1.
Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.
Blokland, GAM, Grove, J, Chen, CY, Cotsapas, C, Tobet, S, Handa, R, , , St Clair, D, Lencz, T, Mowry, BJ, et al
Biological psychiatry. 2022;(1):102-117
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Abstract
BACKGROUND Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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Medical comorbidity in bipolar disorder: The link with metabolic-inflammatory systems.
SayuriYamagata, A, Brietzke, E, Rosenblat, JD, Kakar, R, McIntyre, RS
Journal of affective disorders. 2017;:99-106
Abstract
BACKGROUND Bipolar disorder (BD) is associated with chronic low-grade inflammation, several medical comorbidities and a decreased life expectancy. Metabolic-inflammatory changes have been postulated as one of the main links between BD and medical comorbidity, although there are few studies exploring possible mechanisms underlying this relationship. Therefore, the aims of the current narrative review were 1) synthesize the evidence for metabolic-inflammatory changes that may facilitate the link between medical comorbidity and BD and 2) discuss therapeutic and preventive implications of these pathways. METHODS The PubMed and Google Scholar databases were searched for relevant studies. RESULTS Identified studies suggested that there is an increased risk of medical comorbidities, such as autoimmune disorders, obesity, diabetes and cardiovascular disease in patients with BD. The association between BD and general medical comorbidities seems to be bidirectional and potentially mediated by immune dysfunction. Targeting the metabolic-inflammatory-mood pathway may potential yield improved outcomes in BD; however, further study is needed to determine which specific interventions may be beneficial. LIMITATIONS The majority of identified studies had cross-sectional designs, small sample sizes and limited measurements of inflammation. CONCLUSIONS Treatment and prevention of general medical comorbidities in mood disorders should include preferential prescribing of metabolically neutral agents and adjunctive lifestyle modifications including increased physical activity, improved diet and decreased substance abuse. In addition, the use of anti-inflammatory agents could be a relevant therapeutic target in future research.
3.
Leptin in bipolar disorder: A systematic review and meta-analysis.
Fernandes, BS, Dash, S, Jacka, F, Dodd, S, Carvalho, AF, Köhler, CA, Steiner, J, da Graça Cantarelli, M, Nardin, P, Gonçalves, CA, et al
European psychiatry : the journal of the Association of European Psychiatrists. 2016;:1-7
Abstract
BACKGROUND Bipolar disorder (BD) is a psychiatric disorder associated with increased rates of obesity and inflammation. Leptin is an adipokine that is mainly produced by the white adipose tissue in response to insulin. It stimulates the immune system, increasing the production of pro-inflammatory cytokines. There is currently uncertainty regarding possible alterations in peripheral leptin levels across the mood states in BD. METHODS This study comprises a between-group meta-analysis comparing serum and plasma leptin levels in people with BD in mania, depression or euthymia and healthy controls. We conducted a systematic search for all possibly eligible-English and non-English peer-reviewed articles. We calculated the effect size (ES) utilizing Hedges' adjusted g using random effects. RESULTS Eleven studies were included in the meta-analyses, providing data on 1118 participants. Serum and plasma leptin levels were not altered in subjects with BD when compared to healthy controls in mania (g=-0.99, 95% CI -2.43 to 0.43, P=0.171), in depression (g=0.17, 95% CI -0.45 to 0.79, P=0.584), or in euthymia (g=0.03, 95% CI -0.39 to 0.46, P=0.882). However, we did observe a stronger association between leptin levels and both age and BMI in patients with BD in euthymia compared to healthy controls, such that the greater the age of the individuals, the greater the difference in leptin levels between BD and controls; and the higher the BMI, the greater the difference in leptin levels between BD and controls. CONCLUSIONS Our meta-analysis provides evidence that leptin levels are not altered in BD across the mood spectrum compared to healthy controls. The disproportionate increase of leptin levels with increase in BMI in BD speaks in favour of a potential inflammatory role of white adipose tissue in BD and a disproportionate increase of leptin levels with increase in age.
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Stress and support for parents of youth with bipolar disorder.
Nadkarni, RB, Fristad, MA
The Israel journal of psychiatry and related sciences. 2012;(2):104-10
Abstract
BACKGROUND This article reviews stress related to parenting a youth with bipolar disorder (BD), maladaptive coping, immunologic and physical functioning related to chronic stress; presents preliminary findings about the association between immune parameters and health conditions, mental health indices and interpersonal functioning in parents of children with mood disorders; and provides recommendations for stress management based on clinical trials of family-based psychoeducational psychotherapy (PEP). DATA Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), Epstein Barr Virus (EBV), nutritional markers and measures of physical health, mental health and interpersonal functioning were collected from 26 parents of mood disordered children. Higher CRP was associated with more perceived stress, more depression, increased incidence of illness/ physical conditions, and lower albumin levels. Elevated IL-6 was associated with higher nicotine use. LIMITATIONS Sample size and demographics were restricted, limiting generalizability. CONCLUSION Pilot data are consistent with literature from adult caregivers, and suggest caregivers who are more stressed also evidence some signs of immune abnormality. Evidence-based strategies to support parents are discussed.