Use of archived neonatal bloodspots for examining associations between prenatal exposure to potentially traumatic or stressful life events, maternal herpesvirus infection and lifetime history of generalized anxiety disorder in offspring

Background: Lifetime prevalence of anxiety disorders is over 30% among U.S. adolescents, warranting further investigation into early life risk factors for such conditions. We conducted a pilot study to examine the role that maternal herpesvirus infection may play in the pathway between maternal trauma and stress during pregnancy and offspring generalized anxiety disorder (GAD). Methods: Participants included 69 women in the Detroit Neighborhood Health Study with data on past exposure to 19 potentially traumatic (PTEs) and 9 stressful life events (SLEs). Lifetime history of GAD in the youngest biologic child between 6 and 17 years old born in Michigan (i.e., index child) of each woman was ascertained via the Diagnostic Interview Schedule for Children, 4th edition, parent version. We obtained written informed consent from participants for retrieval of archived neonatal bloodspot samples corresponding to their index child from the Michigan Neonatal Biobank (MNB) and testing of these samples for markers of maternal herpes simplex virus (HSV)-1 and cytomegalovirus (CMV) seropositivity. Logistic regression was used to examine the association between maternal PTEs or SLEs during pregnancy and offspring GAD. Results: A total of 18.1 and 31.9% of women experienced =1 PTE or SLE during pregnancy, respectively, and 10.8% of offspring met the criteria for lifetime history of GAD. We obtained maternal consent for retrieval of and tested bloodspot samples corresponding to the index child of 22 women (38.0%), of which 4.5 and 40.9% were seropositive for HSV-1 and CMV, respectively. We observed positive, although not statistically significant associations between =1 PTE or SLE during pregnancy and offspring lifetime history of GAD. While a greater proportion of offspring with lifetime history of GAD were born to women seropositive for CMV and HSV-1, compared to those without lifetime history, these differences were not statistically significant and we did not further examine the mediating role of maternal herpesvirus seropositivity in this pathway.Conclusion: Findings from this study support the feasibility of utilizing neonatal bloodspots archived in the MNB to examine the role of herpesviruses as mediators between maternal trauma or stress during pregnancy and offspring anxiety disorders in larger Michigan cohorts. © 2016 Simanek, Uddin, Yolken and Aiello

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci

Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10 -6) and rs8057927 in CDH13 (P=1.39 × 10 -5). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10 -7). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10 -7). This signal was replicated in the follow-up analysis (P=2.3 × 10 -2). Significant interaction with maternal CMV infection was found for rs7902091 (P SNP × CMV =7.

Development of a blood-based molecular biomarker test for identification of schizophrenia before disease onset

Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95-1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset or at-risk individuals. The predictive performance achieved by the panel was excellent for identifying USA military personnel (AUC: 0.90 (0.86-0.95)) and help-seeking prodromal individuals (AUC: 0.82 (0.71-0.93)) who developed schizophrenia up to 2 years after baseline sampling. The performance increased further using the latter cohort following the incorporation of CAARMS (Comprehensive Assessment of At-Risk Mental State) positive subscale symptom scores into the model (AUC: 0.90 (0.82-0.98)). The current findings may represent the first successful step towards a test that could address the clinical need for early intervention in psychiatry. Further developments of a combined molecular/symptom-based test will aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention before overt disease onset

Antibodies to infectious agents and the positive symptom dimension of subclinical psychosis: The TRAILS study

Infections have been suggested to play a role in the etiology of schizophrenia, but the evidence for this has been inconsistent. Schizophrenia patients have an increased risk of infections as a result of hospitalizations or life style factors. Therefore a study on early subclinical manifestations of psychosis in relation to virus infections is warranted. We examined whether serum antibodies against human Herpes viruses and Toxoplasma gondii were associated with subclinical symptoms of psychosis in adolescents. Data were collected as part of the TRacking Adolescents' Individual Lives Survey (TRAILS) cohort, a large prospective cohort of Dutch adolescents. A total of 1176 participants with an available Community Assessment of Psychic Experiences (CAPE) and an available blood sample were included in this analysis. Solid-enzyme immunoassay methods were used to measure the presence of immunoglobulin G (IgG) antibodies in serum to the Herpes virus family and to T. gondii. There was no significant association between serologic evidence of infection with human Herpes viruses or T. gondii and the risk of subclinical positive experience of psychosis. Subjects with a positive serological reaction to Epstein-Barr Virus (EBV) had higher scores on the positive dimension of psychosis measured by CAPE (b=0.03, P=0.02). This significant association was observed in males, but not in females. The current study suggests that there is no significant association between serological evidence of infection to human Herpes viruses and positive subclinical experience of psychosis, whereas there was an association between EBV infection and subclinical psychotic symptoms in boys

Association between exposure to HSV1 and cognitive functioning in a general population of adolescents: The TRAILS study

Background Infections with different herpes viruses have been associated with cognitive functioning in psychiatric patients and healthy adults. The aim of this study was to find out whether antibodies to different herpes viruses are prospectively associated with cognitive functioning in a general adolescent population. Methods This study was performed in TRAILS, a large prospective general population cohort (N = 1084, 54% female, mean age 16.2 years (SD 0.6)). At age 16, immunoglobulin G antibodies against HSV1, HSV2, CMV and EBV were measured next to high sensitive C-Reactive Protein (hsCRP). Two years later, immediate memory and executive functioning were assessed using the 15 words task and the self ordered pointing task. Multiple linear regression analysis with bootstrapping was performed to study the association between viral infections and cognitive function, adjusting for gender, socioeconomic status, ethnicity, and cannabis use. Results Presence of HSV1 antibodies was associated with memory function ((B = −0.272, 95% CI = −0.556 to −0.016, p = 0.047)), while the association with executive functioning did not reach statistical significance (B = 0.560, 95% CI is −0.053 to 1.184, p = 0.075). The level of HSV1 antibodies was associated with both memory function (B = −0.160, 95% CI = −0.280 to −0.039, p = 0.014) and executive functioning (B = 0.296, 95% CI = 0.011 to 0.578, p = 0.046). Other herpes viruses and hsCRP were not associated with cognitive functioning. Conclusions Both presence and level of HSV1 antibodies are prospectively associated with reduced cognitive performance in a large cohort of adolescents

Immune activation by casein dietary antigens in bipolar disorder

Objectives: Inflammation and other immune processes are increasingly linked to psychiatric diseases. Antigenic triggers specific to bipolar disorder are not yet defined. We tested whether antibodies to bovine milk caseins were associated with bipolar disorder, and whether patients recognized different epitopes of the casein protein than control individuals. Methods: Anti-bovine casein immunoglobulin G (IgG) levels were measured with solid-phase immunoassays in 75 individuals with bipolar disorder and 65 controls. Epitope recognition was evaluated in immunoassays by cross neutralization with anti-bovine casein polyclonal antibodies of defined reactivity. Group-specific reactivity and associations with symptom severity scores were detected with age-, gender-, and race-controlled regression models. Results: Individuals with bipolar disorder had significantly elevated anti-casein IgG (t-test, p = 0.001) compared to controls. Casein IgG seropositivity conferred odds ratios of 3.97 for bipolar disorder [n = 75, 95% confidence interval (CI): 1.31–12.08, p = 0.015], 5.26 for the bipolar I subtype (n = 56, 95% CI: 1.66–16.64, p = 0.005), and 3.98 for bipolar disorder with psychosis (n = 54, 95% CI: 1.32–12.00, p = 0.014). Lithium and/or antipsychotic medication did not significantly affect anti-casein IgG levels. Casein IgG measures correlated with severity of manic (R2 = 0.15, 95% CI: 0.05–0.24, p = 0.02) but not depressive symptoms. Unlike controls, sera from individuals with bipolar disorder did not inhibit binding of casein-reactive animal sera (t-test/¿2, p = 0.0001). Conclusions: Anti-casein IgG associations with bipolar I diagnoses, psychotic symptom history, and mania severity scores suggest that casein-related immune activation may relate to the psychosis and mania components of this mood disorder. Case-control differences in epitope recognition implicate disease-related alterations in how the casein molecule is digested and/or how resulting casein-derived structures are rendered immunogenic