scholarly journals Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

2018 ◽  
Author(s):  
Satish K Nandakumar ◽  
Sean K McFarland ◽  
Laura Marlene Mateyka ◽  
Caleb A Lareau ◽  
Jacob C Ulirsch ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Target Genes ◽  
Association Studies ◽  
Human Diseases ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genome Wide ◽  
Causal Variants ◽  
Genomic Regions

Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding genomic regions and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes. Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in relevant biological pathways, allowing regulators of human erythropoiesis and blood disease modifiers to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits.

scholarly journals Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Satish K Nandakumar ◽  
Sean K McFarland ◽  
Laura M Mateyka ◽  
Caleb A Lareau ◽  
Jacob C Ulirsch ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Target Genes ◽  
Association Studies ◽  
Human Diseases ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Coding Regions ◽  
Genome Wide ◽  
Causal Variants

Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding regions of the genome and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1–2 candidate genes. Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in specific and relevant biological pathways, allowing regulators of human erythropoiesis and modifiers of blood diseases to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits.

scholarly journals Identification of Novel Genome-Wide Associations for Oral Inflammatory Traits

2020 ◽  
Author(s):  
Yanjiao Jin ◽  
Jie Yang ◽  
Shuyue Zhang ◽  
Jin Li ◽  
Songlin Wang
Keyword(s):  
Candidate Genes ◽  
Immune Regulation ◽  
Functional Annotation ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Protein Protein Interaction ◽  
Genome Wide ◽  
Causal Variants

Abstract Background: Oral diseases impact the majority of the world’s population. The following traits are common in oral inflammatory diseases: mouth ulcers, painful gums, bleeding gums, loose teeth, and toothache. Despite the prevalence of genome-wide association studies, the associations between these traits and common genomic variants, and whether pleiotropic loci are shared by some of these traits remain poorly understood. Methods: In this work, we conducted multi-trait joint analyses based on the summary statistics of genome-wide association studies of these five oral inflammatory traits from the UK Biobank, each of which is comprised of over 10,000 cases and over 300,000 controls. We estimated the genetic correlations between the five traits. We conducted fine-mapping and functional annotation based on multi-omics data to better understand the biological functions of the potential causal variants at each locus. To identify the pathways in which the candidate genes were mainly involved, we applied gene-set enrichment analysis, and further performed protein-protein interaction (PPI) analyses.Results: We identified 39 association signals that surpassed genome-wide significance, including three that were shared between two or more oral inflammatory traits, consistent with a strong correlation. Among these genome-wide significant loci, two were novel for both painful gums and toothache. We performed fine-mapping and identified causal variants at each novel locus. Further functional annotation based on multi-omics data suggested IL10 and IL12A/TRIM59 as potential candidate genes at the novel pleiotropic loci, respectively. Subsequent analyses of pathway enrichment and protein-protein interaction networks suggested the involvement of candidate genes at genome-wide significant loci in immune regulation.Conclusions: Our results highlighted the importance of immune regulation in the pathogenesis of oral inflammatory diseases. Some common immune-related pleiotropic loci or genetic variants are shared by multiple oral inflammatory traits. These findings will be beneficial for risk prediction, prevention, and therapy of oral inflammatory diseases.

scholarly journals Identification of Loci Controlling the Dwarfism Trait in the White Sailfin Molly (Poecilia latipinna) Using Genome-Wide Association Studies Based on Genotyping-By-Sequencing

Genes ◽  
2019 ◽  
Vol 10 (6) ◽  
pp. 418
Author(s):  
Fan Shao ◽  
Jing Liu ◽  
Mengyuan Ren ◽  
Junying Li ◽  
Haigang Bao ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Association Studies ◽  
Genotyping By Sequencing ◽  
Genome Wide Association ◽  
Expression Level ◽  
Genome Wide Association Studies ◽  
Sailfin Molly ◽  
Genome Wide ◽  
Genomic Regions ◽  
Sailfin Mollies

Dwarfism is a condition defined by low harvest weight in fish, but also results in strange body figures which may have potential for the selective breeding of new ornamental fish strains. The objectives of this study are to reveal the physiological causes of dwarfism and identify the genetic loci controlling this trait in the white sailfin molly. Skeletons of dwarf and normal sailfin mollies were observed by X-ray radioscopy and skeletal staining. Genome-wide association studies based on genotyping-by-sequencing (n = 184) were used to map candidate genomic regions associated with the dwarfism trait. Quantitative real-time PCR was performed to determine the expression level of candidate genes in normal (n = 8) and dwarf (n = 8) sailfin mollies. We found that the dwarf sailfin molly has a short and dysplastic spine in comparison to the normal fish. Two regions, located at NW_015112742.1 and NW_015113621.1, were significantly associated with the dwarfism trait. The expression level of three candidate genes, ADAMTS like 1, Larp7 and PPP3CA, were significantly different between the dwarf and normal sailfin mollies in the hepatopancreas, with PPP3CA also showing significant differences in the vertebrae and Larp7 showing significant differences in the muscle. This study identified genomic regions and candidate genes associated with the dwarfism trait in the white sailfin molly and would provide a reference to determine dwarf-causing variations.

scholarly journals Single-step genome-wide association studies (GWAS) and post-GWAS analyses to identify genomic regions and candidate genes for milk yield in Brazilian Girolando cattle

2020 ◽  
Vol 103 (11) ◽  
pp. 10347-10360
Author(s):  
Pamela I. Otto ◽  
Simone E.F. Guimarães ◽  
Mario P.L. Calus ◽  
Jeremie Vandenplas ◽  
Marco A. Machado ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Milk Yield ◽  
Association Studies ◽  
Single Step ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Genomic Regions

scholarly journals Genome-wide associations for immune traits in two maternal pig lines

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Christina M. Dauben ◽  
Maren J. Pröll-Cornelissen ◽  
Esther M. Heuß ◽  
Anne K. Appel ◽  
Hubert Henne ◽  
...  
Keyword(s):  
Immune System ◽  
Candidate Genes ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Production Traits ◽  
Biological Relevance ◽  
Genome Wide ◽  
Major Interest ◽  
Immune Traits ◽  
Genomic Regions

Abstract Background In recent years, animal welfare and health has become more and more important in pig breeding. So far, numerous parameters have been considered as important biomarkers, especially in the immune reaction and inflammation. Previous studies have shown moderate to high heritabilities in most of these traits. However, the genetic background of health and robustness of pigs needs to be extensively clarified. The objective of this study was to identify genomic regions with a biological relevance for the immunocompetence of piglets. Genome-wide Association Studies (GWAS) in 535 Landrace (LR) and 461 Large White (LW) piglets were performed, investigating 20 immune relevant traits. Besides the health indicators of the complete and differential blood count, eight different cytokines and haptoglobin were recorded in all piglets and their biological dams to capture mediating processes and acute phase reactions. Additionally, all animals were genotyped using the Illumina PorcineSNP60v2 BeadChip. Results In summary, GWAS detected 25 genome-wide and 452 chromosome-wide significant SNPs associated with 17 immune relevant traits in the two maternal pig lines LR and LW. Only small differences were observed considering the maternal immune records as covariate within the statistical model. Furthermore, the study identified across- and within-breed differences as well as relevant candidate genes. In LR more significant associations and related candidate genes were detected, compared with LW. The results detected in LR and LW are partly in accordance with previously identified quantitative trait loci (QTL) regions. In addition, promising novel genomic regions were identified which might be of interest for further detailed analysis. Especially putative pleiotropic regions on SSC5, SSC12, SSC15, SSC16 and SSC17 are of major interest with regard to the interacting structure of the immune system. The comparison with already identified QTL gives indications on interactions with traits affecting piglet survival and also production traits. Conclusion In conclusion, results suggest a polygenic and breed-specific background of immune relevant traits. The current study provides knowledge about regions with biological relevance for health and immune traits. Identified markers and putative pleiotropic regions provide first indications in the context of balancing a breeding-based modification of the porcine immune system.

scholarly journals Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results

2011 ◽  
Vol 42 (3) ◽  
pp. 607-616 ◽  
Author(s):  
A. L. Collins ◽  
Y. Kim ◽  
P. Sklar ◽  
M. C. O'Donovan ◽  
P. F. Sullivan ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Candidate Gene ◽  
Candidate Genes ◽  
Association Studies ◽  
Human Diseases ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Common Genetic Variation ◽  
Genome Wide ◽  
Candidate Gene Studies

BackgroundCandidate gene studies have been a key approach to the genetics of schizophrenia (SCZ). However, the results of these studies are confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised by comparison with the results of genome-wide association studies (GWAS).MethodWe describe the characteristics of hypothesis-driven candidate gene studies from the SZGene database, and use pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International Schizophrenia Consortium (ISC).ResultsSZGene contained 732 autosomal genes evaluated in 1374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC studies had 89% power to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISCpvalues in hypothesis-driven candidate genes, nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (SCZ as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes (COMT,DRD3,DRD2,HTR2A,NRG1,BDNF,DTNBP1andSLC6A4) had no notable ISC results.ConclusionsWe did not find support for the idea that the hypothesis-driven candidate genes studied in the literature are enriched for the common genetic variation involved in the etiology of SCZ. Larger samples are required to evaluate this conclusion definitively.

scholarly journals INFERNO - INFERring the molecular mechanisms of NOncoding genetic variants

2017 ◽  
Author(s):  
Alexandre Amlie-Wolf ◽  
Mitchell Tang ◽  
Elisabeth E. Mlynarski ◽  
Pavel P. Kuksa ◽  
Otto Valladares ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Cellular Processes ◽  
Genome Wide ◽  
Causal Variants ◽  
Novel Method

AbstractThe majority of variants identified by genome-wide association studies (GWAS) reside in the noncoding genome, where they affect regulatory elements including transcriptional enhancers. We propose INFERNO (INFERring the molecular mechanisms of NOncoding genetic variants), a novel method which integrates hundreds of diverse functional genomics data sources with GWAS summary statistics to identify putatively causal noncoding variants underlying association signals. INFERNO comprehensively infers the relevant tissue contexts, target genes, and downstream biological processes affected by causal variants. We apply INFERNO to schizophrenia GWAS data, recapitulating known schizophrenia-associated genes including CACNA1C and discovering novel signals related to transmembrane cellular processes.

scholarly journals Extensive germline-somatic interplay drives prostate cancer through HNF1B co-option of TMPRSS2-ERG

2021 ◽  
Author(s):  
Nikolaos Giannareas ◽  
Qin Zhang ◽  
Xiayun Yang ◽  
Yijun Tian ◽  
Peng Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle Progression ◽  
Biological Effects ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Genome Wide ◽  
Transcription Factor Genes ◽  
Causal Variants ◽  
Genomic Regions

Genome-wide association studies have identified 270 loci conferring risk for prostate cancer (PCa), yet the underlying biology and clinical impact remain to be investigated. Here we observe an enrichment of transcription factor genes including HNF1B within PCa risk-associated regions. While focused on the 17q12/HNF1B locus, we find a strong eQTL for HNF1B and multiple potential causal variants involved in the regulation of HNF1B expression in PCa. An unbiased genome-wide co-expression analysis reveals PCa-specific somatic TMPRSS2-ERG fusion as a transcriptional mediator of this locus and the HNF1B eQTL signal is ERG fusion status dependent. We investigate the role of HNF1B and find its involvement in several pathways related to cell cycle progression and PCa severity. Furthermore, HNF1B interacts with TMPRSS2-ERG to co-occupy large proportion of genomic regions with a remarkable enrichment of additional PCa risk alleles. We finally show that HNF1B co-opts ERG fusion to mediate mechanistic and biological effects of the PCa risk-associated locus 17p13.3/VPS53/FAM57A/GEMIN4. Taken together, we report an extensive germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations underpinning PCa risk association and progression.

scholarly journals Uncovering Novel Genomic Regions and Candidate Genes for Senescence-Related Traits by Genome-Wide Association Studies in Upland Cotton (Gossypium hirsutum L.)

2022 ◽  
Vol 12 ◽  
Author(s):  
Qibao Liu ◽  
Libei Li ◽  
Zhen Feng ◽  
Shuxun Yu
Keyword(s):  
Candidate Genes ◽  
Upland Cotton ◽  
Genetic Basis ◽  
Association Studies ◽  
White Flower ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
High Positive Correlation ◽  
Genome Wide ◽  
Genomic Regions

Senescence in plants is a complex trait, which is controlled by both genetic and environmental factors and can affect the yield and quality of cotton. However, the genetic basis of cotton senescence remains relatively unknown. In this study, we reported genome-wide association studies (GWAS) based on 185 accessions of upland cotton and 26,999 high-quality single-nucleotide polymorphisms (SNPs) to reveal the genetic basis of cotton senescence. To determine cotton senescence, we evaluated eight traits/indices. Our results revealed a high positive correlation (r>0.5) among SPAD value 20 days after topping (SPAD20d), relative difference of SPAD (RSPAD), nodes above white flower on topping day (NAWF0d), nodes above white flower 7 days after topping (NAWF7d), and number of open bolls on the upper four branches (NB), and genetic analysis revealed that all traits had medium or high heritability ranging from 0.53 to 0.86. Based on a multi-locus method (FASTmrMLM), a total of 63 stable and significant quantitative trait nucleotides (QTNs) were detected, which represented 50 genomic regions (GWAS risk loci) associated with cotton senescence. We observed three reliable loci located on chromosomes A02 (A02_105891088_107196428), D03 (D03_37952328_38393621) and D13 (D13_59408561_60730103) because of their high repeatability. One candidate gene (Ghir_D03G011060) was found in the locus D03_37952328_38393621, and its Arabidopsis thaliana homologous gene (AT5G23040) encodes a cell growth defect factor-like protein (CDF1), which might be involved in chlorophyll synthesis and cell death. Moreover, qRT-PCR showed that the transcript level of Ghir_D03G011060 was down-regulated in old cotton leaves, and virus-induced gene silencing (VIGS) indicated that silencing of Ghir_D03G011060 resulted in leaf chlorosis and promoted leaf senescence. In addition, two candidate genes (Ghir_A02G017660 and Ghir_D13G021720) were identified in loci A02_105891088_107196428 and D13_59408561_60730103, respectively. These results provide new insights into the genetic basis of cotton senescence and will serve as an important reference for the development and implementation of strategies to prevent premature senescence in cotton breeding programs.

Sign in / Sign up

Export Citation Format

Share Document