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Article ; Online: Pathway-based analyses.

Kent, Jack W

BMC genetics

2016 Volume 17 Suppl 2, Page(s) 5

Abstract: Background: New technologies for acquisition of genomic data, while offering unprecedented opportunities for genetic discovery, also impose severe burdens of interpretation and penalties for multiple testing.: Methods: The Pathway-based Analyses ... ...

Abstract	Background: New technologies for acquisition of genomic data, while offering unprecedented opportunities for genetic discovery, also impose severe burdens of interpretation and penalties for multiple testing. Methods: The Pathway-based Analyses Group of the Genetic Analysis Workshop 19 (GAW19) sought reduction of multiple-testing burden through various approaches to aggregation of highdimensional data in pathways informed by prior biological knowledge. Results: Experimental methods testedincluded the use of "synthetic pathways" (random sets of genes) to estimate power and false-positive error rate of methods applied to simulated data; data reduction via independent components analysis, single-nucleotide polymorphism (SNP)-SNP interaction, and use of gene sets to estimate genetic similarity; and general assessment of the efficacy of prior biological knowledge to reduce the dimensionality of complex genomic data. Conclusions: The work of this group explored several promising approaches to managing high-dimensional data, with the caveat that these methods are necessarily constrained by the quality of external bioinformatic annotation.
MeSH term(s)	Computational Biology/methods ; Gene Expression ; Gene Regulatory Networks ; Genome, Human ; Humans ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2016-02-03
Publishing country	England
Document type	Congress ; Research Support, N.I.H., Extramural
ISSN	1471-2156
ISSN (online)	1471-2156
DOI	10.1186/s12863-015-0314-9
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Article ; Online: Genetic variant rs1205 is associated with COVID-19 outcomes: The Strong Heart Study and Strong Heart Family Study.

Best, Lyle G / Erdei, Esther / Haack, Karin / Kent, Jack W / Malloy, Kimberly M / Newman, Deborah E / O'Leary, Marcia / O'Leary, Rae A / Sun, Quan / Navas-Acien, Ana / Franceschini, Nora / Cole, Shelley A

PloS one

2024 Volume 19, Issue 4, Page(s) e0302464

Abstract: Background: Although COVID-19 infection has been associated with a number of clinical and environmental risk factors, host genetic variation has also been associated with the incidence and morbidity of infection. The CRP gene codes for a critical ... ...

Abstract	Background: Although COVID-19 infection has been associated with a number of clinical and environmental risk factors, host genetic variation has also been associated with the incidence and morbidity of infection. The CRP gene codes for a critical component of the innate immune system and CRP variants have been reported associated with infectious disease and vaccination outcomes. We investigated possible associations between COVID-19 outcome and a limited number of candidate gene variants including rs1205. Methodology/principal findings: The Strong Heart and Strong Heart Family studies have accumulated detailed genetic, cardiovascular risk and event data in geographically dispersed American Indian communities since 1988. Genotypic data and 91 COVID-19 adjudicated deaths or hospitalizations from 2/1/20 through 3/1/23 were identified among 3,780 participants in two subsets. Among 21 candidate variants including genes in the interferon response pathway, APOE, TMPRSS2, TLR3, the HLA complex and the ABO blood group, only rs1205, a 3' untranslated region variant in the CRP gene, showed nominally significant association in T-dominant model analyses (odds ratio 1.859, 95%CI 1.001-3.453, p = 0.049) after adjustment for age, sex, center, body mass index, and a history of cardiovascular disease. Within the younger subset, association with the rs1205 T-Dom genotype was stronger, both in the same adjusted logistic model and in the SOLAR analysis also adjusting for other genetic relatedness. Conclusion: A T-dominant genotype of rs1205 in the CRP gene is associated with COVID-19 death or hospitalization, even after adjustment for relevant clinical factors and potential participant relatedness. Additional study of other populations and genetic variants of this gene are warranted.
MeSH term(s)	Humans ; COVID-19/genetics ; COVID-19/epidemiology ; COVID-19/mortality ; COVID-19/virology ; Female ; Male ; Middle Aged ; SARS-CoV-2/genetics ; Aged ; Polymorphism, Single Nucleotide ; Adult ; C-Reactive Protein/genetics ; Genetic Predisposition to Disease ; Risk Factors ; Genotype ; Hospitalization ; Genetic Variation
Chemical Substances	C-Reactive Protein (9007-41-4)
Language	English
Publishing date	2024-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0302464
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Article ; Online: Rare variants, common markers: synthetic association and beyond.

Kent, Jack W

Genetic epidemiology

2011 Volume 35 Suppl 1, Page(s) S80–4

Abstract: The phenomenon of synthetic association raises the possibility that common variant genetic markers may be coupled with functional rare variants sufficiently often to allow the rare variants to be tagged by the common ones. Using human exome sequence data ...

Abstract	The phenomenon of synthetic association raises the possibility that common variant genetic markers may be coupled with functional rare variants sufficiently often to allow the rare variants to be tagged by the common ones. Using human exome sequence data from the 1000 Genomes Project, two investigative teams in Group 12 of Genetic Analysis Workshop 17 found that stochastic coupling between rare and common variants does occur, although perhaps not sufficiently often that we can expect common variant signals to reflect synthetic association; other teams considered methods for detecting association using both rare and common variants. Common themes were that synthetic association is more apparent in population strata (ancestral or familial) and that careful selection of the unit of analysis (gene, gene network, or other genomic subset) is likely to be crucial to the discovery of rare variants that contribute to risk of disease.
MeSH term(s)	Exome ; Genetic Markers ; Genetic Predisposition to Disease/genetics ; Genotype ; Human Genome Project ; Humans ; Molecular Epidemiology/methods ; Polymorphism, Single Nucleotide/genetics ; Sequence Analysis
Chemical Substances	Genetic Markers
Language	English
Publishing date	2011-11-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	605785-8
ISSN	1098-2272 ; 0741-0395
ISSN (online)	1098-2272
ISSN	0741-0395
DOI	10.1002/gepi.20655
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Article ; Online: Analysis of multiple phenotypes.

Kent, Jack W

Genetic epidemiology

2009 Volume 33 Suppl 1, Page(s) S33–9

Abstract: The complex etiology of common diseases like cardiovascular disease, diabetes, hypertension, and rheumatoid arthritis has led investigators to focus on the genetics of correlated phenotypes and risk factors. Joint analysis of multiple disease-related ... ...

Abstract	The complex etiology of common diseases like cardiovascular disease, diabetes, hypertension, and rheumatoid arthritis has led investigators to focus on the genetics of correlated phenotypes and risk factors. Joint analysis of multiple disease-related phenotypes may reveal genes of pleiotropic effect and increase analytical power, but at the cost of increased analytical and computational complexity. All three data sets provided for analysis at the Genetic Analysis Workshop 16 offered multiple quantitative measures of phenotypes related to underlying disease processes as well as discrete measures of affection status. Participants in Group 6 addressed the challenges and possibilities of association analysis of these data sets on multiple levels, including phenotype definition and data reduction, multivariate approaches to gene discovery, analysis of causality and data structure, and development of predictive models. These approaches included combinations of continuous and discrete phenotypes, use of repeated measures in longitudinal data, and models that included multiple phenotypic measures and multiple single-nucleotide polymorphism variants. Most research teams regarded the use of multiple related phenotypes as a tool for increasing analytical power, as well as for clarifying the underlying biology of complex diseases.
MeSH term(s)	Causality ; Genome-Wide Association Study/methods ; Genome-Wide Association Study/statistics & numerical data ; Humans ; Longitudinal Studies ; Molecular Epidemiology ; Multivariate Analysis ; Phenotype ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2009-11-19
Publishing country	United States
Document type	Congress ; Research Support, N.I.H., Extramural
ZDB-ID	605785-8
ISSN	1098-2272 ; 0741-0395
ISSN (online)	1098-2272
ISSN	0741-0395
DOI	10.1002/gepi.20470
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Article: Novel Toolboxes for the Investigation of Activity-Dependent Myelination in the Central Nervous System.

Heflin, Jack Kent / Sun, Wenjing

Frontiers in cellular neuroscience

2021 Volume 15, Page(s) 769809

Abstract: Myelination is essential for signal processing within neural networks. Emerging data suggest that neuronal activity positively instructs myelin development and myelin adaptation during adulthood. However, the underlying mechanisms controlling activity- ... ...

Abstract	Myelination is essential for signal processing within neural networks. Emerging data suggest that neuronal activity positively instructs myelin development and myelin adaptation during adulthood. However, the underlying mechanisms controlling activity-dependent myelination have not been fully elucidated. Myelination is a multi-step process that involves the proliferation and differentiation of oligodendrocyte precursor cells followed by the initial contact and ensheathment of axons by mature oligodendrocytes. Conventional end-point studies rarely capture the dynamic interaction between neurons and oligodendrocyte lineage cells spanning such a long temporal window. Given that such interactions and downstream signaling cascades are likely to occur within fine cellular processes of oligodendrocytes and their precursor cells, overcoming spatial resolution limitations represents another technical hurdle in the field. In this mini-review, we discuss how advanced genetic, cutting-edge imaging, and electrophysiological approaches enable us to investigate neuron-oligodendrocyte lineage cell interaction and myelination with both temporal and spatial precision.
Language	English
Publishing date	2021-11-02
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2021.769809
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Article ; Online: Genetic Variant rs1205 is Associated with COVID-19 Outcomes: The Strong Heart Study and Strong Heart Family Study.

Best, Lyle G / Erdei, Esther / Haack, Karin / Kent, Jack W / Malloy, Kimberly / Newman, Deborah E / O'Leary, Marcia / O'Leary, Rae / Sun, Quan / Navas-Acien, Ana / Franceschini, Nora / Cole, Shelley A

medRxiv

Abstract	Background: Although COVID-19 infection has been associated with a number of clinical and environmental risk factors, host genetic variation has also been associated with the incidence and morbidity of infection. The CRP gene codes for a critical component of the innate immune system and CRP variants have been reported associated with infectious disease and vaccination outcomes. We investigated possible associations between COVID-19 outcome and a limited number of candidate gene variants including rs1205. Methodology/Principal Findings: The Strong Heart and Strong Heart Family studies have accumulated detailed genetic, cardiovascular risk and event data in geographically dispersed American Indian communities since 1988. Chi-square tests, logistic regression and generalized linear mixed models (implemented in SOLAR) were used in analysis. Genotypic data and 91 COVID-19 adjudicated deaths or hospitalizations from 2/1/20 through 3/1/23 were identified among 3,780 participants in two subsets. Among 21 candidate variants including genes in the interferon response pathway, APOE, TMPRSS2, TLR3, the HLA complex and the ABO blood group, only rs1205, a 39 untranslated region variant in the CRP gene, showed nominally significant association in T-dominant model analyses (odds ratio 1.859, 95%CI 1.001-3.453, p=0.049) after adjustment for age, sex, center, body mass index, and a history of cardiovascular disease. Within the younger subset, association with the rs1205 T-Dom genotype was stronger, both in the same adjusted logistic model and in the SOLAR analysis also adjusting for other genetic relatedness. Conclusion: A T-dominant genotype of rs1205 in the CRP gene is associated with COVID-19 death or hospitalization, even after adjustment for relevant clinical factors and potential participant relatedness. Additional study of other populations and genetic variants of this gene are warranted.
Keywords	covid19
Language	English
Publishing date	2023-08-08
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2023.08.04.23293551
Database	COVID19

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Article: Host Genetics of Response to Porcine Reproductive and Respiratory Syndrome in Sows: Reproductive Performance.

Hickmann, Felipe M W / Braccini Neto, José / Kramer, Luke M / Huang, Yijian / Gray, Kent A / Dekkers, Jack C M / Sanglard, Leticia P / Serão, Nick V L

Frontiers in genetics

2021 Volume 12, Page(s) 707870

Abstract: Porcine Reproductive and Respiratory Syndrome (PRRS) is historically the most economically important swine disease worldwide that severely affects the reproductive performance of sows. However, little is still known about the genetic basis of ... ...

Abstract	Porcine Reproductive and Respiratory Syndrome (PRRS) is historically the most economically important swine disease worldwide that severely affects the reproductive performance of sows. However, little is still known about the genetic basis of reproductive performance in purebred herds during a PRRS outbreak through the comparison of maternal and terminal breeds. Thus, the objective of this work was to explore the host genetics of response to PRRS in purebred sows from two breeds. Reproductive data included 2546 Duroc and 2522 Landrace litters from 894 and 813 purebred sows, respectively, which had high-density genotype data available (29,799 single nucleotide polymorphisms; SNPs). The data were split into pre-PRRS, PRRS, and post-PRRS phases based on standardized farrow-year-week estimates. Heritability estimates for reproductive traits were low to moderate (≤0.20) for Duroc and Landrace across PRRS phases. On the other hand, genetic correlations of reproductive traits between PRRS phases were overall moderate to high for both breeds. Several associations between MARC0034894, a candidate SNP for response to PRRS, with reproductive performance were identified (
Language	English
Publishing date	2021-08-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2021.707870
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Article: A variance component-based gene burden test.

Peralta, Juan M / Almeida, Marcio / Kent, Jack W / Blangero, John

BMC proceedings

2014 Volume 8, Issue Suppl 1 Genetic Analysis Workshop 18Vanessa Olmo, Page(s) S49

Abstract: We propose a novel variance component approach for the analysis of next-generation sequencing data. Our method is based on the detection of the proportion of the trait phenotypic variance that can be explained by the introduction of a new variance ... ...

Abstract	We propose a novel variance component approach for the analysis of next-generation sequencing data. Our method is based on the detection of the proportion of the trait phenotypic variance that can be explained by the introduction of a new variance component that accounts for the local gene-specific departure of the empirical kinship relationship matrix, estimated from single-nucleotide polymorphism (SNP) genotypes, from their theoretical expectation based on the genealogical information in the pedigree. We tested our method with simulated phenotypes and imputed SNP genotypes from the Genetic Analysis Workshop 18 data set. We observed considerable variation in the differences between theoretical and gene-specific kinship estimates that proved to be informative for our test and allowed us to detect the MAP4 causal gene at a genome-wide significance level. The distribution of our test statistic show no inflation under the null hypothesis and results from a random set of genes suggest that the detection of MAP4 is both sensitive and specific. The use of 2 different strategies for the selection of the SNPs used to derive the gene-specific empirical kinship relationship matrices provides us with suggestive evidence that our method is performing as an empirical test of linkage.
Language	English
Publishing date	2014-06-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2411867-9
ISSN	1753-6561
ISSN	1753-6561
DOI	10.1186/1753-6561-8-S1-S49
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Article: Host Genetics of Response to Porcine Reproductive and Respiratory Syndrome in Sows: Antibody Response as an Indicator Trait for Improved Reproductive Performance.

Hickmann, Felipe M W / Braccini Neto, José / Kramer, Luke M / Huang, Yijian / Gray, Kent A / Dekkers, Jack C M / Sanglard, Leticia P / Serão, Nick V L

Frontiers in genetics

2021 Volume 12, Page(s) 707873

Abstract: Antibody response to porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) infection, measured as sample-to-positive (S/P) ratio, has been proposed as an indicator trait for improved reproductive performance during a PRRS outbreak in ... ...

Abstract	Antibody response to porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) infection, measured as sample-to-positive (S/P) ratio, has been proposed as an indicator trait for improved reproductive performance during a PRRS outbreak in Landrace sows. However, this result has not yet been validated in Landrace sows or evaluated in terminal sire lines. The main objectives of this work were to validate the use of S/P ratio as an indicator trait to select pigs during a PRRS outbreak and to explore the genetic basis of antibody response to PRRSV. Farrowing data included 2,546 and 2,522 litters from 894 Duroc and 813 Landrace sows, respectively, split into pre-PRRS, PRRS, and post-PRRS phases. Blood samples were taken from 1,231 purebred sows (541 Landrace and 690 Duroc) following a PRRS outbreak for subsequent PRRSV ELISA analysis for S/P ratio measurement. All animals had high-density genotype data available (29,799 single nucleotide polymorphisms; SNPs). Genetic parameters and genome-wide association studies (GWAS) for S/P ratio were performed for each breed separately. Heritability estimates (± standard error) of S/P ratio during the PRRS outbreak were moderate, with 0.35 ± 0.08 for Duroc and 0.34 ± 0.09 for Landrace. During the PRRS outbreak, favorable genetic correlations of S/P ratio with the number of piglets born alive (0.61 ± 0.34), number of piglets born dead (-0.33 ± 0.32), and number of stillborn piglets (-0.27 ± 0.31) were observed for Landrace sows. For Duroc, the GWAS identified a major quantitative trait locus (QTL) on chromosome (Chr) 7 (24-15 megabases; Mb) explaining 15% of the total genetic variance accounted for by markers (TGVM), and another one on Chr 8 (25 Mb) explaining 2.4% of TGVM. For Landrace, QTL on Chr 7 (24-25 Mb) and Chr 7 (108-109 Mb), explaining 31% and 2.2% of TGVM, respectively, were identified. Some of the SNPs identified in these regions for S/P ratio were associated with reproductive performance but not during the PRRS outbreak. Genomic prediction accuracies for S/P ratio were moderate to high for the within-breed analysis. For the between-breed analysis, these were overall low. These results further support the use of S/P ratio as an indicator trait for improved reproductive performance during a PRRS outbreak in Landrace sows.
Language	English
Publishing date	2021-08-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2021.707873
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Article ; Online: Genomics of response to porcine reproductive and respiratory syndrome virus in purebred and crossbred sows: antibody response and performance following natural infection vs. vaccination.

Sanglard, Leticia P / Hickmann, Felipe M W / Huang, Yijian / Gray, Kent A / Linhares, Daniel C L / Dekkers, Jack C M / Niederwerder, Megan C / Fernando, Rohan L / Braccini Neto, Joseph / Serão, Nick V L

Journal of animal science

2021 Volume 99, Issue 5

Abstract: Antibody response, measured as sample-to-positive (S/P) ratio, to porcine reproductive and respiratory syndrome virus (PRRSV) following a PRRSV-outbreak (S/POutbreak) in a purebred nucleus and following a PRRSV-vaccination (S/PVx) in commercial crossbred ...

Abstract	Antibody response, measured as sample-to-positive (S/P) ratio, to porcine reproductive and respiratory syndrome virus (PRRSV) following a PRRSV-outbreak (S/POutbreak) in a purebred nucleus and following a PRRSV-vaccination (S/PVx) in commercial crossbred herds have been proposed as genetic indicator traits for improved reproductive performance in PRRSV-infected purebred and PRRSV-vaccinated crossbred sows, respectively. In this study, we investigated the genetic relationships of S/POutbreak and S/PVx with performance at the commercial (vaccinated crossbred sows) and nucleus level (non-infected and PRRSV-infected purebred sows), respectively, and tested the effect of previously identified SNP for these indicator traits. Antibody response was measured on 541 Landrace sows ~54 d after the start of a PRRSV outbreak, and on 906 F1 (Landrace × Large White) gilts ~50 d after vaccination with a commercial PRRSV vaccine. Reproductive performance was recorded for 711 and 428 Landrace sows before and during the PRRSV outbreak, respectively, and for 811 vaccinated F1 animals. The estimate of the genetic correlation (rg) of S/POutbreak with S/PVx was 0.72 ± 0.18. The estimates of rg of S/POutbreak with reproductive performance in vaccinated crossbred sows were low to moderate, ranging from 0.05 ± 0.23 to 0.30 ± 0.20. The estimate of rg of S/PVx with reproductive performance in non-infected purebred sows was moderate and favorable with number born alive (0.50 ± 0.23) but low (0 ± 0.23 to -0.11 ± 0.23) with piglet mortality traits. The estimates of rg of S/PVx were moderate and negative (-0.38 ± 0.21) with number of mummies in PRRSV-infected purebred sows and low with other traits (-0.30 ± 0.18 to 0.05 ± 0.18). Several significant associations (P0 > 0.90) of previously reported SNP for S/P ratio (ASGA0032063 and H3GA0020505) were identified for S/P ratio and performance in non-infected purebred and PRRSV-exposed purebred and crossbred sows. Genomic regions harboring the major histocompatibility complex class II region significantly contributed to the genetic correlation of antibody response to PRRSV with most of the traits analyzed. These results indicate that selection for antibody response in purebred sows following a PRRSV outbreak in the nucleus and for antibody response to PRRSV vaccination measured in commercial crossbred sows are expected to increase litter size in purebred and commercial sows.
MeSH term(s)	Animals ; Antibody Formation ; Female ; Genomics ; Porcine Reproductive and Respiratory Syndrome/genetics ; Porcine Reproductive and Respiratory Syndrome/prevention & control ; Porcine respiratory and reproductive syndrome virus ; Pregnancy ; Swine ; Swine Diseases ; Vaccination/veterinary ; Viral Vaccines
Chemical Substances	Viral Vaccines
Language	English
Publishing date	2021-03-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	390959-1
ISSN	1525-3163 ; 0021-8812
ISSN (online)	1525-3163
ISSN	0021-8812
DOI	10.1093/jas/skab097
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