X-chromosome variants are associated with aldosterone producing adenomas

AbstractAldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA) and are characterized by constitutively producing aldosterone, which leads to hypertension. Several mutations have been identified in ion channels or ion channel-associated genes that result in APAs. To date, no studies have used a genome-wide association study (GWAS) approach to search for predisposing loci for APAs. Thus, we investigated Scandinavian APA cases (n = 35) and Swedish controls (n = 60) in a GWAS and discovered a susceptibility locus on chromosome Xq13.3 (rs2224095, OR = 7.9, 95% CI = 2.8–22.4, P = 1 × 10–7) in a 4-Mb region that was significantly associated with APA. Direct genotyping of sentinel SNP rs2224095 in a replication cohort of APAs (n = 83) and a control group (n = 740) revealed persistently strong significance (OR = 6.1, 95% CI = 3.5–10.6, p < 0.0005). We sequenced an adjacent gene, MAGEE1, of the sentinel SNP and identified a rare variant in one APA, p.Gly327Glu, which is complementary to other mutations in our primary cohort. Expression quantitative trait loci (eQTL) were investigated on the X-chromosome, and 24 trans-eQTL were identified. Some of the genes identified by trans-eQTL point towards a novel mechanistic explanation for the association of the SNPs with APAs. In conclusion, our study provides further insights into the genetic basis of APAs.

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Optimizing the Power to Identify the Genetic Basis of Complex Traits with Evolve and Resequence Studies

Molecular Biology and Evolution ◽

10.1093/molbev/msz183 ◽

2019 ◽

Vol 36 (12) ◽

pp. 2890-2905 ◽

Cited By ~ 2

Author(s):

Christos Vlachos ◽

Robert Kofler

Keyword(s):

Complex Traits ◽

Quantitative Traits ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Selection Regime ◽

Genome Wide ◽

A Genome ◽

Higher Power ◽

Powerful Approach ◽

Next Generation Sequencing Ngs

Abstract Evolve and resequence (E&R) studies are frequently used to dissect the genetic basis of quantitative traits. By subjecting a population to truncating selection for several generations and estimating the allele frequency differences between selected and nonselected populations using next-generation sequencing (NGS), the loci contributing to the selected trait may be identified. The role of different parameters, such as, the population size or the number of replicate populations has been examined in previous works. However, the influence of the selection regime, that is the strength of truncating selection during the experiment, remains little explored. Using whole genome, individual based forward simulations of E&R studies, we found that the power to identify the causative alleles may be maximized by gradually increasing the strength of truncating selection during the experiment. Notably, such an optimal selection regime comes at no or little additional cost in terms of sequencing effort and experimental time. Interestingly, we also found that a selection regime which optimizes the power to identify the causative loci is not necessarily identical to a regime that maximizes the phenotypic response. Finally, our simulations suggest that an E&R study with an optimized selection regime may have a higher power to identify the genetic basis of quantitative traits than a genome-wide association study, highlighting that E&R is a powerful approach for finding the loci underlying complex traits.

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Genomic variation across a clinical Cryptococcus population linked to disease outcome

10.1101/2021.11.22.469645 ◽

2021 ◽

Author(s):

Poppy Channa Sakti Sephton-Clark ◽

Jennifer Tenor ◽

Dena Toffaletti ◽

Nancy Meyers ◽

Charles Giamberardino ◽

...

Keyword(s):

Patient Outcomes ◽

Large Scale ◽

Genome Wide Association Study ◽

Sugar Transport ◽

Genomic Variation ◽

Clinical Isolates ◽

Genome Wide ◽

A Genome ◽

Gwas Approach

Cryptococcus neoformans is the causative agent of cryptococcosis, a disease with poor patient outcomes, accounting for approximately 180,000 deaths each year. Patient outcomes may be impacted by the underlying genetics of the infecting isolate, however, our current understanding of how genetic diversity contributes to clinical outcomes is limited. Here, we leverage clinical, in vitro growth and genomic data for 284 C. neoformans isolates to identify clinically relevant pathogen variants within a population of clinical isolates from patients with HIV-associated cryptococcosis in Malawi. Through a genome-wide association study (GWAS) approach, we identify variants associated with fungal burden and growth rate. We also find both small and large-scale variation, including aneuploidy, associated with alternate growth phenotypes, which may impact the course of infection. Genes impacted by these variants are involved in transcriptional regulation, signal transduction, glycolysis, sugar transport, and glycosylation. When combined with clinical data, we show that growth within the CNS is reliant upon glycolysis in an animal model, and likely impacts patient mortality, as CNS burden modulates patient outcome. Additionally, we find genes with roles in sugar transport are under selection in the majority of these clinical isolates. Further, we demonstrate that two hypothetical proteins identified by GWAS impact virulence in animal models. Our approach illustrates links between genetic variation and clinically relevant phenotypes, shedding light on survival mechanisms within the CNS and pathways involved in this persistence.

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A Genome-Wide Association Analysis Reveals a Role for Recombination in the Evolution of Antimicrobial Resistance in Burkholderia multivorans

10.1101/313205 ◽

2018 ◽

Author(s):

Julio Diaz Caballero ◽

Shawn T. Clark ◽

Pauline W. Wang ◽

Sylva L. Donaldson ◽

Bryan Coburn ◽

...

Keyword(s):

Burkholderia Cepacia ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Mortality And Morbidity ◽

Burkholderia Multivorans ◽

Post Transplant ◽

Genome Wide ◽

A Genome ◽

Genomic Study ◽

Gwas Approach

AbstractCystic fibrosis (CF) lung infections caused by members of the Burkholderia cepacia complex, such as Burkholderia multivorans, are associated with high rates of mortality and morbidity. We performed a population genomic study of 111 B. multivorans sputum isolates from a single CF patient through three stages of infection including the initial incident infection, deep sampling of a one-year period of chronic infection, and deep sampling of a post-transplant recolonization. We reconstructed the evolutionary history of the population and used a lineage-controlled genome-wide association study (GWAS) approach to identify genetic variants associated with antibiotic resistance. We found that the incident isolate was more susceptible to agents from three antimicrobial classes (β-lactams, aminoglycosides, quinolones), while the chronic isolates diversified into distinct genetic lineages with reduced antimicrobial susceptibility to the same agents. The post-transplant reinfection isolates displayed genetic and phenotypic signatures that were distinct from sputum isolates from all CF lung specimens. There were numerous examples of parallel pathoadaptation, in which individual loci, or even the same codon, were independently mutated multiple times. This set of loci was enriched for functions associated with virulence and resistance. Our GWAS approach identified one variant in the ampD locus (which was independently mutated four times in our dataset) associated with resistance to β-lactams, and two non-synonymous polymorphisms associated with resistance to both aminoglycosides and quinolones, affecting an araC family transcriptional regulator, which was independently mutated three times, and an outer member porin, which was independently mutated twice. We also performed recombination analysis and identified a minimum of 14 recombination events. Parallel pathoadaptive loci and polymorphisms associated with β-lactam resistance were over-represented in these recombinogenic regions. This study illustrates the power of deep, longitudinal sampling coupled with evolutionary and lineage-corrected GWAS analyses to reveal how pathogens adapt to their hosts.

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Genome-Wide Association Study Reveals the Genetic Basis of Chilling Tolerance in Rice at the Reproductive Stage

Plants ◽

10.3390/plants10081722 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1722

Author(s):

Byeong Yong Jeong ◽

Yoonjung Lee ◽

Yebin Kwon ◽

Jee Hye Kim ◽

Tae-Ho Ham ◽

...

Keyword(s):

Association Study ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Linkage Disequilibrium Block ◽

Chilling Tolerance ◽

Reproductive Stage ◽

Genome Wide Association ◽

Matrix Analysis ◽

Genome Wide ◽

A Genome

A genome-wide association study (GWAS) was used to investigate the genetic basis of chilling tolerance in a collection of 117 rice accessions, including 26 Korean landraces and 29 weedy rices, at the reproductive stage. To assess chilling tolerance at the early young microspore stage, plants were treated at 12 °C for 5 days, and tolerance was evaluated using seed set fertility. GWAS, together with principal component analysis and kinship matrix analysis, revealed five quantitative trait loci (QTLs) associated with chilling tolerance on chromosomes 3, 6, and 7. The percentage of phenotypic variation explained by the QTLs was 11–19%. The genomic region underlying the QTL on chromosome 3 overlapped with a previously reported QTL associated with spikelet fertility. Subsequent bioinformatic and haplotype analyses suggested three candidate chilling-tolerance genes within the QTL linkage disequilibrium block: Os03g0305700, encoding a protein similar to peptide chain release factor 2; Os06g0495700, encoding a beta tubulin, autoregulation binding-site-domain-containing protein; and Os07g0137800, encoding a protein kinase, core-domain-containing protein. Further analysis of the detected QTLs and the candidate chilling-tolerance genes will facilitate strategies for developing chilling-tolerant rice cultivars in breeding programs.

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Genome-Wide Association Study of H/L Traits in Chicken

Animals ◽

10.3390/ani9050260 ◽

2019 ◽

Vol 9 (5) ◽

pp. 260 ◽

Cited By ~ 1

Author(s):

Bo Zhu ◽

Qinghe Li ◽

Ranran Liu ◽

Maiqing Zheng ◽

Jie Wen ◽

...

Keyword(s):

Disease Resistance ◽

Association Study ◽

Genetic Basis ◽

Molecular Mechanisms ◽

Genome Wide Association Study ◽

Gene Annotation ◽

Immune Defense ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

Presently, the heterophil-to-lymphocyte (H/L) ratio is being studied extensively as a disease resistance trait. Through intricate mechanisms to identify and destroy pathogenic microorganisms, heterophils play a pivotal role in the immune defense systems of avian species. To reveal the genetic basis and molecular mechanisms affecting the H/L ratio, phenotypic and H/L data from 1650 white feather chicken broilers were used in performing a genome-wide association study. A self-developed, chicken-specific 55K chip was used for heterophils, lymphocytes, and H/L classification, according to individual genomic DNA profiles. We identified five significant single nucleotide polymorphisms (SNPs) when the genome-wide significance threshold was set to 5% (p < 2.42 × 10−6). A total of 15 SNPs obtained seemingly significant levels (p < 4.84 × 10−5). Gene annotation indicated that CARD11 (Caspase recruitment domain family member 11), BRIX1 (Biogenesis of ribosomes BRX1), and BANP (BTG3 associated nuclear protein) play a role in H/L-associated cell regulation and potentially constitute candidate gene regions for cellular functions dependent on H/L ratios. These results lay the foundation for revealing the genetic basis of disease resistance and future marker-assisted selection for disease resistance.

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Heritability and molecular genetic basis of antisaccade eye tracking error rate: A genome-wide association study

Psychophysiology ◽

10.1111/psyp.12347 ◽

2014 ◽

Vol 51 (12) ◽

pp. 1272-1284 ◽

Cited By ~ 18

Author(s):

Uma Vaidyanathan ◽

Stephen M. Malone ◽

Jennifer M. Donnelly ◽

Micah A. Hammer ◽

Michael B. Miller ◽

...

Keyword(s):

Association Study ◽

Error Rate ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Molecular Genetic ◽

Tracking Error ◽

Genome Wide Association ◽

Genome Wide ◽

Molecular Genetic Basis ◽

A Genome

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A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults

Blood ◽

10.1182/blood-2014-09-595744 ◽

2015 ◽

Vol 125 (4) ◽

pp. 680-686 ◽

Cited By ~ 65

Author(s):

Virginia Perez-Andreu ◽

Kathryn G. Roberts ◽

Heng Xu ◽

Colton Smith ◽

Hui Zhang ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Lymphoblastic Leukemia ◽

Genome Wide Association ◽

Age Group ◽

Genome Wide ◽

A Genome ◽

Key Points ◽

Similarities And Differences

Key Points In this first ALL GWAS in AYAs, we determined that inherited GATA3 variants strongly influence ALL susceptibility in this age group. These findings revealed similarities and differences in the genetic basis of ALL susceptibility between young children and AYAs.

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Exploring the genetic basis of chronic periodontitis: a genome-wide association study

Human Molecular Genetics ◽

10.1093/hmg/ddt065 ◽

2013 ◽

Vol 22 (11) ◽

pp. 2312-2324 ◽

Cited By ~ 144

Author(s):

K. Divaris ◽

K. L. Monda ◽

K. E. North ◽

A. F. Olshan ◽

L. M. Reynolds ◽

...

Keyword(s):

Association Study ◽

Chronic Periodontitis ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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Genetics of fasting and postprandial metabolite levels are overlapping

Physiological Genomics ◽

10.1152/physiolgenomics.00101.2017 ◽

2018 ◽

Vol 50 (4) ◽

pp. 235-236

Author(s):

Ruifang Li-Gao ◽

Renée de Mutsert ◽

Frits R. Rosendaal ◽

Ko Willems van Dijk ◽

Dennis O. Mook-Kanamori

Keyword(s):

Association Study ◽

Human Body ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genetic Associations ◽

Mixed Meal ◽

Genome Wide ◽

A Genome ◽

Metabolite Concentrations

In 2015, a genome-wide association study described 59 independent signals that showed strong associations with 85 fasting metabolite concentrations as measured by the Biocrates AbsoluteIDQ p150 kit. However, the human body resides in a nonfasting state for the greater part of the day, and the genetic basis of postprandial metabolite concentrations remains largely unknown. We systematically examined these previously identified genetic associations in postprandial metabolite concentrations after a mixed meal. Of these 85 metabolites, 23 were identified with significant changes after the meal, for which 38 gene-metabolite associations were analyzed. Of these 38 associations, 31 gene-metabolite associations were replicated with postprandial metabolite concentrations. These data indicate that the genetics of fasting and postprandial metabolite levels are significantly overlapping.

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