The widespread and increasing prevalence of excess body mass represents a major public health concern and has been hypothesized to involve dysfunction of the dopaminergic reward system. However, a detailed, systems-level understanding of interactions between the dopamine system and body mass regulation in humans has been elusive. To address this knowledge gap, we employed positron emission tomography (PET) to directly measure presynaptic dopamine synthesis capacity (with [18F]-FDOPA) and dopamine receptor availability (D1 and D2/3 receptors with [11C]-NNC112 and [18F]-Fallypride, respectively) in 117 individuals with body mass index (BMI) values ranging from normal to moderately obese. We found that elevated BMI was associated with heightened dopamine synthesis capacity in the midbrain and hypothalamus, key regions for homeostatic appetite control, as well as with lower D2/3 receptor availability in the midbrain, where D2 receptors play an important role in the autoregulation of striatal dopamine release. Moreover, we found that the presence and rate of weight gain in the 1–2 years prior to scanning was associated with increased presynaptic dopamine synthesis capacity in the ventral striatum and midbrain, important components of the reward network. These data suggest that upregulation of body mass beyond the normal range is related to increased dopamine synthesis capacity in reward- and homeostatic-related regions coupled with blunted autoregulation.

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 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.

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.

Genetic modifications leading to pain insensitivity phenotypes, while rare, provide invaluable insights into the molecular biology of pain and reveal targets for analgesic drugs. Pain insensitivity typically results from Mendelian loss-of-function mutations in genes expressed in nociceptive (pain-sensing) dorsal root ganglion (DRG) neurons that connect the body to the spinal cord. We document a pain insensitivity mechanism arising from gene overexpression in individuals with the rare 7q11.23 duplication syndrome (Dup7), who have 3 copies of the approximately 1.5-megabase Williams syndrome (WS) critical region. Based on parental accounts and pain ratings, people with Dup7, mainly children in this study, are pain insensitive following serious injury to skin, bones, teeth, or viscera. In contrast, diploid siblings (2 copies of the WS critical region) and individuals with WS (1 copy) show standard reactions to painful events. A converging series of human assessments and cross-species cell biological and transcriptomic studies identified 1 likely candidate in the WS critical region, STX1A, as underlying the pain insensitivity phenotype. STX1A codes for the synaptic vesicle fusion protein syntaxin1A. Excess syntaxin1A was demonstrated to compromise neuropeptide exocytosis from nociceptive DRG neurons. Taken together, these data indicate a mechanism for producing "genetic analgesia" in Dup7 and offer previously untargeted routes to pain control.

Cerebral blood flow (CBF) reflects the delivery of oxygen and nutrients to the brain and is thus an important indicator of neuronal activity. CBF abnormalities have been described in a number of neuropsychiatric conditions that have pubertal onset and sex differences in clinical course. Previous research showed that grey matter CBF decreases with age, and that overall CBF is greater in women than men. However, less is known about these findings across development and into adulthood. Here, using MRI-based arterial spin labeling (ASL), we longitudinally measured CBF in a cohort of healthy children and adults aged 6-40 years.