scholarly journals Informing disease modelling with brain-relevant functional genomic annotations

Brain ◽  
2019 ◽  
Vol 142 (12) ◽  
pp. 3694-3712 ◽  
Author(s):  
Regina H Reynolds ◽  
John Hardy ◽  
Mina Ryten ◽  
Sarah A Gagliano Taliun
Keyword(s):  
Genetic Association ◽  
Association Studies ◽  
Therapeutic Targets ◽  
Genome Wide Association ◽  
Disease Modelling ◽  
Genome Wide Association Studies ◽  
Functional Genomic ◽  
Genome Wide ◽  
Neuropsychiatric Diseases ◽  
Association Data

How can we best translate the success of genome-wide association studies for neurological and neuropsychiatric diseases into therapeutic targets? Reynolds et al. critically assess existing brain-relevant functional genomic annotations and the tools available for integrating such annotations with summary-level genetic association data.

Efficient estimation of disease odds ratios for follow-up genetic association studies

2017 ◽  
Vol 28 (7) ◽  
pp. 1927-1941
Author(s):  
Jiyuan Hu ◽  
Wei Zhang ◽  
Xinmin Li ◽  
Dongdong Pan ◽  
Qizhai Li
Keyword(s):  
Genetic Association ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Efficient Estimation ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Odds Ratios ◽  
Genome Wide ◽  
Follow Up Studies

In the past decade, genome-wide association studies have identified thousands of susceptible variants associated with complex human diseases and traits. Conducting follow-up genetic association studies has become a standard approach to validate the findings of genome-wide association studies. One problem of high interest in genetic association studies is to accurately estimate the strength of the association, which is often quantified by odds ratios in case-control studies. However, estimating the association directly by follow-up studies is inefficient since this approach ignores information from the genome-wide association studies. In this article, an estimator called GFcom, which integrates information from genome-wide association studies and follow-up studies, is proposed. The estimator includes both the point estimate and corresponding confidence interval. GFcom is more efficient than competing estimators regarding MSE and the length of confidence intervals. The superiority of GFcom is particularly evident when the genome-wide association study suffers from severe selection bias. Comprehensive simulation studies and applications to three real follow-up studies demonstrate the performance of the proposed estimator. An R package, “GFcom”, implementing our method is publicly available at https://github.com/JiyuanHu/GFcom .

scholarly journals Multivariate genome-wide association studies on the tissue compartments of human brain identify novel loci underpinning brain development and neuropsychiatric outcomes.

2021 ◽  
Author(s):  
Chun Chieh Fan ◽  
Robert Loughnan ◽  
Diliana Pechva ◽  
Chi-Hua Chen ◽  
Donald Hagler ◽  
...  
Keyword(s):  
Human Brain ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Risk Tolerance ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Imaging Features ◽  
Genome Wide ◽  
Neuropsychiatric Diseases ◽  
Tissue Compartments

It is important to understand the molecular determinants for microstructures of human brain. However, past genome-wide association studies (GWAS) on microstructures of human brain have had limited results due to methodological constraints. Here, we adopt advanced imaging processing methods and multivariate GWAS on two large scale imaging genetic datasets (UK Biobank and Adolescent Brain Cognitive Development study) to identify and validate key genetic association signals. We discovered 503 unique genetic loci that explained more than 50% of the average heritability across imaging features sensitive to tissue compartments. The genome-wide signals are strongly overlapped with neuropsychiatric diseases, cognitive functions, risk tolerance, and immune responses. Our results implicate the shared molecular mechanisms between tissue microstructures of brain and neuropsychiatric outcomes with astrocyte involvement in the early developmental stage.

scholarly journals Coverage Rate of ADME Genes: Application to CYP2C8, CYP2D6 and CYP3A Genes for Personalized Chloroquine Treatment Against Coronavirus

2020 ◽  
Author(s):  
Nabil Zaid ◽  
Loubna Khalki ◽  
Imane Hadri ◽  
Jihane Toughza ◽  
Oussama Badad ◽  
...  
Keyword(s):  
Drug Response ◽  
Statistical Data ◽  
Association Studies ◽  
Therapeutic Targets ◽  
Coverage Rate ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Chloroquine Treatment ◽  
New Therapeutic Targets

Abstract Background: The latest studies have shown the effectiveness of Chloroquine against Coronavirus. However, since the tolerance and effectiveness of statistical data must be taken into account before proposing treatment to a patient, these promising results are often lacking.Since the CYP2C8, CYP2D6 and CYP3A Absorption, Distribution, Metabolism and Elimination (ADME) genes are involved in the drug response of Chloroquine, we are interested in studying the variations of these genes.Methods: The purpose of this study is to make a comparison between the various current genotyping and enrichment platforms, to know which of them allows the best coverage. Conclusions: This will allow us to carry out genome-wide association studies (GWAS) with the aim of finding new therapeutic targets against Coronavirus using Chloroquine.

scholarly journals Sample Reproducibility of Genetic Association Using Different Multimarker TDTs in Genome-Wide Association Studies: Characterization and a New Approach

PLoS ONE ◽  
2012 ◽  
Vol 7 (2) ◽  
pp. e29613 ◽  
Author(s):  
Mara M. Abad-Grau ◽  
Nuria Medina-Medina ◽  
Rosana Montes-Soldado ◽  
Fuencisla Matesanz ◽  
Vineet Bafna
Keyword(s):  
Genetic Association ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
New Approach ◽  
Genome Wide

scholarly journals CCR1 regulatory variants linked to pulmonary macrophage recruitment in severe COVID-19

2021 ◽  
Author(s):  
Bernard Stikker ◽  
Grégoire Stik ◽  
Rudi Hendriks ◽  
Ralph Stadhouders
Keyword(s):  
Genetic Association ◽  
Chemokine Receptor ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Regulatory Regions ◽  
Regulatory Variants ◽  
Genome Wide ◽  
Monocytes And Macrophages ◽  
Mechanistic Basis

AbstractGenome-wide association studies have identified 3p21.31 as the main risk locus for severe symptoms and hospitalization in COVID-19 patients. To elucidate the mechanistic basis of this genetic association, we performed a comprehensive epigenomic dissection of the 3p21.31 locus. Our analyses pinpoint activating variants in regulatory regions of the chemokine receptor-encoding CCR1 gene as potentially pathogenic by enhancing infiltration of monocytes and macrophages into the lungs of patients with severe COVID-19.

scholarly journals Integrative analysis of genome-wide association studies identifies novel loci associated with neuropsychiatric disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xueming Yao ◽  
Joseph T. Glessner ◽  
Junyi Li ◽  
Xiaohui Qi ◽  
Xiaoyuan Hou ◽  
...  
Keyword(s):  
Association Studies ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Genetic Components ◽  
Genome Wide ◽  
Neuropsychiatric Diseases

AbstractNeuropsychiatric disorders, such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), bipolar disorder (BIP), and major depressive disorder (MDD) share common clinical presentations, suggesting etiologic overlap. A substantial proportion of SNP-based heritability for neuropsychiatric disorders is attributable to genetic components, and genome-wide association studies (GWASs) focusing on individual diseases have identified multiple genetic loci shared between these diseases. Here, we aimed at identifying novel genetic loci associated with individual neuropsychiatric diseases and genetic loci shared by neuropsychiatric diseases. We performed multi-trait joint analyses and meta-analysis across five neuropsychiatric disorders based on their summary statistics from the Psychiatric Genomics Consortium (PGC), and further carried out a replication study of ADHD among 2726 cases and 16299 controls in an independent pediatric cohort. In the multi-trait joint analyses, we found five novel genome-wide significant loci for ADHD, one novel locus for BIP, and ten novel loci for MDD. We further achieved modest replication in our independent pediatric dataset. We conducted fine-mapping and functional annotation through an integrative multi-omics approach and identified causal variants and potential target genes at each novel locus. Gene expression profile and gene-set enrichment analysis further suggested early developmental stage expression pattern and postsynaptic membrane compartment enrichment of candidate genes at the genome-wide significant loci of these neuropsychiatric disorders. Therefore, through a multi-omics approach, we identified novel genetic loci associated with the five neuropsychiatric disorders which may help to better understand the underlying molecular mechanism of neuropsychiatric diseases.

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