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Tsuang, Ming

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Tsuang

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Ming

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Tsuang, Ming
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    Genetic loci associated with an earlier age at onset in multiplex schizophrenia
    (Nature Publishing Group UK, 2017) Woolston, Annemarie L.; Hsiao, Po-Chang; Kuo, Po-Hsiu; Wang, Shi-Heng; Lien, Yin-Ju; Liu, Chih-Min; Hwu, Hai-Gwo; Lu, Tzu-Pin; Chuang, Eric Y.; Chang, Li-Ching; Chen, Chien-Hsiun; Wu, Jer-Yuarn; Tsuang, Ming; Chen, Wei J.
    An earlier age at onset (AAO) has been associated with greater genetic loadings in schizophrenia. This study aimed to identify modifier loci associated with an earlier AAO of schizophrenia. A genome-wide association analysis (GWAS) was conducted in 94 schizophrenia probands with the earliest AAO and 91 with the latest AAO. Candidate single nucleotide polymorphisms (SNPs) were then genotyped in the co-affected siblings and unrelated probands. Multi-SNP genetic risk scores (GRS) composed of the candidate loci were used to distinguish patients with an early or late AAO. The 14-SNP GRS could distinguish the co-affected siblings (n = 90) of the earliest probands from those (n = 91) of the latest probands. When 132 patients with an earlier AAO and 158 patients with a later AAO were included, a significant trend in the 14-SNP GRS was detected among those unrelated probands from 4 family groups with the earliest, earlier, later, and latest AAO. The overall effect of the 14 SNPs on an AAO in schizophrenia was verified using co-affected siblings of the GWAS probands and trend effect across unrelated patients. Preliminary network analysis of these loci revealed the involvement of PARK2, a gene intensively reported in Parkinson’s disease and schizophrenia research.
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    F118. ARCHITECTURE OF PSYCHOSIS SYMPTOMS AND NEURAL PREDICTORS OF CONVERSION AMONG CLINICAL HIGH RISK INDIVIDUALS WITH AUTISM SPECTRUM DISORDER
    (Oxford University Press, 2018) Foss-Feig, Jennifer; Velthorst, Eva; Guillory, Sylvia; Hamilton, Holly; Roach, Brian; Bachman, Peter; Belger, Aysenil; Carrion, Ricardo; Duncan, Erica; Johannesen, Jason; Light, Gregory; Niznikiewicz, Margaret; Addington, Jean; Cadenhead, Kristin; Cannon, Tyrone; Cornblatt, Barbara; McGlashan, Thomas; Perkins, Diana; Seidman, Larry; Tsuang, Ming; Walker, Elaine; Woods, Scott; Bearden, Carrie; Mathalon, Daniel
    Abstract Background: Individuals with autism spectrum disorders (ASD) have symptoms, including social and sensory deficits, and neurobiological alterations that overlap with schizophrenia. Though there is evidence of high rates of psychosis symptoms in ASD, little is known about psychosis prodrome in ASD, or about predictors of psychosis conversion in this population. In this study, we leverage data from clinical high risk (CHR) patients from the NAPLS2 consortium to examine: a) baseline differences in psychosis symptoms and social functioning, b) relative risk of conversion, and c) whether neural response to sensory stimuli yields differential predictors of conversion in CHR individuals with and without ASD (CHR/ASD+; CHR/ASD-). Methods: Clinical, electrophysiological, and 24-month follow-up data were available for 305 individuals (14 CHR/ASD+; 291 CHR/ASD-). We examined baseline differences on the SOPS, GFS, and TASIT. Conversion risk was computed with the Cannon conversion calculator, and conversion was defined as SOPS>6 at 2-year outcome. P300 event-related potentials (ERP) were extracted from ongoing EEG collected at baseline in response to Target and Novel auditory and visual stimuli, each presented on 10% of trials within streams of 80% standard stimuli in the same modality. Results: In line with our expectations, CHR/ASD+ had worse functioning than CHR/ASD- on the GF-Social scale (t=-4.2, p<.01) and TASIT total score (t=-2.9, p=<.01), but groups did not differ in their psychotic symptoms on the SOPS (Positive: p=.72; Negative: p=.13; Disorganization: p=.13; General: p=.86). Groups did not differ in the rate at which they converted to psychosis (CHR/ASD+: 15.4%; CHR/ASD-: 11.1%; p=.50), and the Cannon risk score was equally predictive of 2-year conversion across groups (p=.39). EEG data revealed dissociable profiles regarding neural response to sensory stimuli in those who did versus did not convert to psychosis, depending on ASD status. P300 response over central electrodes to Novel visual stimuli was weaker in CHR- converters (n=71) than CHR- non-converters (n=220), but stronger in CHR/ASD+ converters (n=4) than CHR/ASD+ non-converters (n=10) (Novel Stimuli: Modality by ASD interaction, F=5.66, p=.02; Modality by ASD by Converter Interaction, F=3.57, p=.06). For both auditory and visual Target stimuli, P300 response over parietal electrodes did not differ between CHR/ASD- converters and non-converters; however, whereas CHR/ASD+ individuals who did not convert had amplitudes similar to all CHR/ASD- individuals, CHR/ASD+ converters had substantially greater auditory and visual P300 amplitudes (Target Stimuli: ASD by Converter interaction, F=12.12, p=.001). Discussion Individuals with ASD and CHR have greater social deficits than the general CHR population, but show similar psychotic symptoms and have similar risk for conversion to psychosis. Neural response to sensory stimuli is important for understanding risk for conversion, and differs among CHR individuals dependent on whether they have ASD. In particular, whereas all CHR individuals who do not convert share a common pattern of attenuated ERP amplitudes reflecting attention allocation to target and novel auditory and visual stimuli, CHR/ASD+ who convert have a unique pattern of globally heightened P300 responses to infrequent novel and target stimuli. These findings have two important implications: 1) individuals with ASD do convert to psychosis and have similar CHR symptom and risk profiles to non-ASD CHR patients clinically; 2) in CHR individuals with ASD in particular, examining neural markers of attention allocation to sensory stimuli may reveal important predictive clues about risk for conversion.
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    Negative Symptoms of Psychosis Correlate with Gene Expression of the Wnt/β-Catenin Signaling Pathway in Peripheral Blood
    (Hindawi Publishing Corporation, 2013) Bousman, Chad A.; Glatt, Stephen J.; Chandler, Sharon D.; Lohr, James; Kremen, William S.; Tsuang, Ming; Everall, Ian P.
    Genes in the Wnt (wingless)/β-catenin signaling pathway have been implicated in schizophrenia pathogenesis. No study has examined this pathway in the broader context of psychosis symptom severity. We investigated the association between symptom severity scores and expression of 25 Wnt pathway genes in blood from 19 psychotic patients. Significant correlations between negative symptom scores and deshivelled 2 (DVL2) (radj = −0.70; P = 0.0008) and glycogen synthase kinase 3 beta (GSK3B) (radj = 0.48; P = 0.039) were observed. No gene expression levels were associated with positive symptoms. Our findings suggest that the Wnt signaling pathway may harbor biomarkers for severity of negative but not positive symptoms.
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    Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia
    (Proceedings of the National Academy of Sciences, 2009) Whitfield-Gabrieli, S.; Thermenos, Heidi; Milanovic, Snezana M.; Tsuang, Ming; Faraone, Stephen; McCarley, Robert William; Shenton, Martha; Green, Alan; Nieto-Castanon, A.; LaViolette, P.; Wojcik, Joanne; Gabrieli, John; Seidman, Larry Joel
    We examined the status of the neural network mediating the default mode of brain function, which typically exhibits greater activation during rest than during task, in patients in the early phase of schizophrenia and in young first-degree relatives of persons with schizophrenia. During functional MRI, patients, relatives, and controls alternated between rest and performance of working memory (WM) tasks. As expected, controls exhibited task-related suppression of activation in the default network, including medial prefrontal cortex (MPFC) and posterior cingulate cortex/precuneus. Patients and relatives exhibited significantly reduced task-related suppression in MPFC, and these reductions remained after controlling for performance. Increased task-related MPFC suppression correlated with better WM performance in patients and relatives and with less psychopathology in all 3 groups. For WM task performance, patients and relatives had greater activation in right dorsolateral prefrontal cortex (DLPFC) than controls. During rest and task, patients and relatives exhibited abnormally high functional connectivity within the default network. The magnitudes of default network connectivity during rest and task correlated with psychopathology in the patients. Further, during both rest and task, patients exhibited reduced anticorrelations between MPFC and DLPFC, a region that was hyperactivated by patients and relatives during WM performance. Among patients, the magnitude of MPFC task suppression negatively correlated with default connectivity, suggesting an association between the hyperactivation and hyperconnectivity in schizophrenia. Hyperactivation (reduced task-related suppression) of default regions and hyperconnectivity of the default network may contribute to disturbances of thought in schizophrenia and risk for the illness.
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    Haplotypes of the D-Amino Acid Oxidase Gene Are Significantly Associated with Schizophrenia and Its Neurocognitive Deficits
    (Public Library of Science, 2016) Liu, Yu-Li; Wang, Sheng-Chang; Hwu, Hai-Gwo; Fann, Cathy Shen-Jang; Yang, Ueng-Cheng; Yang, Wei-Chih; Hsu, Pei-Chun; Chang, Chien-Ching; Wen, Chun-Chiang; Tsai-Wu, Jyy-Jih; Hwang, Tzung-Jeng; Hsieh, Ming H.; Liu, Chen-Chung; Chien, Yi-Ling; Fang, Chiu-Ping; Faraone, Stephen V.; Tsuang, Ming; Chen, Wei J.; Liu, Chih-Min
    D-amino acid oxidase (DAO) has been reported to be associated with schizophrenia. This study aimed to search for genetic variants associated with this gene. The genomic regions of all exons, highly conserved regions of introns, and promoters of this gene were sequenced. Potentially meaningful single-nucleotide polymorphisms (SNPs) obtained from direct sequencing were selected for genotyping in 600 controls and 912 patients with schizophrenia and in a replicated sample consisting of 388 patients with schizophrenia. Genetic associations were examined using single-locus and haplotype association analyses. In single-locus analyses, the frequency of the C allele of a novel SNP rs55944529 located at intron 8 was found to be significantly higher in the original large patient sample (p = 0.016). This allele was associated with a higher level of DAO mRNA expression in the Epstein-Barr virus-transformed lymphocytes. The haplotype distribution of a haplotype block composed of rs11114083-rs2070586-rs2070587-rs55944529 across intron 1 and intron 8 was significantly different between the patients and controls and the haplotype frequencies of AAGC were significantly higher in patients, in both the original (corrected p < 0.0001) and replicated samples (corrected p = 0.0003). The CGTC haplotype was specifically associated with the subgroup with deficits in sustained attention and executive function and the AAGC haplotype was associated with the subgroup without such deficits. The DAO gene was a susceptibility gene for schizophrenia and the genomic region between intron 1 and intron 8 may harbor functional genetic variants, which may influence the mRNA expression of DAO and neurocognitive functions in schizophrenia.
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    Evidence for Genetic Association of RORB with Bipolar Disorder
    (BioMed Central, 2009) McGrath, Casey L; Glatt, Stephen J; Sklar, Pamela B.; Le-Niculescu, Helen; Niculescu, Alexander B; Kuczenski, Ronald; Doyle, Alysa; Biederman, Joseph; Mick, Eric Owen; Faraone, Stephen; Tsuang, Ming
    Background: Bipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (DBP) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, RAR-related orphan receptors alpha (RORA) and beta (RORB), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in RORA and RORB.Methods We genotyped 355 RORA and RORB SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching. Results: We report that four intronic RORB SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three RORB haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any RORA SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any RORA or RORB SNPs.Conclusion Our findings suggest that clock genes in general and RORB in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.