Although some individuals with schizophrenia are able to maintain gainful employment, many are not. To better understand this differential real-life outcome, we tested general and specific cognitive measures as predictors of future employment and genetic moderators of these relationships. One hundred and twenty-four patients with schizophrenia spectrum illness (31.5 % female, mean age 32.5 ± 10.5 years) participated in a research study at the National Institute of Mental Health Intramural Research Program's Clinical Center and were later recontacted regarding outcomes (average time to recontact = 8.6 ± 4.0 years). At the initial visit, patients completed a comprehensive battery of neuropsychological tests and provided blood samples for genotyping. Cognitive scores at the initial visit were tested as predictors of future employment status (employed vs. unemployed) at follow-up using logistic regressions, and polygenic risk scores for schizophrenia were tested as moderators. At follow-up, 45.2 % of individuals were employed. General cognitive ability indexes ("g" and IQ) and verbal memory were predictive of subsequent employment status. Additionally, polygenic risk for schizophrenia moderated the effect of working memory cognitive scores on the prediction of future employment. The results suggest that certain broad indexes of cognitive dysfunction may be particularly salient in targeting interventions to address real-world functioning in schizophrenia. These data also suggest that further investigation into the genetic underpinnings of real-life outcomes in this illness is warranted.

The hippocampus undergoes substantial structural and functional changes during puberty, and animal studies have demonstrated that puberty-related gonadal hormones may influence hippocampal morphology. However, our understanding of the relationship between puberty-related neuroendocrine processes and hippocampal volume across development in humans remains limited. We longitudinally investigated the possible relationship between the developmental trajectory of hippocampal volume and serum estradiol and testosterone levels in healthy boys and girls from age eight through the pubertal transition to age 18.

The polygenic architecture of schizophrenia implicates several molecular pathways involved in synaptic function. However, it is unclear how polygenic risk funnels through these pathways to translate into syndromic illness. Using tensor decomposition, we analyze gene co-expression in the caudate nucleus, hippocampus, and dorsolateral prefrontal cortex of post-mortem brain samples from 358 individuals. We identify a set of genes predominantly expressed in the caudate nucleus and associated with both clinical state and genetic risk for schizophrenia that shows dopaminergic selectivity. A higher polygenic risk score for schizophrenia parsed by this set of genes predicts greater dopamine synthesis in the striatum and greater striatal activation during reward anticipation. These results translate dopamine-linked genetic risk variation into in vivo neurochemical and hemodynamic phenotypes in the striatum that have long been implicated in the pathophysiology of schizophrenia. Here, the authors report that schizophrenia risk variants mapping to a striatal dopamine-related gene set are associated with increased striatal dopamine synthesis capacity and increased striatal activity during reward anticipation in humans.

Large, recurrent copy number variants (CNVs) are among the strongest risk factors for neuropsychiatric conditions, contributing to multiple phenotypes with overlapping psychiatric and cognitive symptoms. However, the molecular basis of this convergent risk remains unknown. We evaluated the human brain transcriptome in carriers of nine high-risk neuropsychiatric CNVs and matched non-carriers using single nucleus RNA-sequencing. Brain tissue from carriers displayed widespread disruptions of gene expression, with deletions showing greater changes than the reciprocal duplications. Functional enrichment analysis revealed changes in mitochondrial energy metabolism and synaptic function that converged across CNVs and cell types. The direction of effects correlated with CNV gene dosage for mirror CNVs. These findings suggest that a shared pathophysiology underlies risk for convergent brain phenotypes across CNVs and point toward promising therapeutic targets. ### Competing Interest Statement The authors have declared no competing interest.

Sex differences in the course and prevalence of dopamine-related neuropsychiatric disorders may be partially mediated by sex hormone-dopamine interactions. Evidence from rodent studies suggest that endogenous ovarian hormones modulate presynaptic dopamine function. Here, we tested for sex differences as well as effects of menstrual cycle phase on presynaptic dopamine function using PET in healthy men and women.

Understanding neurogenetic mechanisms underlying neuropsychiatric disorders such as schizophrenia and autism is complicated by their inherent clinical and genetic heterogeneity. Williams syndrome (WS), a rare neurodevelopmental condition in which both the genetic alteration (hemideletion of ~ twenty-six 7q11.23 genes) and the cognitive/behavioral profile are well-defined, offers an invaluable opportunity to delineate gene-brain-behavior relationships. People with WS are characterized by increased social drive, including particular interest in faces, together with hallmark difficulty in visuospatial processing. Prior work, primarily in adults with WS, has searched for neural correlates of these characteristics, with reports of altered fusiform gyrus function while viewing socioemotional stimuli such as faces, along with hypoactivation of the intraparietal sulcus during visuospatial processing. Here, we investigated neural function in children and adolescents with WS by using four separate fMRI paradigms, two that probe each of these two cognitive/behavioral domains. During the two visuospatial tasks, but not during the two face processing tasks, we found bilateral intraparietal sulcus hypoactivation in WS. In contrast, during both face processing tasks, but not during the visuospatial tasks, we found fusiform hyperactivation. These data not only demonstrate that previous findings in adults with WS are also present in childhood and adolescence, but also provide a clear example that genetic mechanisms can bias neural circuit function, thereby affecting behavioral traits.

Pubertal timing, including age at menarche (AAM), is a heritable trait linked to lifetime health outcomes. Here, we investigate genetic mechanisms underlying AAM by combining genome-wide association study (GWAS) data with investigations of two rare genetic conditions clinically associated with altered AAM: Williams syndrome (WS), a 7q11.23 hemideletion characterized by early puberty; and duplication of the same genes (7q11.23 Duplication syndrome [Dup7]) characterized by delayed puberty. First, we confirm that AAM-derived polygenic scores in typically developing children (TD) explain a modest amount of variance in AAM (R2 = 0.09; p = 0.04). Next, we demonstrate that 7q11.23 copy number impacts AAM (WS < TD < Dup7; p = 1.2x10-8, h2 = 0.45) and pituitary volume (WS < TD < Dup7; p = 3x10-5, hp2 = 0.2) with greater effect sizes. Finally, we relate an AAM-GWAS signal in 7q11.23 to altered expression in postmortem brains of STAG3L2 (p = 1.7x10-17), a gene we also find differentially expressed with 7q11.23 copy number (p = 0.03). Collectively, these data explicate the role of 7q11.23 in pubertal onset, with STAG3L2 and pituitary development as potential mediators.

Dysfunction of dopamine systems has long been considered a hallmark of schizophrenia, and nearly all current first-line medication treatments block dopamine D2 receptors. However, approximately a quarter of patients will not adequately respond to these agents and are considered treatment-resistant. Whereas abnormally high striatal presynaptic dopamine synthesis capacity has been observed in people with schizophrenia, studies of treatment-resistant patients have not shown this pattern and have even found the opposite - i.e., reductions in striatal presynaptic dopamine synthesis capacity. Whether such reductions in fact represent clinical epiphenomena such as medication or other treatment effects or whether they rather represent neurobiological differences related to etiology has been unclear. To understand the dopaminergic implications of genetic liability for treatment-resistant schizophrenia without the confound of clinical epiphenomena, we studied a cohort of healthy individuals without neuropsychiatric illness using [18F]-FDOPA positron emission tomography (PET) and found that striatal presynaptic dopamine synthesis capacity showed an expected direct association with cumulative genetic risk burden for general schizophrenia but an inverse association with specific polygenic risk for treatment-resistant schizophrenia. Subsequent evaluation of D2/3 dopamine receptor availability in an overlapping cohort using [18F]-fallypride PET did not identify any effects of genetic risk in the striatum but found an association with treatment-resistant schizophrenia polygenic risk in the thalamus. Overall, these results align with prior PET studies in patients and implicate, at least with respect to the dopamine system, fundamentally distinct molecular mechanisms in the unique genetic liability for treatment-resistant schizophrenia.