Genome-wide association study of cryptosporidiosis in infants implicates PRKCA

AbstractDiarrhea is a major cause of both morbidity and mortality worldwide, especially among young children. Cryptosporidiosis is a leading cause of diarrhea in children, particularly in South Asia and Sub-Saharan Africa where it is responsible for over 200,000 deaths per year. Beyond the initial clinical presentation of diarrhea, it is associated with long term sequelae such as malnutrition and neurocognitive developmental deficits. Risk factors include poverty and overcrowding, yet not all children with these risk factors and exposure are infected, nor do all infected children develop symptomatic disease. One potential risk factor to explain these differences is their human genome. To identify genetic variants associated with symptomatic cryptosporidiosis, we conducted a genome-wide association study (GWAS) examining 6.5 million single nucleotide polymorphisms (SNPs) in 873 children from three independent cohorts in Dhaka, Bangladesh: the Dhaka Birth Cohort (DBC), the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study, and the Cryptosporidiosis Birth Cohort (CBC). Associations were estimated separately for each cohort under an additive model, adjusting for height-for-age Z-score at 12 months of age, the first two principal components to account for population substructure, and genotyping batch. The strongest meta-analytic association was with rs58296998 (P=3.73×10−8), an intronic SNP and eQTL of PRKCA. Each additional risk allele conferred 2.4 times the odds of cryptosporidiosis in the first year of life. This genetic association suggests a role for protein kinase C alpha in pediatric cryptosporidiosis and warrants further investigation. This article was submitted to an online preprint archive.(1)ImportanceGlobally, one of the major causes of pediatric morbidity and mortality remains diarrhea. The initial symptoms of diarrhea can often lead to long term consequences for the health of young children, such as malnutrition and neurocognitive developmental deficits. Despite many children having similar exposures to infectious causes of diarrhea, not all develop symptomatic disease, indicating a possible role for human genetic variation. Here we conducted a genetic study of susceptibility to symptomatic disease associated with Cryptosporidium infection (a leading cause of diarrhea) in three independent cohorts of infants from Dhaka, Bangladesh. We identified a genetic variant within protein kinase c alpha (PRKCA) associated with higher risk of cryptosporidiosis in the first year of life. These results indicate a role for human genetics in susceptibility to cryptosporidiosis and warrant further research to elucidate the mechanism.

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Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates PRKCA

mBio ◽

10.1128/mbio.03343-19 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Genevieve L. Wojcik ◽

Poonum Korpe ◽

Chelsea Marie ◽

Alexander J. Mentzer ◽

Tommy Carstensen ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Genome Wide Association Study ◽

First Year ◽

Symptomatic Disease ◽

Kinase C ◽

Genome Wide ◽

Protein Kinase C Alpha ◽

First Year Of Life

ABSTRACT Diarrhea is a major cause of both morbidity and mortality worldwide, especially among young children. Cryptosporidiosis is a leading cause of diarrhea in children, particularly in South Asia and sub-Saharan Africa, where it is responsible for over 200,000 deaths per year. Beyond the initial clinical presentation of diarrhea, it is associated with long-term sequelae such as malnutrition and neurocognitive developmental deficits. Risk factors include poverty and overcrowding, and yet not all children with these risk factors and exposure are infected, nor do all infected children develop symptomatic disease. One potential risk factor to explain these differences is their human genome. To identify genetic variants associated with symptomatic cryptosporidiosis, we conducted a genome-wide association study (GWAS) examining 6.5 million single nucleotide polymorphisms (SNPs) in 873 children from three independent cohorts in Dhaka, Bangladesh, namely, the Dhaka Birth Cohort (DBC), the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study, and the Cryptosporidiosis Birth Cohort (CBC). Associations were estimated separately for each cohort under an additive model, adjusting for length-for-age Z-score at 12 months of age, the first two principal components to account for population substructure, and genotyping batch. The strongest meta-analytic association was with rs58296998 (P = 3.73 × 10−8), an intronic SNP and expression quantitative trait locus (eQTL) of protein kinase C alpha (PRKCA). Each additional risk allele conferred 2.4 times the odds of Cryptosporidium-associated diarrhea in the first year of life. This genetic association suggests a role for protein kinase C alpha in pediatric cryptosporidiosis and warrants further investigation. IMPORTANCE Globally, diarrhea remains one of the major causes of pediatric morbidity and mortality. The initial symptoms of diarrhea can often lead to long-term consequences for the health of young children, such as malnutrition and neurocognitive developmental deficits. Despite many children having similar exposures to infectious causes of diarrhea, not all develop symptomatic disease, indicating a possible role for human genetic variation. Here, we conducted a genetic study of susceptibility to symptomatic disease associated with Cryptosporidium infection (a leading cause of diarrhea) in three independent cohorts of infants from Dhaka, Bangladesh. We identified a genetic variant within protein kinase C alpha (PRKCA) associated with higher risk of cryptosporidiosis in the first year of life. These results indicate a role for human genetics in susceptibility to cryptosporidiosis and warrant further research to elucidate the mechanism.

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Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia

Haematologica ◽

10.3324/haematol.2020.268565 ◽

2021 ◽

Author(s):

Marion K Mateos ◽

Glenn M Marshall ◽

Pasquale M Barbaro ◽

Michael CJ Quinn ◽

Carly George ◽

...

Keyword(s):

Risk Factors ◽

Acute Lymphoblastic Leukemia ◽

Association Study ◽

Aspartate Aminotransferase ◽

Genome Wide Association Study ◽

Lymphoblastic Leukemia ◽

Genome Wide Association ◽

Genome Wide ◽

Serum Aspartate Aminotransferase

Symptomatic methotrexate-related central neurotoxicity, ‘MTX neurotoxicity’, is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1251 consecutive Australian children enrolled on BFM or COG-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95/1251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, OR 2.31 (1.28–4.16)) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age a10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1174) (P=0.047). Five-year CNS relapsefree survival was 89.2%±4.6% when intrathecal MTX was ceased compared to 95.4%±0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified SNPs associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P>1E-06). In conclusion, increased serum aspartate aminotransferase and age a10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.

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Donor genetic variants as risk factors for thrombosis after liver transplantation: A genome‐wide association study

American Journal of Transplantation ◽

10.1111/ajt.16490 ◽

2021 ◽

Author(s):

Yanni Li ◽

Lianne M. Nieuwenhuis ◽

Michiel D. Voskuil ◽

Ranko Gacesa ◽

Shixian Hu ◽

...

Keyword(s):

Risk Factors ◽

Liver Transplantation ◽

Association Study ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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Population genetics of the coral Acropora millepora: Towards a genomic predictor of bleaching

10.1101/867754 ◽

2019 ◽

Cited By ~ 7

Author(s):

Zachary L. Fuller ◽

Veronique J.L. Mocellin ◽

Luke Morris ◽

Neal Cantin ◽

Jihanne Shepherd ◽

...

Keyword(s):

Genome Wide Association Study ◽

Balancing Selection ◽

Genome Wide Association ◽

Conservation Strategies ◽

Genome Sequences ◽

Acropora Millepora ◽

Genome Wide ◽

A Genome ◽

In The Wild

AbstractAlthough reef-building corals are rapidly declining worldwide, responses to bleaching vary both within and among species. Because these inter-individual differences are partly heritable, they should in principle be predictable from genomic data. Towards that goal, we generated a chromosome-scale genome assembly for the coral Acropora millepora. We then obtained whole genome sequences for 237 phenotyped samples collected at 12 reefs distributed along the Great Barrier Reef, among which we inferred very little population structure. Scanning the genome for evidence of local adaptation, we detected signatures of long-term balancing selection in the heat-shock co-chaperone sacsin. We further used 213 of the samples to conduct a genome-wide association study of visual bleaching score, incorporating the polygenic score derived from it into a predictive model for bleaching in the wild. These results set the stage for the use of genomics-based approaches in conservation strategies.

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Multi-trait genome-wide association study identifies novel endometrial cancer risk loci that are associated with obesity or female testosterone levels

10.1101/2021.08.01.21261455 ◽

2021 ◽

Author(s):

Xuemin Wang ◽

Pik Fang Kho ◽

Dhanya Ramachandran ◽

Cemsel Bafligil ◽

Frederic Amant ◽

...

Keyword(s):

Risk Factors ◽

Endometrial Cancer ◽

Cancer Risk ◽

Association Study ◽

Genome Wide Association Study ◽

Cancer Susceptibility ◽

Genome Wide Association ◽

Endometrial Cancer Risk ◽

Cancer Risk Factors ◽

Genome Wide

We have performed genetic correlation and Mendelian randomization analyses using publicly available genome-wide association study (GWAS) data to identify endometrial cancer risk factors. These and previously established risk factors of endometrial cancer were then included in a multi-trait Bayesian GWAS analysis to detect endometrial cancer susceptibility variants, identifying three novel loci (7q22.1, 8q24.3 and 16q12.2); two of which were replicated in an independent endometrial cancer GWAS dataset. These loci are hypothesized to affect endometrial cancer risk through altered sex-hormone levels or through effects on obesity. Consistent with this hypothesis, several genes with established roles in these pathways (CYP11B1, CYP3A7, IRX3 and IRX5) were prioritized as candidate endometrial cancer risk genes by interrogation of quantitative trait loci data and chromatin capture assays in endometrial cell lines. The findings of this study identify additional opportunities for hormone treatment and further support weight loss to reduce the risk of developing endometrial cancer.

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