Surrogate phenotype definition for alcohol use disorders: a genome-wide search for linkage and association

AbstractAlcohol use during emerging adulthood is associated with adverse life outcomes but its risk factors are not well known. Here, we predicted alcohol use in 3,153 young adults aged 22 years from (a) genome-wide polygenic scores (GPS) based on genome-wide association studies for the target phenotypes number of drinks per week and Alcohol Use Disorders Identification Test scores, (b) 30 environmental factors, and (c) their interactions (i.e., GxE effects). Data was collected from 1994 to 2018 as a part of the UK Twins Early Development Study. GPS accounted for up to 1.9% of the variance in alcohol use (i.e., Alcohol Use Disorders Identification Test score), while the 30 measures of environmental factors together accounted for 21.1%. The 30 GPS-environment interactions did not explain any additional variance and none of the interaction terms exceeded the significance threshold after correcting for multiple testing. Our findings suggest that GPS and environmental factors have primarily direct, additive effects rather than interacting systematically.

Download Full-text

Epigenome-Wide Study Identified Methylation Sites Associated with the Risk of Obesity

Nutrients ◽

10.3390/nu13061984 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1984

Author(s):

Majid Nikpay ◽

Sepehr Ravati ◽

Robert Dent ◽

Ruth McPherson

Keyword(s):

Quantitative Trait Locus ◽

Quantitative Trait ◽

Rare Variants ◽

Genome Wide ◽

A Genome ◽

Genome Wide Search ◽

Risk Snps ◽

Trait Locus ◽

Genomic Regions ◽

Eqtl Data

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3, whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11. Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC, ADCY3 and DNAJC27. In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.

Download Full-text

A Genome-Wide Search For Susceptibility Loci to Human Essential Hypertension

Hypertension ◽

10.1161/01.hyp.35.6.1291 ◽

2000 ◽

Vol 35 (6) ◽

pp. 1291-1296 ◽

Cited By ~ 40

Author(s):

Pankaj Sharma ◽

Jennie Fatibene ◽

Franco Ferraro ◽

Haiyan Jia ◽

Sue Monteith ◽

...

Keyword(s):

Essential Hypertension ◽

Susceptibility Loci ◽

Genome Wide ◽

A Genome ◽

Genome Wide Search

Download Full-text

Genome-Wide Prediction of Coaxial Helical Stacking Using Random Forests and Covariance Models

International Journal of Artificial Intelligence Tools ◽

10.1142/s0218213014600082 ◽

2014 ◽

Vol 23 (03) ◽

pp. 1460008

Author(s):

Kevin Byron ◽

Jason T. L. Wang ◽

Dongrong Wen

Keyword(s):

Random Forests ◽

Life Science ◽

Science Research ◽

Genomic Region ◽

Computational Approach ◽

Search Method ◽

Genome Wide ◽

A Genome ◽

Genome Wide Search ◽

Covariance Models

Developing effective artificial intelligence tools to find motifs in DNA, RNA and proteins poses a challenging yet important problem in life science research. In this paper, we present a computational approach for finding RNA tertiary motifs in genomic sequences. Specifically, we predict genomic coordinate locations for coaxial helical stackings in 3-way RNA junctions. These predictions are provided by our tertiary motif search package, named CSminer, which utilizes two versatile methodologies: random forests and covariance models. A coaxial helical stacking tertiary motif occurs in a 3-way RNA junction where two separate helical elements form a pseudocontiguous helix and provide thermodynamic stability to the RNA molecule as a whole. Our CSminer tool first uses a genome-wide search method based on covariance models to find a genomic region that may potentially contain a coaxial helical stacking tertiary motif. CSminer then uses a random forests classifier to predict whether the genomic region indeed contains the tertiary motif. Experimental results demonstrate the effectiveness of our approach.

Download Full-text

Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5

Blood ◽

10.1182/blood-2007-07-104133 ◽

2008 ◽

Vol 111 (3) ◽

pp. 1217-1226 ◽

Cited By ~ 317

Author(s):

Yun Chen ◽

David H. Gorski

Keyword(s):

Binding Sites ◽

Untranslated Region ◽

Vascular Endothelial Cells ◽

Homeobox Gene ◽

Vascular Endothelial ◽

Down Regulation ◽

Antiangiogenic Activity ◽

Genome Wide ◽

A Genome ◽

Genome Wide Search

Abstract Angiogenesis is critical to tumor progression. The homeobox gene GAX inhibits angiogenesis in vascular endothelial cells (ECs). We have identified a microRNA (miR-130a) that regulates GAX expression and hypothesized that it plays a major role in modulating GAX activity in ECs. A 280-bp fragment from the GAX 3′-untranslated region (3′-UTR) containing 2 miR-130a targeting sites was observed to be required for the rapid down-regulation of GAX expression by serum and proangiogenic factors, whereas the activity of the GAX promoter did not vary with exposure to serum or proangiogenic factors. This same 280-bp sequence in the GAX 3′-UTR cloned into the psiCHECK2-Luciferase vector mediated serum-induced down-regulation of the reporter gene when placed 3′ of it. Finally, forced expression of miR-130a inhibits GAX expression through this specific GAX 3′-UTR sequence. A genome-wide search for other possible miR-130a binding sites revealed an miR-130a targeting site in the 3′-UTR of the antiangiogenic homeobox gene HOXA5, the expression and antiangiogenic activity of which are also inhibited by miR-130a. From these data, we conclude that miR-130a is a regulator of the angiogenic phenotype of vascular ECs largely through its ability to modulate the expression of GAX and HOXA5.

Download Full-text

Combining in silico prediction and ribosome profiling in a genome-wide search for novel putatively coding sORFs

BMC Genomics ◽

10.1186/1471-2164-14-648 ◽

2013 ◽

Vol 14 (1) ◽

pp. 648 ◽

Cited By ~ 58

Author(s):

Jeroen Crappé ◽

Wim Van Criekinge ◽

Geert Trooskens ◽

Eisuke Hayakawa ◽

Walter Luyten ◽

...

Keyword(s):

In Silico ◽

Ribosome Profiling ◽

In Silico Prediction ◽

Genome Wide ◽

A Genome ◽

Genome Wide Search

Download Full-text

Item-Level Genome-Wide Association Study of the Alcohol Use Disorders Identification Test in Three Population-Based Cohorts

American Journal of Psychiatry ◽

10.1176/appi.ajp.2020.20091390 ◽

2021 ◽

pp. appi.ajp.2020.2

Author(s):

Travis T. Mallard ◽

Jeanne E. Savage ◽

Emma C. Johnson ◽

Yuye Huang ◽

Alexis C. Edwards ◽

...

Keyword(s):

Alcohol Use ◽

Association Study ◽

Genome Wide Association Study ◽

Alcohol Use Disorders ◽

Population Based ◽

Genome Wide Association ◽

Genome Wide ◽

Item Level ◽

Identification Test

Download Full-text

Posttraumatic psychopathology and the pace of the epigenetic clock: a longitudinal investigation

Psychological Medicine ◽

10.1017/s0033291718001411 ◽

2018 ◽

Vol 49 (5) ◽

pp. 791-800 ◽

Cited By ~ 14

Author(s):

Erika J. Wolf ◽

Mark W. Logue ◽

Filomene G. Morrison ◽

Elizabeth S. Wilcox ◽

Annjanette Stone ◽

...

Keyword(s):

Dna Methylation ◽

Alcohol Use ◽

Psychiatric Symptoms ◽

Alcohol Use Disorders ◽

Cellular Aging ◽

Epigenetic Clock ◽

Afghanistan War ◽

Genome Wide ◽

Dna Methylation Age ◽

Over Time

AbstractBackgroundPosttraumatic stress disorder (PTSD) and stress/trauma exposure are cross-sectionally associated with advanced DNA methylation age relative to chronological age. However, longitudinal inquiry and examination of associations between advanced DNA methylation age and a broader range of psychiatric disorders is lacking. The aim of this study was to examine if PTSD, depression, generalized anxiety, and alcohol-use disorders predicted acceleration of DNA methylation age over time (i.e. an increasing pace, or rate of advancement, of the epigenetic clock).MethodsGenome-wide DNA methylation and a comprehensive set of psychiatric symptoms and diagnoses were assessed in 179 Iraq/Afghanistan war veterans who completed two assessments over the course of approximately 2 years. Two DNA methylation age indices (Horvath and Hannum), each a weighted index of an array of genome-wide DNA methylation probes, were quantified. The pace of the epigenetic clock was operationalized as change in DNA methylation age as a function of time between assessments.ResultsAnalyses revealed that alcohol-use disorders (p = 0.001) and PTSD avoidance and numbing symptoms (p = 0.02) at Time 1 were associated with an increasing pace of the epigenetic clock over time, per the Horvath (but not the Hannum) index of cellular aging.ConclusionsThis is the first study to suggest that posttraumatic psychopathology is longitudinally associated with a quickened pace of the epigenetic clock. Results raise the possibility that accelerated cellular aging is a common biological consequence of stress-related psychopathology, which carries implications for identifying mechanisms of stress-related cellular aging and developing interventions to slow its pace.

Download Full-text