Problematic alcohol use associates with sodium channel and clathrin linker 1 (<i>SCLT1</i>) in trauma‐exposed populations

Almli, Lynn M.; Lori, Adriana; Meyers, Jacquelyn L.; Shin, Jaemin; Fani, Negar; Maihofer, Adam X.; Nievergelt, Caroline M.; Smith, Alicia K.; Mercer, Kristina B.; Kerley, Kimberly; Leveille, Jennifer M.; Feng, Hao; Abu‐Amara, Duna; Flory, Janine D.; Yehuda, Rachel; Marmar, Charles R.; Baker, Dewleen G.; Bradley, Bekh; Koenen, Karestan C.; Conneely, Karen N.; Ressler, Kerry J.

doi:10.1111/adb.12569

Cited by 10 publications

(12 citation statements)

References 108 publications

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“…14 decreased in post-mortem frontal cortex of alcoholics (Liu et al, 2007). CHL1 (cell adhesion molecule L1 like) was associated with response to trauma and total AUDIT score (Almli et al, 2017) and decreased in post-mortem frontal cortex (Liu et al, 2007).…”

Section: Accepted Manuscriptmentioning

confidence: 95%

Ethanol activates immune response in lymphoblastoid cells

McClintick

Tischfield

Deng

et al. 2019

Alcohol

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The short-term effects of alcohol on gene expression in brain tissue cannot directly be studied in humans. Because neuroimmune signaling is altered by alcohol, immune cells are a logical, accessible choice to study and might provide biomarkers. RNAseq was used to study the effects of 48 h exposure to ethanol on lymphoblastoid cell lines (LCLs) from 20 alcoholics and 20 controls. Ethanol exposure resulted in differential expression of 4,456 of the 12,503 genes detectably expressed in the LCLs (FDR ≤ 0.05); 52% of these showed increased expression. Cells from alcoholics and controls responded similarly. The genes whose expression changed fell into many pathways: NFκB, neuroinflammation, IL6, IL2, IL8, and dendritic cell maturation pathways were activated, consistent with increased signaling by NFκB, TNF, IL1, IL4, IL18, TLR4, and LPS. Signaling by Interferons A and B decreased, as did EIF2 signaling, phospholipase C signaling and Glycolysis. Baseline gene expression patterns were similar in LCLs from alcoholics and controls. At relaxed stringency (p<0.05), 465 genes differed, 230 of which were also affected by ethanol. There was a suggestion of compensation because baseline differences (no ethanol) were in the opposite direction of differences due to ethanol exposure in 78% of these genes. Pathways with IL8, phospholipase C, and α-adrenergic signaling were significant. The pattern of expression was consistent with increased signaling by several cytokines including interferons, TLR2 and TLR3 in alcoholics. Expression of genes in the cholesterol biosynthesis pathway, including the ratelimiting enzyme HMGCR, was lower in alcoholics. LCLs show many effects of ethanol exposure, some of which might provide biomarkers for alcohol use disorders. Identifying genes and pathways altered by ethanol can aid in interpreting

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Section: Accepted Manuscriptmentioning

confidence: 95%

Ethanol activates immune response in lymphoblastoid cells

McClintick

Tischfield

Deng

et al. 2019

Alcohol

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“…See reference for details. [106][107][108] This is a multi-site study that ran through NYUMC and Stanford University and Palo Alto VAMC. The VA Palo Alto Health Care System has an affiliation with Stanford University School of Medicine.…”

Section: Cohen Veterans Center Study (Com1; Supplementary Table 1 #50)mentioning

confidence: 99%

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Nievergelt

Klengel

et al. 2018

Preprint

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Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson's Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.Comparability of PGC2 studies PGC2 compiled the largest collection of global PTSD GWAS to date, with subjects recruited from both clinically deeply characterized, small patient groups and large cohorts with self-reported PTSD symptoms. We did not restrict the type of trauma subjects were exposed to, and trauma included both civilian and/or military events, often with pre-existing exposure to childhood trauma. To evaluate the comparability of these phenotypically heterogeneous studies we first estimated genetic correlations with LDSC, 15 a method that leverages GWAS summary results, the only data type available to PGC-PTSD for several of the larger military and non-US cohorts. We found significant genetic correlations (r g ) between studies using a cross-validation approach including all PGC2 EUA subjects (10 runs with studies randomly placed into 2 groups; mean r g = 0.56, mean SE = 0.23, mean p = 0.029, Supplementary Table 8).Next, additional analyses on the UK Biobank cohort (UKBB) were performed. This cohort comprises a very large proportion of the data, with almost as many EUA cases as the rest of the EUA PGC2 combined (referred to as PGC1.5). PTSD screening in UKBB was based on self-reported symptoms from a mental health survey. 16 We found a considerable genetic correlation between the UKBB and PGC1.5 EUA subjects (r g = 0.73, SE = 0.21, p = 0.0005; Supplementary Table 9). Further, sensitivity analyses in the UKBB using 3 alternative inclusion criteria for PTSD cases and controls showed stable correlations with PGC1.5 (P1 -P3; r g = 0.72 -0.79; Supplementary Table 10). Subsequent analyses were based on the UKBB phenotype including the largest number of subjects (P1; N = 126,188). Sex-stratified genetic correlations support the findings of a significant genetic signal...

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Section: Blood Mqtls Are Highly Replicable In An Independent Dataset mentioning

confidence: 99%

“…To evaluate whether our blood mQTLs are unique to IBD, or more common to the human condition, we tested all cis associations in an independent cohort of 780 blood samples (GTP cohort) collected previously [16]. More details about demographic information of this dataset are available in Almli et al [16] as well as in our methods section. Notably, while our discovery dataset consists of pediatric patients with predominantly Caucasian ancestry (78%), the GTP dataset is composed of prospectively-recruited adult individuals with predominantly African American ancestry (93%), with a mean age of 42.…”

Section: Blood Mqtls Are Highly Replicable In An Independent Dataset mentioning

confidence: 99%

“…Blood genotypes for GTP cohort: Study design and genotyping of the replication cohort was previously described in recent studies [29,30]. Briefly, GTP individuals were prospectively recruited from waiting rooms at Grady Memorial Hospital in Atlanta, GA between 2005-2008 for a study of stressful life events and symptoms of post-traumatic stress disorder (PTSD).…”

Section: Study Population and Design Of Discovery Cohort: The Discovementioning

confidence: 99%

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Methylation Quantitative Trait Loci are Largely Consistent across Disease States in Crohn’s disease

Venkateswaran

Kilaru

et al. 2020

Preprint

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BackgroundIn a recent study, we identified 1189 CpG sites whose DNA methylation (DNAm) level in blood distinguished Crohn’s disease (CD) cases from controls. We also demonstrated that the vast majority of these differences were a consequence of disease, rather than a cause of CD. Since methylation can be influenced by both genetic and environmental factors, here we focus on CpGs under demonstrable genetic control (methylation quantitative trait loci, or mQTLs). By comparing mQTL patterns across disease states and tissue (blood vs. ileum), we may distinguish patterns unique to CD. Such DNAm patterns may be relevant for the developmental origins of CD.MethodsWe investigated three datasets: (i) 402 blood samples from 164 newly diagnosed pediatric CD patients taken at two time points, and 74 non-IBD controls (ii) 780 blood samples from a non-CD adult population and (iii) 40 ileal biopsies (17 CD cases and 23 non-IBD controls) from group (i). Genome-wide DNAm profiling and genotyping were performed using the Illumina MethylationEPIC and Illumina Multi-Ethnic arrays. SNP-CpG associations were tested via linear models adjusted for age, gender, disease status, disease subtype, estimated cell type and three genotype-based principal components. We used a Bonferroni-adjusted significance threshold to identify significantly associated SNP-CpG pairs, but also considered larger sets identified by a false discovery rate criterionResultsIn total, we observed 535,448 SNP-CpG associations between 287,881 SNPs and 12,843 CpG sites (P<8.21×10−14). These associations and their effects are highly consistent across different ages, races, disease states, and tissue types, suggesting that the vast majority of these mQTLs participate in common gene regulation. However, genes near CpGs associated with IBD SNPs were enriched for 18 KEGG pathways relevant to IBD-linked immune function and inflammatory responses. We observed suggestive evidence for a small number of tissue-specific associations and disease-specific ileal associations in ileum, though larger studies will be needed to confirm these results.ConclusionThe vast majority of blood derived mQTLs are commonly shared across individuals. However, we have identified a subset of such, which may be involved in processes related to CD. Independent cohort studies will be required to validate these findings.

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Problematic alcohol use associates with sodium channel and clathrin linker 1 (SCLT1) in trauma‐exposed populations

Cited by 10 publications

References 108 publications

Ethanol activates immune response in lymphoblastoid cells

Ethanol activates immune response in lymphoblastoid cells

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Methylation Quantitative Trait Loci are Largely Consistent across Disease States in Crohn’s disease

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