scholarly journals Genetic colocalization atlas points to common regulatory sites and genes for hematopoietic traits and hematopoietic contributions to disease phenotypes

2019 ◽  
Author(s):  
CS Thom ◽  
BF Voight
Keyword(s):  
Progenitor Cells ◽  
Genetic Relationships ◽  
Genetic Associations ◽  
Crohns Disease ◽  
Erythroid Progenitor ◽  
End Points ◽  
Disease Phenotypes ◽  
Genome Wide ◽  
Genetic Signal ◽  
Shared Genetic

AbstractBackgroundGenetic associations link hematopoietic traits and disease end-points, but most causal variants and genes underlying these relationships are unknown. Here, we used genetic colocalization to nominate loci and genes related to shared genetic signal for hematopoietic, cardiovascular, autoimmune, neuropsychiatric and cancer phenotypes.ResultsOur findings recapitulate developmental hematopoietic lineage relationships, identify loci associating traits with causal genetic relationships, and reveal novel associations. Out of 2706 loci with genome-wide significant signal for at least 1 blood trait, we identified 1779 unique sites (66%) with shared genetic signal for 2+ hematologic traits at a false discovery rate <5%. We could assign some sites to specific developmental cell types during hematopoiesis based on affected traits, including those likely to impact hematopoietic progenitor cells and/or megakaryocyte-erythroid progenitor cells. Through an expanded analysis of 70 human traits, we define 2+ colocalizing traits at 2007 loci from an analysis of 9852 sites (20%) containing genome-wide significant signal for at least 1 GWAS trait. In addition to variants and genes underlying shared genetic signal between blood traits and disease phenotypes that had been previously related through mendelian randomization studies, we define loci and related genes underlying shared signal between eosinophil count and eczema. We also identified colocalizing signals in a number of clinically relevant coding mutations, including in sites linking PTPN22 with Crohns disease, NIPA with coronary artery disease and platelet trait variation, and the hemochromatosis gene HFE with altered lipid levels. Finally, we anticipate potential off-target effects on blood traits related novel therapeutic targets, including TRAIL.ConclusionsOur findings provide a road map for gene validation experiments and novel therapeutics related to hematopoietic development, and offer a rationale for pleiotropic interactions between hematopoietic loci and disease end-points.

scholarly journals Integrative Genetics Analysis of Juvenile Idiopathic Arthritis Identifies Novel Loci

2020 ◽  
Author(s):  
Yun R. Li ◽  
Jin Li ◽  
Joseph T. Glessner ◽  
Jie Yang ◽  
Michael E. March ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Clinical Presentation ◽  
Immune Cell ◽  
Drug Repositioning ◽  
Cell Types ◽  
Disease Phenotypes ◽  
Genome Wide ◽  
Immune Mediated ◽  
Mhc Locus ◽  
Shared Genetic

Juvenile Idiopathic Arthritis (JIA) is the most common type of arthritis among children, encompassing a highly heterogeneous group of immune-mediated joint disorders, being classified into seven subtypes based on clinical presentation. To systematically understand the distinct and shared genetic underpinnings of JIA subtypes, we conducted a heterogeneity-sensitive GWAS encompassing a total of 1245 JIA cases classified into 7 subtypes and 9250 controls. In addition to the MHC locus, we uncovered 16 genome-wide significant loci, among which 15 were shared between at least two JIA subtypes, including 11 novel loci. Functional annotation indicates that candidate genes at these loci are expressed in diverse immune cell types. Further, based on the association results, the 7 JIA subtypes were classified into two groups, reflecting their autoimmune vs autoinflammatory nature. Our results suggest a common genetic mechanism underlying these subtypes in spite of their different clinical disease phenotypes, and that there may be drug repositioning opportunities for rare JIA subtypes.

scholarly journals Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

2020 ◽  
Author(s):  
Siddhartha P. Kar ◽  
Sara Lindström ◽  
Rayjean J. Hung ◽  
Kate Lawrenson ◽  
Marjanka K. Schmidt ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Meta Analysis ◽  
Effective Sample Size ◽  
Susceptibility Loci ◽  
Genetic Associations ◽  
Genome Wide ◽  
Gene Level ◽  
Association Data ◽  
Genomic Regions ◽  
Shared Genetic

ABSTRACTWe report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants (P<5×10−8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes (P<2.6×10−6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.

scholarly journals Genome-wide ChIP-Seq reveals a dramatic shift in the binding of the transcription factor erythroid Kruppel-like factor during erythrocyte differentiation

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. e139-e148 ◽  
Author(s):  
Andre M. Pilon ◽  
Subramanian S. Ajay ◽  
Swathi Ashok Kumar ◽  
Laurie A. Steiner ◽  
Praveen F. Cherukuri ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Progenitor Cells ◽  
Massively Parallel Sequencing ◽  
Promoter Regions ◽  
Erythroid Progenitor ◽  
Regulatory Pathways ◽  
Gata Factors ◽  
Erythroid Progenitor Cells ◽  
Genome Wide ◽  
Dramatic Shift

Abstract Erythropoiesis is dependent on the activity of transcription factors, including the erythroid-specific erythroid Kruppel-like factor (EKLF). ChIP followed by massively parallel sequencing (ChIP-Seq) is a powerful, unbiased method to map trans-factor occupancy. We used ChIP-Seq to study the interactome of EKLF in mouse erythroid progenitor cells and more differentiated erythroblasts. We correlated these results with the nuclear distribution of EKLF, RNA-Seq analysis of the transcriptome, and the occupancy of other erythroid transcription factors. In progenitor cells, EKLF is found predominantly at the periphery of the nucleus, where EKLF primarily occupies the promoter regions of genes and acts as a transcriptional activator. In erythroblasts, EKLF is distributed throughout the nucleus, and erythroblast-specific EKLF occupancy is predominantly in intragenic regions. In progenitor cells, EKLF modulates general cell growth and cell cycle regulatory pathways, whereas in erythroblasts EKLF is associated with repression of these pathways. The EKLF interactome shows very little overlap with the interactomes of GATA1, GATA2, or TAL1, leading to a model in which EKLF directs programs that are independent of those regulated by the GATA factors or TAL1.

scholarly journals Unravelling the genetic architecture of musical rhythm

2019 ◽  
Author(s):  
Maria Niarchou ◽  
J. Fah Sathirapongsasuti ◽  
Nori Jacoby ◽  
Eamonn Bell ◽  
Evonne McArthur ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Genome Wide Association Study ◽  
Genetic Associations ◽  
Musical Rhythm ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
Polygenic Scores ◽  
Genome Variations ◽  
Shared Genetic

AbstractWhile timing and rhythm-related phenotypes are heritable, the human genome variations underlying these traits are not yet well-understood. We conducted a genome-wide association study to identify common genetic variants associated with a self-reported musical rhythm phenotype in 606,825 individuals. Rhythm exhibited a highly polygenic architecture with sixty-eight loci reaching genome-wide significance (p<5×10−8) and SNP-based heritability of 13%-16%. Polygenic scores for rhythm predicted the presence of musician-related keywords in the BioVU electronic health record biobank. Genetic associations with rhythm were enriched for genes expressed in brain tissues. Genetic correlation analyses revealed shared genetic architecture with several traits relevant to cognition, emotion, health, and circadian rhythms, paving the way to a better understanding of the neurobiological pathways of musicality.

Human thymic epithelial cells maintain long-term survival of clonogenic myeloid and erythroid progenitor cells in vitro

2000 ◽  
Vol 111 (1) ◽  
pp. 363-370 ◽  
Author(s):  
Katsuto Takenaka ◽  
Mine Harada ◽  
Tomoaki Fujisaki ◽  
Koji Nagafuji ◽  
Shinichi Mizuno ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Progenitor Cells ◽  
Thymic Epithelial Cells ◽  
Erythroid Progenitor ◽  
Term Survival ◽  
Long Term Survival ◽  
Erythroid Progenitor Cells

scholarly journals Fetal erythropoiesis in steel mutant mice. III. Defect in differentiation from BFU-E to CFU-E during early development

Blood ◽  
1978 ◽  
Vol 51 (3) ◽  
pp. 539-547 ◽  
Author(s):  
DH Chui ◽  
SK Liao ◽  
K Walker
Keyword(s):  
Progenitor Cells ◽  
Early Development ◽  
The Other ◽  
Mutant Mice ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Other Hand ◽  
Colony Forming Units ◽  
Fetal Erythropoiesis

Abstract Erythroid progenitor cells in +/+ and Sl/Sld fetal livers manifested as burst-forming units-erythroid (BFU-E) and colony-forming units- erythroid (CFU-E) were assayed in vitro during early development. The proportion of BFU-E was higher as mutant than in normal fetal livers. On the other hand, the proportion of CFU-E was less in the mutant than in the normal. These results suggest that the defect in Sl/Sld fetal hepatic erythropoiesis is expressed at the steps of differentiation that effect the transition from BFU-E to CFU-E.

scholarly journals Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. McCartney ◽  
Josine L. Min ◽  
Rebecca C. Richmond ◽  
Ake T. Lu ◽  
Maria K. Sobczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Biological Aging ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Biomarkers Of Aging ◽  
Genome Wide ◽  
Shared Genetic

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Shared genetic architecture across psychiatric disorders

2021 ◽  
pp. 1-7
Author(s):  
Andrew D. Grotzinger
Keyword(s):  
Risk Factors ◽  
Psychiatric Disorders ◽  
Genetic Correlations ◽  
Fine Grained ◽  
Level Data ◽  
Symptom Level ◽  
Genetic Level ◽  
Genetic Signal ◽  
Family Based ◽  
Shared Genetic

Abstract Psychiatric disorders overlap substantially at the genetic level, with family-based methods long pointing toward transdiagnostic risk pathways. Psychiatric genomics has progressed rapidly in the last decade, shedding light on the biological makeup of cross-disorder risk at multiple levels of analysis. Over a hundred genetic variants have been identified that affect multiple disorders, with many more to be uncovered as sample sizes continue to grow. Cross-disorder mechanistic studies build on these findings to cluster transdiagnostic variants into meaningful categories, including in what tissues or when in development these variants are expressed. At the upper-most level, methods have been developed to estimate the overall shared genetic signal across pairs of traits (i.e. single-nucleotide polymorphism-based genetic correlations) and subsequently model these relationships to identify overarching, genomic risk factors. These factors can subsequently be associated with external traits (e.g. functional imaging phenotypes) to begin to understand the makeup of these transdiagnostic risk factors. As psychiatric genomic efforts continue to expand, we can begin to gain even greater insight by including more fine-grained phenotypes (i.e. symptom-level data) and explicitly considering the environment. The culmination of these efforts will help to inform bottom-up revisions of our current nosology.

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 Genome-wide association analysis of metabolic syndrome quantitative traits in the GENNID multiethnic family study

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jia Y. Wan ◽  
Deborah L. Goodman ◽  
Emileigh L. Willems ◽  
Alexis R. Freedland ◽  
Trina M. Norden-Krichmar ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Family Study ◽  
Genome Wide Association ◽  
European American ◽  
Japanese American ◽  
Genetic Associations ◽  
Chromosome 11 ◽  
Genome Wide ◽  
American Families

Abstract Background To identify genetic associations of quantitative metabolic syndrome (MetS) traits and characterize heterogeneity across ethnic groups. Methods Data was collected from GENetics of Noninsulin dependent Diabetes Mellitus (GENNID), a multiethnic resource of Type 2 diabetic families and included 1520 subjects in 259 African-American, European-American, Japanese-Americans, and Mexican-American families. We focused on eight MetS traits: weight, waist circumference, systolic and diastolic blood pressure, high-density lipoprotein, triglycerides, fasting glucose, and insulin. Using genotyped and imputed data from Illumina’s Multiethnic array, we conducted genome-wide association analyses with linear mixed models for all ethnicities, except for the smaller Japanese-American group, where we used additive genetic models with gene-dropping. Results Findings included ethnic-specific genetic associations and heterogeneity across ethnicities. Most significant associations were outside our candidate linkage regions and were coincident within a gene or intergenic region, with two exceptions in European-American families: (a) within previously identified linkage region on chromosome 2, two significant GLI2-TFCP2L1 associations with weight, and (b) one chromosome 11 variant near CADM1-LINC00900 with pleiotropic blood pressure effects. Conclusions This multiethnic family study found genetic heterogeneity and coincident associations (with one case of pleiotropy), highlighting the importance of including diverse populations in genetic research and illustrating the complex genetic architecture underlying MetS.

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