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

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.

A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus.

Traumatic life experiences are associated with alcohol use problems, an association that is likely to be moderated by genetic predisposition. To understand these interactions, we conducted a gene-by-environment genome-wide interaction study (GEWIS) of alcohol use problems in two independent samples, the Army STARRS (STARRS, N=16 361) and the Yale-Penn (N=8084) cohorts. Because the two cohorts were assessed using different instruments, we derived separate dimensional alcohol misuse scales and applied a proxy-phenotype study design. In African-American subjects, we identified an interaction of PRKG1 rs1729578 with trauma exposure in the STARRS cohort and replicated its interaction with trauma exposure in the Yale-Penn cohort (discovery-replication meta-analysis: z=5.64, P=1.69 × 10-8). PRKG1 encodes cyclic GMP-dependent protein kinase 1, which is involved in learning, memory and circadian rhythm regulation. Considering the loci identified in stage-1 that showed same effect directions in stage-2, the gene ontology (GO) enrichment analysis showed several significant results, including calcium-activated potassium channels (GO:0016286; P=2.30 × 10-5), cognition (GO:0050890; P=1.90 × 10-6), locomotion (GO:0040011; P=6.70 × 10-5) and Stat3 protein regulation (GO:0042517; P=6.4 × 10-5). To our knowledge, this is the largest GEWIS performed in psychiatric genetics, and the first GEWIS examining risk for alcohol misuse. Our results add to a growing body of literature highlighting the dynamic impact of experience on individual genetic risk.

Lack of association between GSTM1, GSTP1, and GSTT1 gene polymorphisms and asthma in adult patients from Rome, central Italy.

BACKGROUND: Asthma is a complex multifactorial disease that is not yet fully understood. Oxidative stress due to an imbalance between the oxidative forces and the antioxidant defense systems has been implicated in asthma pathogenesis. However, much debate still surrounds the key genetic factors involved in the development of this disease. Candidate genes include the glutathione S-transferases (GSTs). In particular, mu, pi, and theta classes of GSTs play an important role in regulating inflammatory responses. However, few and contradictory data are available on the association between asthma development and GST gene polymorphisms (GSTM1, GSTP1, and GST1). OBJECTIVE: To investigate whether GSTM1, GSTT1, and GSTP1 polymorphisms are associated with asthma development. METHODS: We recruited 200 unrelated healthy individuals and 199 asthmatic patients from Rome in Central Italy. Genotyping of GSTMI and GSTT1 genes was performed by a multiplex polymerase chain reaction (PCR) while the GSTP1 polymorphism (rs1695) was determined using PCR-restriction fragment length polymorphism analysis. RESULTS: Our results suggest that the GST polymorphisms analyzed are not associated with asthma, confirming the uncertain role of GST genes in the development of asthma. CONCLUSIONS: Oxidative stress is certainly involved in the development of asthma, and GSTs may therefore influence asthma risk, although, as our results show, their role in pathogenesis remains to be elucidated. Future studies should focus on the interactions of GST genes with the environment and other antioxidant genes to shed light on the role of GSTs in asthma.

Glutathione S-transferase gene polymorphisms and air pollution as interactive risk factors for asthma in a multicentre Italian field study: A preliminary study.

BACKGROUND: Asthma is one of the most common chronic diseases. Several studies have indicated that oxidative stress impairs pulmonary function. Glutathione S-transferases (GSTs) are believed to be critical in the protection of cells from reactive oxygen species. AIM: In this case-control study we analysed the possible association between polymorphism in several cytosolic GST genes, air pollution and asthma development. METHODS: Genotyping of GSTM1 and GSTT1 genes was carried out by a multiplex PCR; GSTA1, GSTO1, GSTO2, GSTP1 polymorphisms were determined using the PCR-RFLP method. Data on atmospheric pollutants were collected by the regional air-quality monitoring network. RESULTS: Among all the polymorphisms studied, the frequencies of GSTA1, GSTM1, GSTO2 and GSTT1 genotypes found in the group of asthmatic patients seem to differ from the frequencies of those found in the control group. Air pollutants were analysed and the air quality parameters considered proved to be significantly different, and therefore suitable for this study. CONCLUSION: The final result of this research should hopefully lead to a better understanding of gene-environment interactions, so allowing earlier prediction and diagnosis of asthma disease and providing an efficient means of prevention.