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.

• Keywords
• Bipolar disorder, Genome-wide association study, Genotype-by-sex interaction, Major depressive disorder, Schizophrenia, Sex differences,
• MeSH
• Bipolar Disorder genetics   MeSH
• Genome-Wide Association Study MeSH
• Depressive Disorder, Major * genetics   MeSH
• Endothelial Cells MeSH
• Genetic Predisposition to Disease MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Sex Characteristics * MeSH
• Psychotic Disorders * genetics   MeSH
• Receptors, Vascular Endothelial Growth Factor MeSH
• Schizophrenia genetics   MeSH
• Sulfurtransferases MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• MOCOS protein, human MeSH Browser
• Receptors, Vascular Endothelial Growth Factor MeSH
• Sulfurtransferases MeSH

Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring's risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-α levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-α:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.

• Keywords
• functional brain imaging, prenatal immune programming, prenatal stress, sex, stress circuitry,
• MeSH
• Cytokines blood   MeSH
• Adult MeSH
• Hypothalamus diagnostic imaging   MeSH
• Connectome * MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Stress, Psychological diagnostic imaging   MeSH
• Sex Factors MeSH
• Pregnancy MeSH
• Prenatal Exposure Delayed Effects diagnostic imaging   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Cytokines MeSH

Cardiac autonomic dysregulation has been implicated in the comorbidity of major psychiatric disorders and cardiovascular disease, potentially through dysregulation of physiological responses to negative stressful stimuli (here, shortened to stress response). Further, sex differences in these comorbidities are substantial. Here, we tested the hypothesis that mood- and sex-dependent alterations in brain circuitry implicated in the regulation of the stress response are associated with reduced peripheral parasympathetic activity during negative emotional arousal. Fifty subjects (28 females) including healthy controls and individuals with major depression, bipolar psychosis and schizophrenia were evaluated. Functional magnetic resonance imaging and physiology (cardiac pulse) data were acquired during a mild visual stress reactivity challenge. Associations between changes in activity and functional connectivity of the stress response circuitry and variations in cardiovagal activity [normalized high frequency power of heart rate variability (HFn)] were evaluated using GLM analyses, including interactions with depressed mood and sex across disorders. Our results revealed that in women with high depressed mood, lower cardiovagal activity in response to negative affective stimuli was associated with greater activation of hypothalamus and right amygdala and reduced connectivity between hypothalamus and right orbitofrontal cortex, amygdala, and hippocampus. No significant associations were observed in women with low levels of depressed mood or men. Our results revealed mood- and sex-dependent interactions in the central regulation of cardiac autonomic activity in response to negative affective stimuli. These findings provide a potential pathophysiological mechanism for previously observed sex differences in the comorbidity of major depression and cardiovascular disease.

• MeSH
• Amygdala MeSH
• Depressive Disorder, Major * MeSH
• Hippocampus MeSH
• Humans MeSH
• Magnetic Resonance Imaging * MeSH
• Brain diagnostic imaging   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH