variants robustly associated with both smoking phenotypes and personality traits. Here we use publicly available GWAS summary statistics in addition to individual-level data from UK Biobank to investigate the link between smoking and personality. We first estimate genetic overlap between traits using LD score regression and then use bidirectional Mendelian randomisation methods to unpick the nature of this relationship.ResultsWe found clear evidence of a modest genetic correlation between smoking behaviours and both neuroticism and extraversion. We found some evidence that personality traits are causally linked to certain smoking phenotypes: among current smokers each additional neuroticism risk allele was associated with smoking an additional 0.07 cigarettes per day (95% CI 0.02–0.12, p = 0.009), and each additional extraversion effect allele was associated with an elevated odds of smoking initiation (OR 1.015, 95% CI 1.01–1.02, p = 9.6 × 10−7).ConclusionWe found some evidence for specific causal pathways from personality to smoking phenotypes, and weaker evidence of an association from smoking initiation to personality. These findings could be used to inform future smoking interventions or to tailor existing schemes.

scholarly journals The Mediation Effects of Aluminum in Plasma and Dipeptidyl Peptidase Like Protein 6 (DPP6) Polymorphism on Renal Function via Genome-Wide Typing Association

2021 ◽  
Vol 18 (19) ◽  
pp. 10484
Author(s):  
Ting-Hao Chen ◽  
Chen-Cheng Yang ◽  
Kuei-Hau Luo ◽  
Chia-Yen Dai ◽  
Yao-Chung Chuang ◽  
...  
Keyword(s):  
Renal Function ◽  
Mediation Analysis ◽  
Association Studies ◽  
Dipeptidyl Peptidase ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Mediation Effects ◽  
Genome Wide ◽  
Estimated Glomerular Filtration Rates

Aluminum (Al) toxicity is related to renal failure and the failure of other systems. Although there were some genome-wide association studies (GWAS) in Australia and England, there were no GWAS about Han Chinese to our knowledge. Thus, this research focused on using whole genomic genotypes from the Taiwan Biobank for exploring the association between Al concentrations in plasma and renal function. Participants, who underwent questionnaire interviews, biomarkers, and genotyping, were from the Taiwan Biobank database. Then, we measured their plasma Al concentrations with ICP-MS in the laboratory at Kaohsiung Medical University. We used this data to link genome-wide association (GWA) tests while looking for candidate genes and associated plasma Al concentration to renal function. Furthermore, we examined the path relationship between Single Nucleotide Polymorphisms (SNPs), Al concentrations, and estimated glomerular filtration rates (eGFR) through the mediation analysis with 3000 replication bootstraps. Following the principles of GWAS, we focused on three SNPs within the dipeptidyl peptidase-like protein 6 (DPP6) gene in chromosome 7, rs10224371, rs2316242, and rs10268004, respectively. The results of the mediation analysis showed that all of the selected SNPs have indirectly affected eGFR through a mediation of Al concentrations. Our analysis revealed the association between DPP6 SNPs, plasma Al concentrations, and eGFR. However, further longitudinal studies and research on mechanism are in need. Our analysis was still be the first study that explored the association between the DPP6, SNPs, and Al in plasma affecting eGFR.

scholarly journals Impact of Pre and Post Variant Filtration Strategies on Imputation

2020 ◽  
Author(s):  
Celine Charon ◽  
Rodrigue Allodji ◽  
Vincent Meyer ◽  
Jean-François Deleuze
Keyword(s):  
Quality Control ◽  
Rare Variants ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Direct Effects ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Conservative Post

Abstract Quality control methods for genome-wide association studies and fine mapping are commonly used for imputation, however, they result in loss of many single nucleotide polymorphisms (SNPs). To investigate the consequences of filtration on imputation, we studied the direct effects on the number of markers, their allele frequencies, imputation quality scores and post-filtration events. We pre-phrased 1,031 genotyped individuals from diverse ethnicities and compared the imputed variants to 1,089 NCBI recorded individuals for additional validation.Without variant pre-filtration based on quality control (QC), we observed no impairment in the imputation of SNPs that failed QC whereas with pre-filtration there was an overall loss of information. Significant differences between frequencies with and without pre-filtration were found only in the range of very rare (5E-04-1E-03) and rare variants (1E-03-5E-03) (p < 1E-04). Increasing the post-filtration imputation quality score from 0.3 to 0.8 reduced the number of single nucleotide variants (SNVs) <0.001 2.5 fold with or without QC pre-filtration and halved the number of very rare variants (5E-04). As a result, to maintain confidence and enough SNVs, we propose here a 2-step post-filtration approach to increase the number of very rare and rare variants compared to conservative post-filtration methods.

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