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Search Results for all work with filters:

  • Almli, Lynn
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Work 1-10 of 10

Sorted by relevance

Article

Prioritizing individual genetic variants after kernel machine testing using variable selection

by Qianchuan He; Tianxi Cai; Yan Liu; Ni Zhao; Quaker E. Harmon; Lynn Almli; Elisabeth Binder; Stephanie M. Engel; Kerry Ressler; Karen Conneely; Xihong Lin; Michael C. Wu

2016

Subjects
  • Biology, Genetics
  • Health Sciences, Public Health
  • Health Sciences, Epidemiology
  • File Download
  • View Abstract

Abstract:Close

Kernel machine learning methods, such as the SNP-set kernel association test (SKAT), have been widely used to test associations between traits and genetic polymorphisms. In contrast to traditional single-SNP analysis methods, these methods are designed to examine the joint effect of a set of related SNPs (such as a group of SNPs within a gene or a pathway) and are able to identify sets of SNPs that are associated with the trait of interest. However, as with many multi-SNP testing approaches, kernel machine testing can draw conclusion only at the SNP-set level, and does not directly inform on which one(s) of the identified SNP set is actually driving the associations. A recently proposed procedure, KerNel Iterative Feature Extraction (KNIFE), provides a general framework for incorporating variable selection into kernel machine methods. In this article, we focus on quantitative traits and relatively common SNPs, and adapt the KNIFE procedure to genetic association studies and propose an approach to identify driver SNPs after the application of SKAT to gene set analysis. Our approach accommodates several kernels that are widely used in SNP analysis, such as the linear kernel and the Identity by State (IBS) kernel. The proposed approach provides practically useful utilities to prioritize SNPs, and fills the gap between SNP set analysis and biological functional studies. Both simulation studies and real data application are used to demonstrate the proposed approach.

Article

DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression

by Aliza Wingo; Lynn Almli; Jennifer J. Stevens; Torsten Klengel; Monica Uddin; Yujing Li; Angela C. Bustamante; Adriana Lori; Nastassja Koen; Dan J. Stein; Alicia Smith; Allison E. Aiello; Karestan C. Koenen; Derek E. Wildman; Sandro Galea; Bekh Bradley-Davino; Elisabeth Binder; Peng Jin; Greg Gibson; Kerry Ressler

2015

Subjects
  • Psychology, General
  • Psychology, Behavioral
  • File Download
  • View Abstract

Abstract:Close

DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.

Article

Oxytocin Receptor Genetic and Epigenetic Variations: Association With Child Abuse and Adult Psychiatric Symptoms

by Erica L. Smearman; Lynn Almli; Karen Conneely; Gene H. Brody; Jessica Sales; Bekh Bradley-Davino; Kerry Ressler; Alicia Smith

2016

Subjects
  • Biology, Genetics
  • Biology, Neuroscience
  • File Download
  • View Abstract

Abstract:Close

Childhood abuse can alter biological systems and increase risk for adult psychopathology. Epigenetic mechanisms, alterations in DNA structure that regulate the gene expression, are a potential mechanism underlying this risk. While abuse associates with methylation of certain genes, particularly those in the stress response system, no study to date has evaluated abuse and methylation of the oxytocin receptor (OXTR). However, studies support a role for OXTR in the link between abuse and adverse adult outcomes, showing that abuse can confer greater risk for psychiatric symptoms in those with specific OXTR genotypes. This study therefore sought to (a) assess the role of epigenetics in the link between abuse and psychopathology and (b) begin to integrate the genetic and epigenetic literature by exploring associations between OXTR genotypes and DNA CpG methylation. Data on 18 OXTR CpG sites, 44 single nucleotide polymorphisms, childhood abuse, and adult depression and anxiety symptoms were assessed in 393 African American adults (age = 41 ± 12.8 years). Overall, 68% of genotypes were associated with methylation of nearby CpG sites, with a subset surviving multiple test correction. Child abuse associated with higher methylation of two CpG sites yet did not survive correction or serve as a mediator of psychopathology. However, abuse interacted with CpG methylation to predict psychopathology. These findings suggest a role for OXTR in understanding the influence of early environments on adult psychiatric symptoms.

Article

A DNA methylation biomarker of alcohol consumption

by C Liu; RE Marioni; AK Hedman; L Pfeiffer; P-C Tsai; LM Reynolds; AC Just; Q Duan; CG Boer; T Tanaka; CE Elks; S Aslibekyan; JA Brody; B Kuehnel; C Herder; Lynn Almli; D Zhi; Y Wang; T Huan; C Yao; MM Mendelson; R Joehanes; L Liang; S-A Love; W Guan; S Shah; AF Mcrae; A Kretschmer; H Prokisch; K Strauch; A Peters; PM Visscher; NR Wray; X Guo; KL Wiggins; Alicia K Smith; EB Binder; Kerry Ressler; MR Irvin; DM Absher; D Hernandez; L Ferrucci; S Bandinelli; K Lohman; J Ding; L Trevisi; S Gustafsson; JH Sandling; L Stolk; AG Uitterlinden; I Yet; JE Castillo-Fernandez; TD Spector; JD Schwartz; P Vokonas; L Lind; Y Li; M Fornage; DK Arnett; NJ Wareham; N Sotoodehnia; KK Ong; JBJ van Meurs; Karen N Conneely; AA Baccarelli; IJ Deary; JT Bell; KE North; Y Liu; M Waldenberger; SJ London; E Ingelsson; D Levy

2018

Subjects
  • Health Sciences, Epidemiology
  • Health Sciences, Public Health
  • Biology, Genetics
  • File Download
  • View Abstract

Abstract:Close

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (n total = 13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n = 6926) and identified 144 CpGs that provided substantial discrimination (area under the curve = 0.90-0.99) for current heavy alcohol intake (≥42 g per day in men and ≥28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P < 1×10 -7 . Analysis of the monocyte-derived DNA (n = 1251) identified 62 alcohol-related CpGs at P < 1×10 -7 . In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

Article

Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD

by Stephanie A. Maddox; Varun Kilaru; Jaemin Shin; Tanja Jovanovic; Lynn Almli; Brian Dias; Seth Norrholm; Negar Fani; Vasiliki Michopoulos; Ziyu Ding; Karen Conneely; Elisabeth Binder; Kerry Ressler; Alicia K Smith

2017

Subjects
  • Biology, Genetics
  • File Download
  • View Abstract

Abstract:Close

Women are at increased risk of developing post-traumatic stress disorder (PTSD) following a traumatic event. Recent studies suggest that this may be mediated, in part, by circulating estrogen levels. This study evaluated the hypothesis that individual variation in response to estrogen levels contributes to fear regulation and PTSD risk in women. We evaluated DNA methylation from blood of female participants in the Grady Trauma Project and found that serum estradiol levels associates with DNA methylation across the genome. For genes expressed in blood, we examined the association between each CpG site and PTSD diagnosis using linear models that adjusted for cell proportions and age. After multiple test correction, PTSD associated with methylation of CpG sites in the HDAC4 gene, which encodes histone deacetylase 4, and is involved in long-term memory formation and behavior. DNA methylation of HDAC4 CpG sites were tagged by a nearby single-nucleotide polymorphism (rs7570903), which also associated with HDAC4 expression, fear-potentiated startle and resting-state functional connectivity of the amygdala in traumatized humans. Using auditory Pavlovian fear conditioning in a rodent model, we examined the regulation of Hdac4 in the amygdala of ovariectomized (OVX) female mice. Hdac4 messenger RNA levels were higher in the amygdala 2 h after tone-shock presentations, compared with OVX-homecage control females. In naturally cycling females, tone-shock presentations increased Hdac4 expression relative to homecage controls for metestrous (low estrogen) but not the proestrous (high estrogen) group. Together, these results support an estrogenic influence of HDAC4 regulation and expression that may contribute to PTSD in women.

Article

Genome-wide association study of positive emotion identifies a genetic variant and a role for microRNAs

by Aliza Wingo; Lynn Almli; Jennifer S. Stevens; Tanja Jovanovic; Thomas Wingo; Gregory Tharp; Yujing Li; Adriana Lori; Maria Briscione; Peng Jin; Elisabeth Binder; Bekh Bradley-Davino; Greg Gibson; Kerry Ressler

2016

Subjects
  • Biology, Neuroscience
  • Biology, Genetics
  • Psychology, Clinical
  • File Download
  • View Abstract

Abstract:Close

Positive affect denotes a state of pleasurable engagement with the environment eliciting positive emotion such as contentment, enthusiasm or happiness. Positive affect is associated with favorable psychological, physical and economic outcomes in many longitudinal studies. With a heritability of ⩽64%, positive affect is substantially influenced by genetic factors; however, our understanding of genetic pathways underlying individual differences in positive affect is still limited. Here, through a genome-wide association study of positive affect in African-American participants, we identify a single-nucleotide polymorphism, rs322931, significantly associated with positive affect at P<5 × 10-8, and replicate this association in another cohort. Furthermore, we show that the minor allele of rs322931 predicts expression of microRNAs miR-181a and miR-181b in human brain and blood, greater nucleus accumbens reactivity to positive emotional stimuli and enhanced fear inhibition. Prior studies have suggested that miR-181a is part of the reward neurocircuitry. Taken together, we identify a novel genetic variant for further elucidation of genetic underpinning of positive affect that mediates positive emotionality potentially via the nucleus accumbens and miR-181.

Article

Accounting for Population Stratification in DNA Methylation Studies

by Richard T. Barfield; Lynn Almli; Varun Kilaru; Alicia Smith; KristinaB. Mercer; Richard Duncan; Torsten Klengel; Divya Mehta; Elisabeth B. Binder; Karen N Conneely; Michael Epstein; Kerry Ressler

2014

Subjects
  • Biology, Genetics
  • Biology, Biostatistics
  • Psychology, Behavioral
  • File Download
  • View Abstract

Abstract:Close

DNA methylation is an important epigenetic mechanism that has been linked to complex diseases and is of great interest to researchers as a potential link between genome, environment, and disease. As the scale of DNA methylation association studies approaches that of genome-wide association studies, issues such as population stratification will need to be addressed. It is well-documented that failure to adjust for population stratification can lead to false positives in genetic association studies, but population stratification is often unaccounted for in DNA methylation studies. Here, we propose several approaches to correct for population stratification using principal components (PCs) from different subsets of genome-wide methylation data. We first illustrate the potential for confounding due to population stratification by demonstrating widespread associations between DNA methylation and race in 388 individuals (365 African American and 23 Caucasian). We subsequently evaluate the performance of our PC-based approaches and other methods in adjusting for confounding due to population stratification. Our simulations show that (1) all of the methods considered are effective at removing inflation due to population stratification, and (2) maximum power can be obtained with single-nucleotide polymorphism (SNP)-based PCs, followed by methylation-based PCs, which outperform both surrogate variable analysis and genomic control. Among our different approaches to computing methylation-based PCs, we find that PCs based on CpG sites chosen for their potential to proxy nearby SNPs can provide a powerful and computationally efficient approach to adjust for population stratification in DNA methylation studies when genome-wide SNP data are unavailable.

Article

Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder

by V. Kilaru; Shruti Iyer; Lynn Almli; J.S. Stevens; Adriana Lori; Tanja Jovanovic; T.D. Ely; Bekh Bradley-Davino; Elisabeth B. Binder; N. Koen; D.J. Stein; Karen N Conneely; Aliza Wingo; Alicia K Smith; Kerry Ressler

2016

Subjects
  • Biology, Genetics
  • Psychology, Clinical
  • Psychology, Behavioral
  • File Download
  • View Abstract

Abstract:Close

Post-traumatic stress disorder (PTSD) develops in only some people following trauma exposure, but the mechanisms differentially explaining risk versus resilience remain largely unknown. PTSD is heritable but candidate gene studies and genome-wide association studies (GWAS) have identified only a modest number of genes that reliably contribute to PTSD. New gene-based methods may help identify additional genes that increase risk for PTSD development or severity. We applied gene-based testing to GWAS data from the Grady Trauma Project (GTP), a primarily African American cohort, and identified two genes (NLGN1 and ZNRD1-AS1) that associate with PTSD after multiple test correction. Although the top SNP from NLGN1 did not replicate, we observed gene-based replication of NLGN1 with PTSD in the Drakenstein Child Health Study (DCHS) cohort from Cape Town. NLGN1 has previously been associated with autism, and it encodes neuroligin 1, a protein involved in synaptogenesis, learning, and memory. Within the GTP dataset, a single nucleotide polymorphism (SNP), rs6779753, underlying the gene-based association, associated with the intermediate phenotypes of higher startle response and greater functional magnetic resonance imaging activation of the amygdala, orbitofrontal cortex, right thalamus and right fusiform gyrus in response to fearful faces. These findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD.

Article

DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression (vol 6, 10106, 2015)

by Aliza Wingo; Lynn Almli; Alicia Smith; Jennifer Stevens; Torsten Klengel; Monica Uddin; Yujing Li; Angela C. Bustamante; Adriana Lori; Nastassja Koen; Dan J. Stein; Allison E. Aiello; Karestan C. Koenen; Derek E. Wildman; Sandro Galea; Bekh Bradley-Davino; Elisabeth B. Binder; Peng Jin; Greg Gibson; Kerry Ressler

2016

Subjects
  • Psychology, General
  • Psychology, Behavioral
  • File Download
  • View Abstract

Abstract:Close

DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.

Article

Correcting Systematic Inflation in Genetic Association Tests That Consider Interaction Effects Application to a Genome-wide Association Study of Posttraumatic Stress Disorder

by Lynn Almli; Richard Duncan; Hao Feng; Debashis Ghosh; Elisabeth B. Binder; Bekh Bradley-Davino; Kerry Ressler; Karen N Conneely; Michael Epstein

2014

Subjects
  • Health Sciences, Mental Health
  • Biology, Genetics
  • File Download
  • View Abstract

Abstract:Close

IMPORTANCE Genetic association studies of psychiatric outcomes often consider interactions with environmental exposures and, in particular, apply tests that jointly consider gene and gene-environment interaction effects for analysis. Using a genome-wide association study (GWAS) of posttraumatic stress disorder (PTSD), we report that heteroscedasticity (defined as variability in outcome that differs by the value of the environmental exposure) can invalidate traditional joint tests of gene and gene-environment interaction. OBJECTIVES To identify the cause of bias in traditional joint tests of gene and gene-environment interaction in a PTSD GWAS and determine whether proposed robust joint tests are insensitive to this problem. DESIGN, SETTING, AND PARTICIPANTS The PTSD GWAS data set consisted of 3359 individuals (978 men and 2381 women) from the Grady Trauma Project (GTP), a cohort study from Atlanta, Georgia. The GTP performed genome-wide genotyping of participants and collected environmental exposures using the Childhood Trauma Questionnaire and Trauma Experiences Inventory. MAIN OUTCOMES AND MEASURES We performed joint interaction testing of the Beck Depression Inventory and modified PTSD Symptom Scale in the GTP GWAS.We assessed systematic bias in our interaction analyses using quantile-quantile plots and genome-wide inflation factors. RESULTS Application of the traditional joint interaction test to the GTP GWAS yielded systematic inflation across different outcomes and environmental exposures (inflation-factor estimates ranging from 1.07 to 1.21), whereas application of the robust joint test to the same data set yielded no such inflation (inflation-factor estimates ranging from 1.01 to 1.02). Simulated data further revealed that the robust joint test is valid in different heteroscedasticity models, whereas the traditional joint test is invalid. The robust joint test also has power similar to the traditional joint test when heteroscedasticity is not an issue. CONCLUSIONS AND RELEVANCE We believe the robust joint test should be used in candidate-gene studies and GWASs of psychiatric outcomes that consider environmental interactions. To make the procedure useful for applied investigators, we created a software tool that can be called from the popular PLINK package for analysis.
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