First genome-wide association study of non-severe malaria in two birth cohorts in Benin

AbstractRecent research efforts to identify genes involved in malaria susceptibility using genome-wide approaches have focused on severe malaria. Here we present the first GWAS on non-severe malaria designed to identify genetic variants involved in innate immunity or innate resistance mechanisms. Our study was performed on two cohorts of infants from southern Benin (525 and 250 individuals respectively) closely followed from birth to 18-24 months of age, with an assessment of a space-and time-dependent environmental risk of exposure. Both the recurrence of mild malaria attacks and the recurrence of malaria infections as a whole (symptomatic and asymptomatic) were considered. Our study highlights a role of PTPRT, a tyrosine phosphatase receptor involved in STAT3 pathway and several other genes whose biological functions are relevant in malaria infection. Results shows that GWAS on non-severe malaria can successfully identify new candidate genes and inform physiological mechanisms underlying natural protection against malaria.

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First genome-wide association study of non-severe malaria in two birth cohorts in Benin

Human Genetics ◽

10.1007/s00439-019-02079-5 ◽

2019 ◽

Vol 138 (11-12) ◽

pp. 1341-1357 ◽

Cited By ~ 3

Author(s):

Jacqueline Milet ◽

Anne Boland ◽

Pierre Luisi ◽

Audrey Sabbagh ◽

Ibrahim Sadissou ◽

...

Keyword(s):

Association Study ◽

Severe Malaria ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Birth Cohorts ◽

Genome Wide

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Genome-wide association study indicates two novel resistance loci for severe malaria

Nature ◽

10.1038/nature11334 ◽

2012 ◽

Vol 489 (7416) ◽

pp. 443-446 ◽

Cited By ~ 148

Author(s):

Christian Timmann ◽

Thorsten Thye ◽

Maren Vens ◽

Jennifer Evans ◽

Jürgen May ◽

...

Keyword(s):

Association Study ◽

Severe Malaria ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide

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Inflammation and JNK's Role in Niacin-GPR109A Diminished Flushed Effect in Microglial and Neuronal Cells With Relevance to Schizophrenia

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.771144 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sabrina H. Ansarey

Keyword(s):

Inflammatory Mediators ◽

Neuronal Death ◽

Microglial Activation ◽

Negative Symptoms ◽

Genome Wide Association Study ◽

Genetic Mutation ◽

Genome Wide ◽

Ultra High Risk ◽

Altered Proteins

Schizophrenia is a neuropsychiatric illness with no single definitive aetiology, making its treatment difficult. Antipsychotics are not fully effective because they treat psychosis rather than the cognitive or negative symptoms. Antipsychotics fail to alleviate symptoms when patients enter the chronic stage of illness. Topical application of niacin showed diminished skin flush in the majority of patients with schizophrenia compared to the general population who showed flushing. The niacin skin flush test is useful for identifying patients with schizophrenia at their ultra-high-risk stage, and understanding this pathology may introduce an effective treatment. This review aims to understand the pathology behind the diminished skin flush response, while linking it back to neurons and microglia. First, it suggests that there are altered proteins in the GPR109A-COX-prostaglandin pathway, inflammatory imbalance, and kinase signalling pathway, c-Jun N-terminal kinase (JNK), which are associated with diminished flush. Second, genes from the GPR109A-COX-prostaglandin pathway were matched against the 128-loci genome wide association study (GWAS) for schizophrenia using GeneCards, suggesting that G-coupled receptor-109A (GPR109A) may have a genetic mutation, resulting in diminished flush. This review also suggests that there may be increased pro-inflammatory mediators in the GPR109A-COX-prostaglandin pathway, which contributes to the diminished flush pathology. Increased levels of pro-inflammatory markers may induce microglial-activated neuronal death. Lastly, this review explores the role of JNK on pro-inflammatory mediators, proteins in the GPR109A-COX-prostaglandin pathway, microglial activation, and neuronal death. Inhibiting JNK may reverse the changes observed in the diminished flush response, which might make it a good therapeutic target.

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The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

Science Advances ◽

10.1126/sciadv.abb3063 ◽

2020 ◽

Vol 6 (43) ◽

pp. eabb3063

Author(s):

Wei Xu ◽

Si-Da Han ◽

Can Zhang ◽

Jie-Qiong Li ◽

Yan-Jiang Wang ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Genome Wide Association Study ◽

In Vitro Study ◽

Genome Wide ◽

A Genome ◽

Increased Risk ◽

Pathophysiological Role ◽

Independent Cohort

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10−12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

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Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture

Arthritis & Rheumatology ◽

10.1002/art.39504 ◽

2016 ◽

Vol 68 (4) ◽

pp. 932-943 ◽

Cited By ~ 67

Author(s):

Marta E. Alarcón-Riquelme ◽

Julie T. Ziegler ◽

Julio Molineros ◽

Timothy D. Howard ◽

Andrés Moreno-Estrada ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Association Study ◽

Lupus Erythematosus ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Systemic Lupus ◽

Genome Wide

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ESR1, WT1, WNT4, ATM and TERT loci are major contributors to uterine leiomyoma predisposition

10.1101/291237 ◽

2018 ◽

Author(s):

Niko Välimäki ◽

Heli Kuisma ◽

Annukka Pasanen ◽

Oskari Heikinheimo ◽

Jari Sjöberg ◽

...

Keyword(s):

Estrogen Receptor Alpha ◽

Genome Wide Association Study ◽

Benign Tumors ◽

Risk Alleles ◽

Estrogen Exposure ◽

Genome Wide ◽

A Genome ◽

Genetic Level ◽

Genomic Risk

ABSTRACTUterine leiomyomas (ULs) are benign tumors that are a major burden to women’s health. A genome-wide association study on 5,417 UL cases and 331,791 controls was performed, followed by replication of the genomic risk in two cohorts. Effects of the identified risk alleles were evaluated in view of molecular and clinical features.Five loci displayed a genome-wide significant association; the previously reported TNRC6B, and four novel loci ESR1 (ERα), WT1, WNT4, and ATM. The sixth hit TERT is also a conceivable target. The combined polygenic risk contributed by these loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis. While the fundamental role of sex hormones in UL aetiology has been clear, this work reveals a connection to estrogen receptor alpha on genetic level and suggests that determinants of UL growth associated with estrogen exposure have an inherited component.

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Genomic and functional gene studies suggest a key role of beta-carotene oxygenase 1 like (bco1l) gene in salmon flesh color

10.1101/821652 ◽

2019 ◽

Author(s):

Hanna Helgeland ◽

Marte Sodeland ◽

Nina Zoric ◽

Jacob Seilø Torgersen ◽

Fabian Grammes ◽

...

Keyword(s):

Genome Wide Association Study ◽

Beta Carotene ◽

Color Variation ◽

Flesh Color ◽

Functional Studies ◽

Genetic Components ◽

Genome Wide ◽

A Genome ◽

Mrna And Protein Expression

AbstractRed coloration of muscle tissue (flesh) is a unique trait in several salmonid genera, including Atlantic salmon. The color results from dietary carotenoids deposited in the flesh, whereas the color intensity is affected both by diet and genetic components. Herein we report on a genome-wide association study (GWAS) to identify genetic variation underlying this trait. Two SNPs on ssa26 showed strong associations to the flesh color in salmon. Two genes known to be involved in carotenoid metabolism were located in this QTL-region: beta-carotene oxygenase 1 (bco1) and beta-carotene oxygenase 1 like (bco1l). To determine whether flesh color variation is caused by one, or both, of these genes, several functional studies were carried out including mRNA and protein expression in fish with red and pale flesh color. The catalytic abilities of these two genes were also tested with different carotenoids. Our results suggest bco1l to be the most likely gene to explain the flesh color variation observed in this population.

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Genome-wide heritability analysis of severe malaria susceptibility and resistance reveals evidence of polygenic inheritance

10.1101/649095 ◽

2019 ◽

Author(s):

Delesa Damena ◽

Emile R. Chimusa

Keyword(s):

Severe Malaria ◽

Genome Wide Association Study ◽

Summary Statistics ◽

Cell Type ◽

Protein Coding ◽

Polygenic Inheritance ◽

Genome Wide ◽

Cell Type Specific ◽

Malaria Susceptibility ◽

Susceptibility And Resistance

ABSTRACTObjectiveEstimating SNP-heritability (h2g) of severe malaria/resistance and its distribution across the genome might shed new light in to the underlying biology.MethodWe investigated h2g of severe malaria susceptibility and resistance from genome-wide association study (GWAS) dataset (sample size =11, 657). We partitioned the h2g in to chromosomes, allele frequencies and annotations. We further examined none-cell type specific and cell type specific enrichments from GWAS-summary statistics.ResultsWe estimated the h2g of severe malaria at 0.21 (se=0.05, p=2.7×10−5), 0.20 (se =0.05, p=7.5×10−5) and 0.17 (se =0.05, p= 7.2×10−4) in Gambian, Kenyan and Malawi populations, respectively. The h2g attributed to the GWAS significant SNPs and the well-known sickle cell (HbS) variant was approximately 0.07 and 0.03, respectively. We prepared African population reference panel and obtained comparable h2g estimate (0.21 (se = 0.02, p< 1×10−5)) from GWAS-summary statistics meta-analysed across the three populations. Partitioning analysis from raw genotype data showed significant enrichment of h2g in protein coding genic SNPs while summary statistics analysis suggests pattern of enrichment in multiple categories.ConclusionWe report for the first time that the heritability of malaria susceptibility and resistance is largely ascribed by common SNPs and the causal variants are overrepresented in protein coding regions of the genome. Overall, our results suggest that malaria susceptibility and resistance is a polygenic trait. Further studies with larger sample sizes are needed to better understand the underpinning genetics of resistance and susceptibility to severe malaria.

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ANGI — Anorexia Nervosa Genetics Initiative

Twin Research and Human Genetics ◽

10.1017/thg.2020.24 ◽

2020 ◽

Vol 23 (2) ◽

pp. 135-136

Author(s):

Cynthia Bulik ◽

Martin Kennedy ◽

Tracey Wade

Keyword(s):

Anorexia Nervosa ◽

Genetic Variants ◽

Large Scale ◽

Genome Wide Association Study ◽

Genetic Correlations ◽

Genome Wide Association ◽

Life Threatening Illness ◽

Genome Wide ◽

Life Threatening

AbstractIdentification of genetic variants associated with eating disorders is underway. The Anorexia Nervosa Genetics Initiative, an initiative of the Klarman Family Foundation, has contributed to advancing the field, yielding a large-scale genome-wide association study published in Nature Genetics. Eight genetic variants significantly associated with anorexia nervosa were identified, along with patterns of genetic correlations that suggest both psychiatric and metabolic origins of this serious and life-threatening illness. This article details the role of Professor Nick Martin in contributing to this important collaboration.

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Genomic and functional gene studies suggest a key role of beta-carotene oxygenase 1 like (bco1l) gene in salmon flesh color

Scientific Reports ◽

10.1038/s41598-019-56438-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Hanna Helgeland ◽

Marte Sodeland ◽

Nina Zoric ◽

Jacob Seilø Torgersen ◽

Fabian Grammes ◽

...

Keyword(s):

Genome Wide Association Study ◽

Beta Carotene ◽

Color Variation ◽

Flesh Color ◽

Functional Studies ◽

Genetic Components ◽

Genome Wide ◽

A Genome ◽

Mrna And Protein Expression

AbstractRed coloration of muscle tissue (flesh) is a unique trait in several salmonid genera, including Atlantic salmon. The color results from dietary carotenoids deposited in the flesh, whereas the color intensity is affected both by diet and genetic components. Herein we report on a genome-wide association study (GWAS) to identify genetic variation underlying this trait. Two SNPs on ssa26 showed strong associations to the flesh color in salmon. Two genes known to be involved in carotenoid metabolism were located in this QTL- region: beta-carotene oxygenase 1 (bco1) and beta-carotene oxygenase 1 like (bco1l). To determine whether flesh color variation is caused by one, or both, of these genes, functional studies were carried out including mRNA and protein expression in fish with red and pale flesh color. The catalytic abilities of these two genes were also tested with different carotenoids. Our results suggest bco1l to be the most likely gene to explain the flesh color variation observed in this population.

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