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Trauma exposure interacts with the genetic risk of bipolar disorder in alcohol misuse of US soldiers.

ABSTRACT: OBJECTIVE:To investigate whether trauma exposure moderates the genetic correlation between substance use disorders and psychiatric disorders, we tested whether trauma exposure modifies the association of genetic risks for mental disorders with alcohol misuse and nicotine dependence (ND) symptoms. METHODS:High-resolution polygenic risk scores (PRSs) were calculated for 10 732 US Army soldiers (8346 trauma-exposed and 2386 trauma-unexposed) based on genome-wide association studies of bipolar disorder (BD), major depressive disorder, and schizophrenia. RESULTS:The main finding was a significant BD PRS-by-trauma interaction with respect to alcohol misuse (P = 6.07 × 10-3 ). We observed a positive correlation between BD PRS and alcohol misuse in trauma-exposed soldiers (r = 0.029, P = 7.5 × 10-3 ) and a negative correlation in trauma-unexposed soldiers (r = -0.071, P = 5.61 × 10-4 ). Consistent (nominally significant) result with concordant effect, directions were observed in the schizophrenia PRS-by-trauma interaction analysis. The variants included in the BD PRS-by-trauma interaction showed significant enrichments for gene ontologies related to high voltage-gated calcium channel activity (GO:0008331, P = 1.51 × 10-5 ; GO:1990454, P = 4.49 × 10-6 ; GO:0030315, P = 2.07 × 10-6 ) and for Beta1/Beta2 adrenergic receptor signaling pathways (P = 2.61 × 10-4 ). CONCLUSIONS:These results indicate that the genetic overlap between alcohol misuse and BD is significantly moderated by trauma exposure. This provides molecular insight into the complex mechanisms that link substance abuse, psychiatric disorders, and trauma exposure.

SUBMITTER: Polimanti R

PROVIDER: S-EPMC6110087 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Trauma exposure interacts with the genetic risk of bipolar disorder in alcohol misuse of US soldiers.

Polimanti R R Kaufman J J Zhao H H Kranzler H R HR Ursano R J RJ Kessler R C RC Stein M B MB Gelernter J J

Acta psychiatrica Scandinavica 20171211 2

<h4>Objective</h4>To investigate whether trauma exposure moderates the genetic correlation between substance use disorders and psychiatric disorders, we tested whether trauma exposure modifies the association of genetic risks for mental disorders with alcohol misuse and nicotine dependence (ND) symptoms.<h4>Methods</h4>High-resolution polygenic risk scores (PRSs) were calculated for 10 732 US Army soldiers (8346 trauma-exposed and 2386 trauma-unexposed) based on genome-wide association studies o ...[more]

PMID: 29230810

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Project description:BACKGROUND:Problem drinking that predates enlistment into military service may contribute to the overall burden of alcohol misuse in the Armed Forces; however, evidence bearing on this issue is limited. This study examines prevalence and correlates of alcohol misuse among new U.S. Army soldiers. METHODS:Cross-sectional survey data were collected from soldiers reporting for basic combat training. The survey retrospectively assessed lifetime alcohol consumption and substance abuse/dependence, enabling estimation of the prevalence of lifetime binge drinking and heavy drinking in a sample of 30,583 soldiers and of probable alcohol use disorder (AUD) among 26,754 soldiers with no/minimal lifetime use of other drugs. Co-occurrence of mental disorders and other adverse outcomes with binge drinking, heavy drinking, and AUD was examined. Discrete-time survival analysis, with person-year the unit of analysis and a logistic link function, was used to estimate associations of AUD with subsequent onset of mental disorders and vice versa. RESULTS:Weighted prevalence of lifetime binge drinking was 27.2% (SE = 0.4) among males and 18.9% (SE = 0.7) among females; respective estimates for heavy drinking were 13.9% (SE = 0.3) and 9.4% (SE = 0.4). Among soldiers with no/minimal drug use, 9.5% (SE = 0.2) of males and 7.2% (SE = 0.5) of females had lifetime AUD. Relative to no alcohol misuse, binge drinking, heavy drinking, and AUD were associated with increased odds of all mental disorders and other adverse outcomes under consideration (adjusted odds ratios [AORs] = 1.5 to 4.6; ps < 0.001). Prior mental disorders and suicidal ideation were associated with onset of AUD (AORs = 2.3 to 2.8; ps < 0.001), and prior AUD was associated with onset of mental disorders and suicidal ideation (AORs = 2.0 to 3.2, ps < 0.005). CONCLUSIONS:Strong bidirectional associations between alcohol misuse and mental disorders were observed in a cohort of soldiers beginning Army service. Conjoint recognition of alcohol misuse and mental disorders upon enlistment may provide opportunities for risk mitigation early in a soldier's career.

Project description:OBJECTIVE:In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD). METHODS:Treatment of Early Age Mania (TEAM) study enrollment and sample collection took place from 2003 to 2008. Mayo Clinic Bipolar Biobank samples were collected from 2009 to 2013. Genotyping and analyses for the present study took place from 2013 to 2014. The diagnosis of BD was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Eight single-nucleotide polymorphisms (SNPs), previously reported in genome-wide association studies to be associated with BD, were chosen for GRS analysis in early-onset bipolar disease. These SNPs map to 3 genes: CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit), ANK3 (ankyrin-3, node of Ranvier [ankyrin G]), and ODZ4 (teneurin transmembrane protein 4 [formerly "odz, odd Oz/10-m homolog 4 {Drosophila}, ODZ4"]). The 8 candidate SNPs were genotyped in patients from the TEAM study (n = 69); adult patients with BD (n = 732), including a subset with early-onset illness (n = 192); and healthy controls (n = 776). GRS analyses were performed to compare early-onset cases with controls. In addition, associations of early-onset BD with individual SNPs and haplotypes were explored. RESULTS:GRS analysis revealed associations of the risk score with early-onset BD (P = .01). Gene-level haplotype analysis comparing TEAM patients with controls suggested association of early-onset BD with a CACNA1C haplotype (global test, P = .01). At the level of individual SNPs, comparison of TEAM cases with healthy controls provided nominally significant evidence for association of SNP rs10848632 in CACNA1C with early-onset BD (P = .017), which did not remain significant after correction for multiple comparisons. CONCLUSIONS:These preliminary analyses suggest that previously identified BD risk loci, especially CACNA1C, have a role in early-onset BD, possibly with stronger effects than for late-onset BD.

Project description:The association of alcohol use with in-hospital trauma deaths remains unclear. This study identifies the association of blood alcohol content (BAC) with in-hospital death accounting for injury severity and mechanism.This study involves a historical cohort of 46,222 admissions to a statewide trauma center between January 1, 2002, and October 31, 2011. Blood alcohol was evaluated as an ordinal variable: 1 mg/dL to 100 mg/dL as moderate blood alcohol, 101 mg/dL to 230 mg/dL as high blood alcohol, and greater than 230 mg/dL as very high blood alcohol.Blood alcohol was recorded in 44,502 patients (96.3%). Moderate blood alcohol was associated with an increased odds for both penetrating mechanism (odds ratio [OR], 2.22; 95% confidence interval [CI], 2.04-2.42) and severe injury (OR, 1.25; 95% CI, 1.16-1.35). Very high blood alcohol had a decreased odds for penetrating mechanism (OR, 0.75; 95% CI, 0.67-0.85) compared with the undetectable blood alcohol group. An inverse U-shaped association was shown for severe injury and penetrating mechanism by alcohol group (p < 0.001). Moderate blood alcohol had an increased odds for in-hospital death (OR, 1.50; 95% CI, 1.25-1.79), and the odds decreased for very high blood alcohol (OR, 0.69; 95% CI, 0.54-0.87). An inverse U-shaped association was also shown for in-hospital death by alcohol group (p < 0.001). Model discrimination for in-hospital death had an area under the receiver operating characteristic curve of 0.64 (95% CI, 0.63-0.65).Injury severity and mechanism are strong intermediate outcomes between alcohol and death. Severe injury itself carried the greatest odds for death, and with the moderate BAC group at greatest odds for severe injury and the very high BAC group at the lowest odds for severe injury. The result was a similar inverse-U shaped curve for odds for in-hospital death. Clear associations between blood alcohol and in-hospital death cannot be analyzed without consideration for the different injuries by blood alcohol groups.Epidemiologic study, level III.

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Trauma exposure interacts with the genetic risk of bipolar disorder in alcohol misuse of US soldiers.

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Trauma exposure interacts with the genetic risk of bipolar disorder in alcohol misuse of US soldiers.

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