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Purpose: The primary purpose of this descriptive cross-sectional study was to examine the associations between sleep-wake characteristics (total sleep time, sleep variability, sleep onset latency, and sleep efficiency), distress symptoms (general and diabetes), and diabetes physical symptoms in young adults ages 18 to 30 years with type 1 diabetes (T1D). The secondary purpose was to determine whether biological sex, body mass index (BMI), and T1D duration (covariates) influence the relationships among the study variables. Methods: Forty-six young adults with T1D, recruited from diabetes clinics from December 2018 to February 2020, wore a wrist actigraph and continuous glucose monitor concurrently for 6 to 14 days and completed the PROMIS Emotional Distress Scale, Diabetes Distress Scale, and Diabetes Symptom Checklist-Revised. Results: Shorter total sleep time and poorer sleep efficiency were associated with higher diabetes emotional distress symptoms. Higher sleep variability was associated with higher neurological pain symptoms. A longer sleep onset latency was associated with higher symptoms of diabetes distress, including psychological, cognitive, hyperglycemia, and a higher total symptom burden. Associations remained statistically significant after adjusting for biological sex and BMI, with the exception of sleep onset latency and total symptom burden. Conclusions: Poorer objective sleep-wake characteristics were associated with higher diabetes symptoms even after considering biological sex and BMI among young adults with T1D.

Androgen deprivation therapy (ADT) has been associated with adverse effects on the brain. ADT alters testosterone levels via its action on the hypothalamus-pituitary-gonadal axis and may influence hypothalamic functions. Given the wide regional connectivity of the hypothalamus and its role in regulating cognition and behavior, we assessed the effects of ADT on hypothalamic resting state functional connectivity (rsFC) and their cognitive and clinical correlates.In a prospective observational study, 22 men with nonmetastatic prostate cancer receiving ADT and 28 patients not receiving ADT (controls), matched in age, years of education, and Montreal Cognitive Assessment score, participated in N-back task and quality of life (QoL) assessments and brain imaging at baseline and at 6 months. Imaging data were processed with published routines and the results of a group by time flexible factorial analysis were evaluated at a corrected threshold.ADT and control groups did not differ in N-back performance or QoL across time points. Relative to controls, patients receiving ADT showed significantly higher hypothalamus-right mid-cingulate cortex (MCC) and precentral gyrus (PCG) rsFC during follow-up versus baseline. Further, the changes in MCC and PCG rsFC were correlated positively with the change in QoL score and 0-back correct response rate, respectively, in patients with undergoing ADT.Six-month ADT affects hypothalamic functional connectivity with brain regions critical to cognitive motor and affective functions. Elevated hypothalamic MCC and PCG connectivity likely serve to functionally compensate for the effects of ADT and sustain attention and overall QoL. The longer-term effects of ADT remain to be investigated.

Previous research investigated the cerebral volumetric correlates of impulsivity largely in moderate-sized samples and few have examined the distinct correlates of dimensions of impulsivity, sex differences, or heritability of the correlates. Here, we performed voxel-based morphometry analysis of data (n = 11,474; 5,452 girls, 9-10 years) curated from the Adolescent Brain Cognition Development project. In a linear regression with all five UPPS-P subscores as regressors and age in months, total intracranial volume, study site, and scanner model as covariates, higher levels of lack of premeditation, and sensation seeking were correlated with larger cortical and subcortical gray matter volumes (GMVs). In contrast, higher positive urgency was correlated with smaller GMVs in many of the same regions. The dimensional impulsivity traits also involved distinct volumetric correlates, with, for instance, sensation seeking and positive urgency specifically implicating bilateral caudate head/mid-cingulate cortex and bilateral lateral orbitofrontal cortex/left precentral gyrus, respectively. Boys relative to girls scored higher in all impulsivity dimensions. Girls relative to boys showed significantly stronger positive and negative correlations between sensation seeking and insula, putamen, and inferior frontal gyrus (IFG) GMVs and between positive urgency and cingulate cortex, insula, and IFG GMVs, respectively. With a subsample of twins, the dimensional impulsivity traits were weakly to moderately heritable in both girls and boys, and the GMV correlates were highly heritable in girls and boys combined. These findings collectively suggest shared and nonshared as well as sex differences in the cerebral volumetric bases of dimensional impulsivity traits and may facilitate research of externalizing psychopathology in children.

Obsessive-compulsive disorder (OCD) is a heterogeneous psychiatric illness with a complex array of symptoms and potentially distinct neural underpinnings. We employed meta-analysis and connectivity modeling of symptom dimensions to delineate the circuit mechanisms of OCD.With the activation likelihood estimation (ALE) algorithm we performed meta-analysis of whole-brain functional magnetic resonance imaging (fMRI) studies of symptom provocation. We contrasted all OCD patients and controls in a primary analysis and divided the studies according to clinical symptoms in secondary meta-analyses. Finally, we employed meta-analytic connectivity modeling analyses (MACMs) to examine co-activation patterns of the brain regions revealed in the primary meta-analysis.A total of 14 experiments from 12 eligible studies with a total of 238 OCD patients (124 men) and 219 healthy controls (120 men) were included in the primary analysis. OCD patients showed higher activation in the right caudate body/putamen/insula and lower activation in the left orbitofrontal cortex (OFC), left inferior frontal gyrus (IFG), left caudate body/middle cingulate cortex (MCC), right middle temporal gyrus (MTG), middle occipital gyrus (MOG) and right lateral occipital gyrus (LOG). MACMs revealed significant co-activation between left IFG and left caudate body/MCC, left MOG and right LOG, right LOG and MTG. In the secondary meta-analyses, the washing subgroup showed higher activation in the right OFC, bilateral ACC, left MOG and right caudate body.OCD patients showed elevated dorsal striatal activation during symptom provocation. In contrast, the washing subgroup engaged higher activation in frontal, temporal and posterior cortical structures as well as right caudate body. Broadly consistent with the proposition of cortico-striatal-thalamic-cortical circuit dysfunction, these findings highlight potentially distinct neural circuits that may underlie the symptoms and potentially etiological subtypes of OCD.

Background Alcohol dependence (AD) is a disorder with a high recurrence rate that leads to a considerable public health burden. The risk of relapse appears to be related to a complex interplay of multiple factors. Herein, we aimed to explore the potential neural predictors of relapse in Chinese male patients with AD. Methods This study enrolled 58 male patients with AD who had undergone acute detoxification. General demographic information and clinical features were collected. Magnetic resonance imaging (MRI) data were used to measure cortical thickness across 34 regions of the brain. Patients were followed up at 6 months, and 51 patients completed the follow-up visit. These patients were divided into a relapser and an abstainer group. A binary logistic regression analysis was performed to investigate the potential risk factors of relapse. Results Compared to abstainers, relapsers showed higher inattention and non-planning impulsivity on the 11th version of the Barratt Impulsive Scale. The cortical thicknesses of the inferior-parietal lobule were significantly greater in abstainers compared with those in relapsers. Furthermore, binary logistic regression analysis showed that the thickness of the inferior parietal lobule predicted relapse. Conclusions Relapsers show poorer impulse control than abstainers, and MRI imaging shows a decreased thickness of the inferior parietal lobule in relapsers. Our results indicate the thickness of the inferior parietal lobule as a potential relapse predictor in male patients with AD.

To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega‐analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case‐ and control‐only sites led to the inadvertent learning of site‐effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary‐based feature selection leveraging leave‐one‐site‐out cross‐validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test‐set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi‐site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD., To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, we developed classifiers on data collected from multiple sites. Exploratory data analysis revealed that inclusion of case‐ and control‐only sites led to the inadvertent learning of site‐effects. Evolutionary‐based feature selection leveraging leave‐one‐site‐out cross‐validation, to combat unintentional learning, yielded a test‐set area under the receiver operating characteristic curve of 0.768.

Attention deficit hyperactivity disorder (ADHD) is associated with reduction of cortical and subcortical gray matter volumes (GMVs). The kinectin 1 gene (KTN1) has recently been reported to significantly regulate GMVs and ADHD risk. In this study, we aimed to identify sex-specific, replicable risk KTN1 alleles for ADHD and to explore their regulatory effects on mRNA expression and cortical and subcortical GMVs. We examined a total of 1020 KTN1 SNPs in one discovery sample (ABCD cohort: 5573 males and 5082 females) and three independent replication European samples (Samples #1 and #2 each with 802/122 and 472/141 male/female offspring with ADHD; and Sample #3 with 14,154/4945 ADHD and 17,948/16,246 healthy males/females) to identify replicable associations within each sex. We examined the regulatory effects of ADHD-risk alleles on the KTN1 mRNA expression in two European brain cohorts (n = 348), total intracranial volume (TIV) in 46 European cohorts (n = 18,713) and the ABCD cohort, as well as the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258) and of 118 cortical and subcortical regions in the ABCD cohort. We found that four KTN1 variants significantly regulated the risk of ADHD with the same direction of effect in males across discovery and replication samples (0.003 ≤ p ≤ 0.041), but none in females. All four ADHD-risk alleles significantly decreased KTN1 mRNA expression in all brain regions examined (1.2 × 10–5 ≤ p ≤ 0.039). The ADHD-risk alleles significantly increased basal ganglia (2.8 × 10–22 ≤ p ≤ 0.040) and hippocampus (p = 0.010) GMVs but reduced amygdala GMV (p = 0.030) and TIV (0.010 KTN1 alleles for ADHD, specifically in males. KTN1 may play a critical role in the pathogenesis of ADHD, and the reduction of specific cortical and subcortical, including amygdalar but not basal ganglia or hippocampal, GMVs may serve as a neural marker of the genetic effects.

Emerging evidence suggests distinct neurobiological correlates of alcohol use disorder (AUD) between sexes, which however remain largely unexplored. This work from ENIGMA Addiction Working Group aimed to characterize the sex differences in gray matter (GM) and white matter (WM) correlates of AUD using a whole-brain, voxelbased, multi-tissue mega-analytic approach, thereby extending our recent surfacebased region of interest findings on a nearly matching sample using a complementary methodological approach. T1-weighted magnetic resonance imaging (MRI) data from 653 people with AUD and 326 controls was analyzed using voxel-based morphometry. The effects of group, sex, group-by-sex, and substance use severity in AUD on brain volumes were assessed using General Linear Models. Individuals with AUD relative to controls had lower GM volume in striatal, thalamic, cerebellar, and widespread cortical clusters. Group-by-sex effects were found in cerebellar GM and WM volumes, which were more affected by AUD in females than males. Smaller groupby- sex effects were also found in frontotemporal WM tracts, which were more affected in AUD females, and in temporo-occipital and midcingulate GM volumes, which were more affected in AUD males. AUD females but not males showed a negative association between monthly drinks and precentral GM volume. Our results suggest that AUD is associated with both shared and distinct widespread effects on GM and WM volumes in females and males. This evidence advances our previous region of interest knowledge, supporting the usefulness of adopting an exploratory perspective and the need to include sex as a relevant moderator variable in AUD.

Accumulating evidence suggests that hypothalamic-pituitary-adrenal axis dysfunction might play an important role in the pathophysiology of schizophrenia. The aim of this study was to explore the cortisol response to psychological stress in patients with schizophrenia. In this study, patients with schizophrenia (n = 104) and healthy volunteers (n = 59) were asked to complete psychological stress challenge tasks, which included the Paced Auditory Serial Addition Task and Mirror-Tracing Persistence Task, and pre- and post-task saliva samples were collected to measure cortisol levels. Emotions and psychopathology were assessed by the Positive and Negative Affect Schedule and Positive and Negative Syndrome Scale. The results showed (1) that the cortisol response and negative emotions in patients with schizophrenia differed significantly from those in healthy volunteers, (2) there were significant interactions between the sampling time and diagnosis for saliva cortisol levels, (3) there were significant interactions between the scoring time and diagnosis for the negative affect score of the PANAS, and (4) the changes in salivary cortisol levels and negative affect scores before and after the psychological stress challenge tasks were not correlated with clinical symptoms in patients with schizophrenia. These findings indicated an abnormal cortisol profile in patients with schizophrenia, which might be a biological characteristic of the disease.

Context Short sleep duration and sleep disruptions are associated with impaired glucoregulation in type 1 diabetes (T1D). However, the mechanistic pathways between sleep and glucose variability remain unclear. Objective To determine within- and between-person associations between objective sleep-wake characteristics and glucose variability indices. Methods Multilevel models were used to analyze concurrent sleep and glucose patterns over 7 days in 42 young adults with T1D in their natural home environment. Young adults with T1D (mean age 22.2 ± 3.0 years, HbA1c 7.2%, 32.6% male) for at least 6 months with no other medical or major psychiatric comorbidity were included. Sleep-wake characteristics were measured via wrist actigraphy and glucose variability indices via a continuous glucose monitor (CGM). Results Lower sleep efficiency predicted higher glucose variability (less time in range β = 0.011 and more time in hyperglycemia β = −0.011) within-person. A longer wake after sleep onset and more sleep disruptions were associated with higher glucose variability between persons (β = 0.28 and 0.31). Higher glucose variability predicted poorer sleep within-person (delayed bedtime, waketime, mid-sleep time, and lower sleep efficiency), while higher glucose variability was associated with poorer sleep and more sleep disruptions between persons (lower sleep efficiency, longer wake after sleep onset, and a higher sleep fragmentation index). Conclusion Clinicians can address the reciprocal nature of the sleep-glucose relationship by optimizing sleep and targeting efforts toward a euglycemic range overnight. Sleep habits are a modifiable personal target in diabetes care.

Background Immune disturbance has been postulated to be one of the mechanisms underlying the pathogenesis of tardive dyskinesia (TD). Recently, the role of autoimmune abnormality in TD has been increasingly recognized. Autoantibodies against neuronal N-methyl-D-aspartate receptor (NMDAR) may be cross-reactive in the brain in neuropsychiatric disorders, and the choroid plexus (CP) is a crucial immune barrier in the central nervous system (CNS). We supposed that NMDAR antibodies might underlie the pathophysiological process of TD through the mediation of CP. Methods Serum NMDAR antibody levels were assessed by enzyme-linked immunosorbent assay, CP and ventricle volumes were assessed by magnetic resonance imaging in schizophrenia patients with TD (n = 61), without TD (NTD, n = 61), and in healthy controls (n = 74). Psychopathology and TD severity were assessed by the Positive and Negative Syndrome Scale and Abnormal Involuntary Movement Scale (AIMS). Results NMDAR antibody levels were significantly higher, CP volumes were larger in the TD group than in the NTD group (p = 0.022; p = 0.019, respectively). In the TD group, higher NMDAR antibody level was correlated with larger CP volume (β = 0.406, p = 0.002). An elevated NMDAR antibody level and enlarged CP volume were correlated with orofacial AIMS score (β = 0.331, p = 0.011; β = 0.459, p = 3.34 × 10−4, respectively). In a mediation model, the effect of NMDAR antibody level on the orofacial AIMS score was mediated by the CP volume (indirect effect: β = 0.08, 95% confidence interval = 0.002–0.225; direct effect: β = 0.14, p = 0.154). Conclusions Our findings highlight a potential NMDAR antibody-associated mechanism in orofacial TD, which may be mediated by increased CP volume.

Prefrontal cortical dysfunctions underlying inhibitory control deficits in addiction are complex and likely dependent on population characteristics. Here, we conducted a meta-analysis to examine alterations in brain activations during response inhibition in addicted individuals. We characterized imaging findings based on substance use status, diagnosis, substance classes, and task performance. Results revealed in those with active drug addiction hypoactivation of the left dorsal anterior cingulate cortex (dACC) and right middle frontal gyrus (MFG), compared with healthy controls. Weakening of the dACC and MFG activations was particularly pronounced in nicotine users, respectively. Impaired task performance was also associated with diminished MFG activation. In contrast, abstinent users did not exhibit any significant differences compared with healthy controls. Those with behavioral addictions were characterized by higher midcingulate cortical activation. Thus, the neural disengagement during response inhibition in active drug addiction was limited to a small number of prefrontal cortical regions and dependent on population characteristics. Finally, the evidence for potential normalization of hypofrontality following substance use cessation highlights the benefits of abstinence in restoring cerebral functions.

ObjectiveOur study aimed to investigate the associations between the serum level of kynurenine pathway (KP) metabolites and P50 auditory gating in non-smoking patients with first-episode schizophrenia (FES).Materials and methodsIn this study, 82 non-smoking patients with FES and 73 healthy controls (HC). P50 auditory gating was measured using a fully functional digital 64-channel EEG system, and the components included S1 amplitude, S2 amplitude, gating ratio (S2/S1), and amplitude difference (S1–S2). Serum levels of kynurenine and kynurenine acid were assessed using a combination of liquid chromatography with tandem mass spectrometry. Psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS).ResultsThe serum kynurenine (251.46 ± 65.93 ng/ml vs. 320.65 ± 65.89 ng/ml, t = –6.38, p < 0.001), and kynurenine acid levels (5.19 ± 2.22 ng/ml vs. 13.26 ± 4.23 ng/ml, t = –14.73, p < 0.001), S1 amplitude [2.88 (1.79, 3.78) μV vs. 3.08 (2.46, 4.56) μV, Z = –2.17, p = 0.030] and S1–S2 [1.60 (0.63, 2.49) μV vs. 1.92 (1.12, 2.93) μV, Z = –2.23, p = 0.026] in patients with FES were significantly lower than those in HC. The serum kynurenine and kynurenine acid levels were negatively associated with S1–S2 (r = –0.32, p = 0.004 and r = –0.42, p < 0.001; respectively) and positively correlated with S2/S1 ratio (r = 0.34, p = 0.002 and r = 0.35, p = 0.002; respectively) in patients.ConclusionOur findings suggested that neuroactive metabolites of the KP might play an important role in sensory gating deficit in first episode patients with schizophrenia. Furthermore, metabolites of the KP may be a new target for the treatment of cognitive impairments in schizophrenia.

Studies have associated chemotherapy-elicited changes in cognitive function with impaired white matter integrity in cancer patients. Androgen deprivation therapy (ADT) may lead to cognitive deficits in prostate cancer patients; however, whether ADT influences white matter integrity has never been investigated. In a prospective study, 15 men with non-metastatic prostate cancer receiving ADT and 15 not receiving ADT (controls or CON), comparable in age and years of education, participated in N-back task, flankers' task, and quality-of-life (QoL) assessments. All participants underwent diffusion tensor imaging of the brain at baseline and at 6 months. Imaging data were processed with published routines. The results of a paired t-test of 6-month follow-up vs. baseline were evaluated at a corrected threshold for the whole brain each in ADT and CON. ADT patients showed significantly worse 1-back accuracy during follow-up, but the two groups did not differ in 2-back accuracy, 1- or 2-back reaction time (RT), flankers' task RT or QoL across time points. In ADT, significantly reduced fractional anisotropy (FA) was noted in the corpus callosum, forceps minor/anterior thalamic radiation, superior and posterior corona radiata. The differences in FA correlated significantly with changes in 2-back and flankers' task RT. No significant FA changes were noted during follow-up in CON. Six-month ADT affects white matter integrity, and the deficits were associated with slower processing speed. These findings add to the literature supporting the deleterious effects of androgen deprivation on the brain and cognition in prostate cancer patients.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1,024 OCD patients and 1,028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen’s d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen’s d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC=0.702) than unmedicated (AUC=0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Craving reflects the subjective urge to use drugs and can be triggered by both positive and negative emotional states. However, no studies have systematically investigated the relative roles of these mechanisms in the pathophysiology of substance misuse or distinguished the mechanisms in individual vulnerability to substance use disorders. In the current study, we performed meta-analyses of drug cue-elicited reactivity and win and loss processing in the monetary incentive delay task to identify distinct neural correlates of appetitive and aversive responses during cue exposure. We then characterized the appetitive and aversive cue responses in seventy-six alcohol drinkers performing a cue craving task during fMRI. Imaging data were processed according to published routines. The appetitive circuit involved medial cortical regions and the ventral striatum, and the aversive circuit involved the insula, caudate and mid-cingulate cortex. We observed a significant correlation of β estimates of cue-elicited activity of the appetitive and aversive circuit. However, individuals varied in appetitive and aversive cue responses. From the regression of appetitive (y) vs. aversive (x) β, we identified participants in the top 1/3 each of those with positive (n = 15) and negative (n = 11) residuals as “approach” and “avoidance” biotype, with the others as the “mixed” biotype (n = 50). For clinical characteristics, the avoidance biotype showed higher sensitivity to punishment. In contrast, the approach biotype showed higher levels of sensation seeking and alcohol expectancy for social and physical pressure. The findings highlighted distinct neural underpinnings of appetitive and aversive components of cue-elicited reactivity and substantiated the importance of biotyping substance misuse.

Background Negative emotions precipitate drug craving. Individuals vary in how they engage in negative emotions, as may be reflected in physiological arousal elicited by the emotions. It remains unclear whether physiological responses to negative emotions relate to cocaine craving and how regional brain activations support this relationship. Methods We examined brain activation and skin conductance responses (SCRs) among 40 cocaine-dependent (CD) subjects and 37 healthy control subjects during exposure to negative-emotional and neutral images. Imaging and SCR data were processed with published routines, and the results were evaluated at a corrected threshold. Results Relative to control subjects, CD subjects showed increased activation in the hippocampus, inferior parietal gyrus, and caudate in response to negative-emotional versus neutral images. CD subjects relative to control subjects showed diminished SCR to negative-emotional versus neutral images, and the difference (SCRNE-NU) was positively correlated with chronic craving, as evaluated by the Cocaine Craving Questionnaire, and craving rating (negative-emotional – neutral), in CD subjects. Activations of the midcingulate cortex (MCC) were positively correlated with both chronic cocaine craving and SCRNE-NU and completely mediated the correlation between chronic cocaine craving and SCRNE-NU. Further, path analyses suggested a directional influence of SCRNE-NU on craving rating (negative-emotional – neutral): chronic craving → MCC activation → SCRNE-NU → craving rating. Conclusions CD subjects demonstrate hypoactive SCRs to negative emotions. Less diminution of SCR is associated with higher cocaine craving and MCC response to negative emotions. A hub of the limbic motor circuit, the MCC may translate chronic cocaine craving into physiological responses that precipitate cocaine seeking.

Objectives: Genome-wide association studies have identified a significant risk gene, CACNA1C, for schizophrenia. In this study, we comprehensively investigated a large set of CACNA1C single-nucleotide polymorphisms (SNPs) to identify the replicable risk alleles for schizophrenia and explore their biological functions. Methods: One Jewish (1044 cases vs 2052 controls), one European (1350 cases vs 1378 controls) and one exploratory African American samples (98 cases vs 20 controls) were analyzed to identify replicable single-nucleotide polymorphism–schizophrenia associations. The regulatory effects of risk alleles on CACNA1C messenger RNA expression were examined. The most robust risk tagSNP (rs1006737) was meta-analyzed on 17 studies (74,122 cases vs 109,062 controls), and associated with the gray matter volumes of seven subcortical structures in 38,258 Europeans, and the surface areas and thickness of 34 cortical regions in 33,992 Europeans and 2944 non-Europeans. Results: Forty-seven replicable risk single-nucleotide polymorphisms, including a 20-single-nucleotide polymorphism haplotype block, were identified in our samples (1.8 × 10−4 ⩽ p ⩽ 0.049). This variant block was consistently associated with schizophrenia across four independent Psychiatric Genomics Consortium cohorts (79,645 cases vs 109,590 controls; 2.5 × 10–17 ⩽ p ⩽ 0.017). This block showed significant expression quantitative trait loci in three independent European brain cohorts (5.1 × 10–12 ⩽ p ⩽ 8.3 × 10–3) and could be tagged by the most significant risk single-nucleotide polymorphism rs1006737. The minor allele A of rs1006737 significantly increased risk for schizophrenia across the Jewish and European samples ( p = 0.029 and 0.004, respectively), and this association was highly significant in the meta-analysis ( p = 1.62 × 10–42). This allele also significantly altered the CACNA1C messenger RNA expression in five brain regions (5.1 × 10–12 ⩽ p ⩽ 0.05), decreased the gray matter volume of thalamus ( p = 0.010), the surface area of isthmus cingulate cortex ( p = 0.013) and the thickness of transverse temporal and superior temporal sulcus cortexes (0.005 ⩽ p ⩽ 0.043). Conclusion: We identified an independent, replicable, functional, and significant risk variant block at CACNA1C for schizophrenia, which could be tagged by the most robust risk marker rs1006737, suggesting an important role of CACNA1C in the pathogenesis of schizophrenia.