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1.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci 
Ripke, Stephan | Neale, Benjamin M | Corvin, Aiden | Walters, James TR | Farh, Kai-How | Holmans, Peter A | Lee, Phil | Bulik-Sullivan, Brendan | Collier, David A | Huang, Hailiang | Pers, Tune H | Agartz, Ingrid | Agerbo, Esben | Albus, Margot | Alexander, Madeline | Amin, Farooq | Bacanu, Silviu A | Begemann, Martin | Belliveau, Richard A | Bene, Judit | Bergen, Sarah E | Bevilacqua, Elizabeth | Bigdeli, Tim B | Black, Donald W | Bruggeman, Richard | Buccola, Nancy G | Buckner, Randy L | Byerley, William | Cahn, Wiepke | Cai, Guiqing | Campion, Dominique | Cantor, Rita M | Carr, Vaughan J | Carrera, Noa | Catts, Stanley V | Chambert, Kimberley D | Chan, Raymond CK | Chan, Ronald YL | Chen, Eric YH | Cheng, Wei | Cheung, Eric FC | Chong, Siow Ann | Cloninger, C Robert | Cohen, David | Cohen, Nadine | Cormican, Paul | Craddock, Nick | Crowley, James J | Curtis, David | Davidson, Michael | Davis, Kenneth L | Degenhardt, Franziska | Del Favero, Jurgen | Demontis, Ditte | Dikeos, Dimitris | Dinan, Timothy | Djurovic, Srdjan | Donohoe, Gary | Drapeau, Elodie | Duan, Jubao | Dudbridge, Frank | Durmishi, Naser | Eichhammer, Peter | Eriksson, Johan | Escott-Price, Valentina | Essioux, Laurent | Fanous, Ayman H | Farrell, Martilias S | Frank, Josef | Franke, Lude | Freedman, Robert | Freimer, Nelson B | Friedl, Marion | Friedman, Joseph I | Fromer, Menachem | Genovese, Giulio | Georgieva, Lyudmila | Giegling, Ina | Giusti-Rodríguez, Paola | Godard, Stephanie | Goldstein, Jacqueline I | Golimbet, Vera | Gopal, Srihari | Gratten, Jacob | de Haan, Lieuwe | Hammer, Christian | Hamshere, Marian L | Hansen, Mark | Hansen, Thomas | Haroutunian, Vahram | Hartmann, Annette M | Henskens, Frans A | Herms, Stefan | Hirschhorn, Joel N | Hoffmann, Per | Hofman, Andrea | Hollegaard, Mads V | Hougaard, David M | Ikeda, Masashi | Joa, Inge | Julià, Antonio | Kahn, René S | Kalaydjieva, Luba | Karachanak-Yankova, Sena | Karjalainen, Juha | Kavanagh, David | Keller, Matthew C | Kennedy, James L | Khrunin, Andrey | Kim, Yunjung | Klovins, Janis | Knowles, James A | Konte, Bettina | Kucinskas, Vaidutis | Kucinskiene, Zita Ausrele | Kuzelova-Ptackova, Hana | Kähler, Anna K | Laurent, Claudine | Lee, Jimmy | Lee, S Hong | Legge, Sophie E | Lerer, Bernard | Li, Miaoxin | Li, Tao | Liang, Kung-Yee | Lieberman, Jeffrey | Limborska, Svetlana | Loughland, Carmel M | Lubinski, Jan | Lönnqvist, Jouko | Macek, Milan | Magnusson, Patrik KE | Maher, Brion S | Maier, Wolfgang | Mallet, Jacques | Marsal, Sara | Mattheisen, Manuel | Mattingsdal, Morten | McCarley, Robert W | McDonald, Colm | McIntosh, Andrew M | Meier, Sandra | Meijer, Carin J | Melegh, Bela | Melle, Ingrid | Mesholam-Gately, Raquelle I | Metspalu, Andres | Michie, Patricia T | Milani, Lili | Milanova, Vihra | Mokrab, Younes | Morris, Derek W | Mors, Ole | Murphy, Kieran C | Murray, Robin M | Myin-Germeys, Inez | Müller-Myhsok, Bertram | Nelis, Mari | Nenadic, Igor | Nertney, Deborah A | Nestadt, Gerald | Nicodemus, Kristin K | Nikitina-Zake, Liene | Nisenbaum, Laura | Nordin, Annelie | O’Callaghan, Eadbhard | O’Dushlaine, Colm | O’Neill, F Anthony | Oh, Sang-Yun | Olincy, Ann | Olsen, Line | Van Os, Jim | Pantelis, Christos | Papadimitriou, George N | Papiol, Sergi | Parkhomenko, Elena | Pato, Michele T | Paunio, Tiina | Pejovic-Milovancevic, Milica | Perkins, Diana O | Pietiläinen, Olli | Pimm, Jonathan | Pocklington, Andrew J | Powell, John | Price, Alkes | Pulver, Ann E | Purcell, Shaun M | Quested, Digby | Rasmussen, Henrik B | Reichenberg, Abraham | Reimers, Mark A | Richards, Alexander L | Roffman, Joshua L | Roussos, Panos | Ruderfer, Douglas M | Salomaa, Veikko | Sanders, Alan R | Schall, Ulrich | Schubert, Christian R | Schulze, Thomas G | Schwab, Sibylle G | Scolnick, Edward M | Scott, Rodney J | Seidman, Larry J | Shi, Jianxin | Sigurdsson, Engilbert | Silagadze, Teimuraz | Silverman, Jeremy M | Sim, Kang | Slominsky, Petr | Smoller, Jordan W | So, Hon-Cheong | Spencer, Chris C A | Stahl, Eli A | Stefansson, Hreinn | Steinberg, Stacy | Stogmann, Elisabeth | Straub, Richard E | Strengman, Eric | Strohmaier, Jana | Stroup, T Scott | Subramaniam, Mythily | Suvisaari, Jaana | Svrakic, Dragan M | Szatkiewicz, Jin P | Söderman, Erik | Thirumalai, Srinivas | Toncheva, Draga | Tosato, Sarah | Veijola, Juha | Waddington, John | Walsh, Dermot | Wang, Dai | Wang, Qiang | Webb, Bradley T | Weiser, Mark | Wildenauer, Dieter B | Williams, Nigel M | Williams, Stephanie | Witt, Stephanie H | Wolen, Aaron R | Wong, Emily HM | Wormley, Brandon K | Xi, Hualin Simon | Zai, Clement C | Zheng, Xuebin | Zimprich, Fritz | Wray, Naomi R | Stefansson, Kari | Visscher, Peter M | Adolfsson, Rolf | Andreassen, Ole A | Blackwood, Douglas HR | Bramon, Elvira | Buxbaum, Joseph D | Børglum, Anders D | Cichon, Sven | Darvasi, Ariel | Domenici, Enrico | Ehrenreich, Hannelore | Esko, Tõnu | Gejman, Pablo V | Gill, Michael | Gurling, Hugh | Hultman, Christina M | Iwata, Nakao | Jablensky, Assen V | Jönsson, Erik G | Kendler, Kenneth S | Kirov, George | Knight, Jo | Lencz, Todd | Levinson, Douglas F | Li, Qingqin S | Liu, Jianjun | Malhotra, Anil K | McCarroll, Steven A | McQuillin, Andrew | Moran, Jennifer L | Mortensen, Preben B | Mowry, Bryan J | Nöthen, Markus M | Ophoff, Roel A | Owen, Michael J | Palotie, Aarno | Pato, Carlos N | Petryshen, Tracey L | Posthuma, Danielle | Rietschel, Marcella | Riley, Brien P | Rujescu, Dan | Sham, Pak C | Sklar, Pamela | St Clair, David | Weinberger, Daniel R | Wendland, Jens R | Werge, Thomas | Daly, Mark J | Sullivan, Patrick F | O’Donovan, Michael C
Nature  2014;511(7510):421-427.
Summary
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
doi:10.1038/nature13595
PMCID: PMC4112379  PMID: 25056061
2.  Impairment in Functional Capacity as an Endophenotype Candidate in Severe Mental Illness 
Schizophrenia Bulletin  2011;38(6):1318-1326.
Impairment in everyday functioning (also referred to as “disability”) is a central feature of schizophrenia (SZ) and bipolar disorder, as well as other neuropsychiatric conditions. There is a genetic contribution to both SZ and bipolar illness (BPI), and the primary putative determinant of impairments in everyday functioning across these 2 conditions, cognitive impairments, also show substantial heritability and in fact have been proposed to be endophenotypes for these disorders. In this article, we review data and make our case that impairments in functional capacity, the functional abilities that result in functional disability, may also be a heritable trait that is common across neuropsychiatric illnesses such BPI and SZ. While there has been little previous research on the heritability of these abilities, it is an area receiving substantial research attention. We consider advances in the measurement of cognitive functioning in SZ that may facilitate the discovery of genetic influences on functional capacity. Functional capacity measures are proximal to real-world impairments, measured with suitable psychometric precision to be used in heritability analyses, and appear to be minimally influenced by environmental factors that may cause disability such as environmental factors, symptoms, and disability compensation. Our conclusion is that these functional capacity measures have potential to be the target of genetic analyses and that these measures should be considered across neuropsychiatric conditions where impairments in everyday functioning are present.
doi:10.1093/schbul/sbr046
PMCID: PMC3494058  PMID: 21562142
schizophrenia; disability; endophenotypes
3.  Prediction of Real World Functional Disability in Chronic Mental Disorders: A Comparison of Schizophrenia and Bipolar Disorder 
The American journal of psychiatry  2010;167(9):1116-1124.
OBJECTIVE
Schizophrenia (SZ) and Bipolar Disorder (BD) are associated with multidimensional disability. This study examined differential predictors of functional deficits between the disorders.
METHODS
Community dwelling individuals with SZ (N=161) or BD (N=130) were administered neuropsychological tests, symptom measures, performance-based social and adaptive (i.e., everyday-living skills) functional competence measures, and rated on domains of real-world functioning: 1) Community and Household activities, 2) Work skills, and 3) Interpersonal relationships. We used confirmatory path analysis to find the best fitting models to examine the direct and indirect (as mediated by competence) prediction of the three domains of real-world functioning.
RESULTS
In all models for both groups, neurocognition’s relationship with outcomes was largely mediated by competence. Symptoms were negatively associated with outcomes but unassociated with competence, with the exception of depression, which was a direct and mediated (through social competence) predictor in BD. In both groups, neurocognition was related to Activities directly and through a mediated relationship with adaptive competence. Work Skills were directly and indirectly (through mediation with social competence) predicted by neurocognition in SZ and entirely mediated by adaptive and social competence in BD. Neurocognition was associated with Interpersonal Relationships directly in the SZ group, and mediated by social competence in both groups.
CONCLUSIONS
Although there was greater disability in SZ, neurocognition predicted worse functioning in all outcome domains in both disorders. Our study supports the shared role of neurocognition in BD and SZ in producing disability, with predictive differences between disorders observed in domain-specific effects of symptoms and social and adaptive competence.
doi:10.1176/appi.ajp.2010.09101406
PMCID: PMC3694770  PMID: 20478878
4.  Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia 
Human genetics  2011;130(5):635-643.
Dopamine β-hydroxylase (DβH) catalyzes the conversion of dopamine to norepinephrine. DβH enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma DβH activity (pDβH) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pDβH to ABO on 9q34, and positive evidence for linkage to the complement fixation locus on 19p13.2-13.3. Subsequent association studies strongly supported DBH, which maps adjacent to ABO, as the locus regulating a large proportion of the heritable variation in pDβH. Prior studies have suggested that variation in pDβH, or genetic variants at DβH, associate with differences in expression of psychotic symptoms in patients with schizophrenia and other idiopathic or drug-induced brain disorders, suggesting that DBH might be a genetic modifier of psychotic symptoms. As a first step toward investigating that hypothesis, we performed linkage analysis on pDβH in patients with schizophrenia and their relatives. The results strongly confirm linkage of markers at DBH to pDβH under several models (maximum multipoint LOD score, 6.33), but find no evidence to support linkage anywhere on chromosome 19. Accounting for the contributions to the linkage signal of three SNPs at DBH, rs1611115, rs1611122, and rs6271 reduced but did not eliminate the linkage peak, whereas accounting for all SNPs near DBH eliminated the signal entirely. Analysis of markers genome-wide uncovered positive evidence for linkage between markers at chromosome 20p12 (multi-point LOD = 3.1 at 27.2 cM). The present results provide the first direct evidence for linkage between DBH and pDβH, suggest that rs1611115, rs1611122, rs6271 and additional unidentified variants at or near DBH contribute to the genetic regulation of pDβH, and suggest that a locus near 20p12 also influences pDβH.
doi:10.1007/s00439-011-0989-6
PMCID: PMC3193571  PMID: 21509519
5.  Sensitivity and Specificity of the UCSD Performance-based Skills Assessment (UPSA-B) for Identifying Functional Milestones in Schizophrenia 
Schizophrenia research  2011;132(2-3):165-170.
Schizophrenia is a highly debilitating illness that often results in disruption to independent living and employment. However, “gold standard” methods of assessing functional abilities to achieve these milestones are still lacking. In a sample of 367 individuals with schizophrenia, we examined the sensitivity and specificity of the Brief UCSD Performance-based Skills Assessment (UPSA-B) to predict both residential and employment status. Of all individuals residing independently, 75.9% scored 78 or above on the UPSA-B, and of all individuals not residing independently, 59% scored below 78 on the UPSA-B. Of individuals who were employed, 73.9% scored above 82 on the UPSA-B, and of those not employed, 57.8% scored below 82. These results expand upon both the population base and functional milestones with which the UPSA-B is validated, although future work should examine whether the UPSA-B can be used as a decision aid in the likelihood of success in a longitudinal study, such as at critical transitions (post-hospitalization, cessation of supported housing).
doi:10.1016/j.schres.2011.07.022
PMCID: PMC3195873  PMID: 21843926
Psychosis; Functional Capacity; Functioning; Employment; Independence; Well-being
6.  Relationship of the Brief UCSD Performance-based Skills Assessment (UPSA-B) to multiple indicators of functioning in people with schizophrenia and bipolar disorder 
Bipolar disorders  2010;12(1):45-55.
Objective
This study assessed the relationship between multiple indicators of ‘real-world’ functioning and scores on a brief performance-based measure of functional capacity known as the Brief University of California San Diego (UCSD) Performance-based Skills Assessment (UPSA-B) in a sample of 205 patients with either serious bipolar disorder (n = 89) or schizophrenia (n = 116).
Methods
Participants were administered the UPSA-B and assessed on the following functional domains: (i) independent living status (e.g., residing independently as head of household, living in residential care facility); (ii) informant reports of functioning (e.g., work skills, daily living skills); (iii) educational attainment and estimated premorbid IQ as measured by years of education and Wide Range Achievement Test reading scores, respectively; and (iv) employment.
Results
Better scores on the UPSA-B were associated with greater residential independence after controlling for age, diagnosis, and symptoms of psychopathology. Among both bipolar disorder and schizophrenia patients, higher UPSA-B scores were significantly related to better informant reports of functioning in daily living skills and work skills domains. Greater estimated premorbid IQ was associated with higher scores on the UPSA-B for both schizophrenia and bipolar disorder participants. Participants who were employed scored higher on the UPSA-B when controlling for age and diagnosis, but not when controlling for symptoms of psychopathology.
Conclusions
These data suggest the UPSA-B may be useful for assessing capacity for functioning in a number of domains in both people diagnosed with schizophrenia and bipolar disorder.
doi:10.1111/j.1399-5618.2009.00787.x
PMCID: PMC2846793  PMID: 20148866
employment; functional capacity; functional outcome; independence; severe; mental illness
7.  European Population Genetic Substructure: Further Definition of Ancestry Informative Markers for Distinguishing among Diverse European Ethnic Groups 
Molecular Medicine  2009;15(11-12):371-383.
The definition of European population genetic substructure and its application to understanding complex phenotypes is becoming increasingly important. In the current study using over 4,000 subjects genotyped for 300,000 single-nucleotide polymorphisms (SNPs), we provide further insight into relationships among European population groups and identify sets of SNP ancestry informative markers (AIMs) for application in genetic studies. In general, the graphical description of these principal components analyses (PCA) of diverse European subjects showed a strong correspondence to the geographical relationships of specific countries or regions of origin. Clearer separation of different ethnic and regional populations was observed when northern and southern European groups were considered separately and the PCA results were influenced by the inclusion or exclusion of different self-identified population groups including Ashkenazi Jewish, Sardinian, and Orcadian ethnic groups. SNP AIM sets were identified that could distinguish the regional and ethnic population groups. Moreover, the studies demonstrated that most allele frequency differences between different European groups could be controlled effectively in analyses using these AIM sets. The European substructure AIMs should be widely applicable to ongoing studies to confirm and delineate specific disease susceptibility candidate regions without the necessity of performing additional genome-wide SNP studies in additional subject sets.
doi:10.2119/molmed.2009.00094
PMCID: PMC2730349  PMID: 19707526
8.  Sex-Specific Clinical Correlates of Hoarding in Obsessive-Compulsive Disorder 
Behaviour research and therapy  2008;46(9):1040-1046.
Little is known about whether the clinical correlates of hoarding behavior are different in men and women with obsessive-compulsive disorder (OCD). In the current study, we evaluated the association of hoarding with categories of obsessions and compulsions, psychiatric disorders, personality dimensions, and other clinical characteristics separately in 151 men and 358 women with OCD who were examined during the OCD Collaborative Genetics Study. We found that, among men but not women, hoarding was associated with aggressive, sexual, and religious obsessions and checking compulsions. In men, hoarding was associated with generalized anxiety disorder and tics whereas, among women, hoarding was associated with social phobia, post-traumatic stress disorder, body dysmorphic disorder, nail biting, and skin picking. In women but not men, hoarding was associated with schizotypal and dependent personality disorder dimensions, and with low conscientiousness. These findings indicate that specific clinical correlates of hoarding in OCD are different in men and women and may reflect sex-specific differences in the course, expression, and/or etiology of hoarding behavior in OCD.
doi:10.1016/j.brat.2008.06.005
PMCID: PMC2578847  PMID: 18692168
Obsessive-compulsive disorder; hoarding; comorbidity; personality disorders; personality; sex differences
9.  PCM1 is recruited to the centrosome by the cooperative action of DISC1 and BBS4 and is a candidate for psychiatric illness 
Archives of general psychiatry  2008;65(9):996-1006.
Context
A role for the centrosome has been suggested in the pathology of major mental illnesses, especially schizophrenia (SZ).
Objectives
To show that pericentriolar material-1 protein (PCM1) forms a complex at the centrosome with Disrupted-In-Schizophrenia-1 (DISC1) and Bardet-Biedl syndrome-4 protein (BBS4), which provides a crucial pathway for cortical development associated with the pathology of SZ. To identify mutations in the PCM1 gene in a SZ population.
Design
Interaction of DISC1, PCM1, and BBS proteins was assessed by immunofluorescent staining and co-immunoprecipitation. Effects of PCM1, DISC1, and BBS on centrosomal functions and corticogenesis in vivo were tested by RNAi. PCM1 gene was examined by sequencing 39 exons and flanking splice sites.
Setting and Patients
Thirty-two probands with SZ from families that had excess allele sharing among affected individuals at 8p22, and 219 Caucasian controls.
Main Outcome Measures
Protein interaction and recruitment at the centrosome in cells; neuronal migration in the cerebral cortex; variant discovery in PCM1 in SZ patients.
Results
PCM1 forms a complex with DISC1 and BBS4 through discrete binding domains in each protein. DISC1 and BBS4 are required for targeting PCM1 and other cargo proteins, such as ninein, to the centrosome in a synergistic manner. In the developing cerebral cortex, suppression of PCM1 leads to neuronal migration defects, which are phenocopied by the suppression of either DISC1 or BBS4, and are exacerbated by the concomitant suppression of both. Furtheremore, a nonsense mutation that segregates with schizophrenia-spectrum psychosis is found in one family.
Conclusion
Our data further support for the role of centrosomal proteins in cortical development and suggest that perturbation of centrosomal function contributes to the development of mental diseases including SZ.
doi:10.1001/archpsyc.65.9.996
PMCID: PMC2727928  PMID: 18762586
10.  Analysis and Application of European Genetic Substructure Using 300 K SNP Information 
PLoS Genetics  2008;4(1):e4.
European population genetic substructure was examined in a diverse set of >1,000 individuals of European descent, each genotyped with >300 K SNPs. Both STRUCTURE and principal component analyses (PCA) showed the largest division/principal component (PC) differentiated northern from southern European ancestry. A second PC further separated Italian, Spanish, and Greek individuals from those of Ashkenazi Jewish ancestry as well as distinguishing among northern European populations. In separate analyses of northern European participants other substructure relationships were discerned showing a west to east gradient. Application of this substructure information was critical in examining a real dataset in whole genome association (WGA) analyses for rheumatoid arthritis in European Americans to reduce false positive signals. In addition, two sets of European substructure ancestry informative markers (ESAIMs) were identified that provide substantial substructure information. The results provide further insight into European population genetic substructure and show that this information can be used for improving error rates in association testing of candidate genes and in replication studies of WGA scans.
Author Summary
Ancestry differences corresponding to ethnic groups may be important in determining disease risk factors and optimizing treatment. Our study further defines ancestry relationship among different European ethnic groups by examining over 300 thousand variations in DNA, in over 2,000 individuals. This study allowed a clearer ascertainment of differences that could not be discerned in smaller studies using more limited numbers of DNA variations. We show clear differences among European American participants of different self-identified ethnic affiliation. The analyses showed multiple components of variation. The components showing the largest variations generally corresponded to the grandparental country or region of origin within Europe. We also show the importance of applying this information in determining genetic risk factors for complex diseases. Moreover, the results have enabled a better selection of smaller numbers of DNA variations that can be used in future disease studies to identify more homogenous participant groups and minimize false positive and false negative results in assessing genetic risk factors for disease.
doi:10.1371/journal.pgen.0040004
PMCID: PMC2211544  PMID: 18208329
11.  Neuropsychological Functioning in Bipolar Disorder and Schizophrenia 
Biological psychiatry  2006;62(2):179-186.
Background
Some patients with bipolar disorder (BD) demonstrate neuropsychological deficits even when stable. However, it remains unclear whether these differ qualitatively from those seen in schizophrenia (SZ).
Method
We compared the nature and severity of cognitive deficits shown by 106 patients with SZ and 66 patients with BD to 316 healthy adults (NC). All participants completed a cognitive battery with 19 individual measures. After adjusting their test performance for age, sex, race, education, and estimated premorbid IQ, we derived regression-based T-scores for each measure and the six cognitive domains.
Results
Both patient groups performed significantly worse than NCs on most (BD) or all (SZ) cognitive tests and domains. The resulting effect sizes ranged from 0.37 to 1.32 (mean = 0.97) across tests for SZ patients and from 0.23 to 0.87 (mean = 0.59) for BD patients. The Pearson correlation of these effect sizes was 0.71 (p < 0.001).
Conclusions
Patients with bipolar disorder suffer from cognitive deficits that are milder but qualitatively similar to those of patients with schizophrenia. These findings support the notion that schizophrenia and bipolar disorder show greater phenotypic similarity in terms of the nature than severity of their neuropsychological deficits.
doi:10.1016/j.biopsych.2006.09.025
PMCID: PMC2041824  PMID: 17161829
bipolar disorder; schizophrenia; cognitive testing; neuropsychology; biomarker

Results 1-11 (11)