L E DeLisi

Harvard Medical School, Boston, Massachusetts, United States

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Publications (291)1570.49 Total impact

  • Lynn E. DeLisi
    Schizophrenia Research 01/2014; · 4.59 Impact Factor
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    ABSTRACT: The rs1344706, an intronic SNP within the zinc-finger protein 804A gene (ZNF804A), was identified as one of the most compelling risk SNPs for schizophrenia (SZ) and bipolar disorder (BD). It is however not clear by which molecular mechanisms ZNF804A increases disease risk. We evaluated the role of ZNF804A in SZ and BD by genotyping the originally associated rs1344706 SNP and an exonic SNP (rs12476147) located in exon four of ZNF804A in a sample of 422 SZ, 382 BD, and 507 controls from the isolated population of the Costa Rica Central Valley. We also investigated the rs1344706 SNP for allelic specific expression (ASE) imbalance in the dorsolateral prefrontal cortex (DLPFC) of 46 heterozygous postmortem brains. While no significant association between rs1344706 and SZ or BD was observed in the Costa Rica sample, we observed an increased risk of SZ for the minor allele (A) of the exonic rs12476147 SNP (p=0.026). Our ASE assay detected a significant over-expression of the rs12476147 A allele in DLPFC of rs1344706 heterozygous subjects. Interestingly, cDNA allele ratios were significantly different according to the intronic rs1344706 genotypes (p-value=0.03), with the rs1344706 A allele associated with increased ZNF804A rs12476147 A allele expression (average 1.06, p-value=0.02, for heterozygous subjects vs. genomic DNA). In conclusion, we have demonstrated a significant association of rs12476147 with SZ, and using a powerful within-subject design, an allelic expression imbalance of ZNF804A exonic SNP rs12476147 in the DLPFC. Although this data does not preclude the possibility of other functional variants in ZNF804A, it provides evidence that the rs1344706 SZ risk allele is the cis-regulatory variant directly responsible for this allelic expression imbalance in adult cortex.
    Schizophrenia Research 12/2013; · 4.59 Impact Factor
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    ABSTRACT: Cannabis is one of the most highly abused illicit drugs in the world. Several studies suggest a link between adolescent cannabis use and schizophrenia. An understanding of this link would have significant implications for legalization of cannabis and its medicinal value. The present study aims to determine whether familial morbid risk for schizophrenia is the crucial factor that underlies the association of adolescent cannabis use with the development of schizophrenia. Consecutively obtained probands were recruited into four samples: sample 1: 87 non-psychotic controls with no drug use; sample 2: 84 non-psychotic controls with cannabis use; sample 3: 32 patients with a schizophrenia spectrum psychosis with no drug use; sample 4: 76 patients with schizophrenia spectrum psychosis with cannabis use. All cannabis using subjects used this drug during adolescence, and no other substance, with the exception of alcohol. Structured interviews of probands and family informants were used to obtain diagnostic information about probands and all their known relatives. There was an increased morbid risk for schizophrenia in relatives of the cannabis using and non-using patient samples compared with their respective non-psychotic control samples (p=.002, p<.001 respectively). There was no significant difference in morbid risk for schizophrenia between relatives of the patients who use or do not use cannabis (p=.43). The results of the current study suggest that having an increased familial morbid risk for schizophrenia may be the underlying basis for schizophrenia in cannabis users and not cannabis use by itself.
    Schizophrenia Research 12/2013; · 4.59 Impact Factor
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    ABSTRACT: Abnormalities in language and language neural circuitry are observed in schizophrenia (SZ). Similar, but less pronounced language deficits are also seen in young first-degree relatives of people with SZ, who are at higher familial risk (FHR) for the disorder than the general population. The neural underpinnings of these deficits in people with FHR are unclear. Participants were 43 people with FHR and 32 comparable controls. fMRI scans were collected while participants viewed associated and unrelated word pairs, and performed a lexical decision task. fMRI analyses conducted in SPM8 examined group differences in the modulation of hemodynamic activity by semantic association. There were no group differences in demographics, IQ or behavioral semantic priming, but FHR participants had more schizotypal traits than controls. Controls exhibited the expected suppression of hemodynamic activity to associated versus unrelated word pairs. Compared to controls, FHR participants showed an opposite pattern of hemodynamic modulation to associated versus unrelated word pairs, in the left inferior frontal gyrus (IFG), right superior and middle temporal gyrus (STG) and the left cerebellum. Group differences in activation were significant, FWE-corrected for multiple comparisons (p<0.05). Activity within the IFG during the unrelated condition predicted schizotypal symptoms in FHR participants. FHR for SZ is associated with abnormally increased neural activity to semantic associates within an inferior frontal/temporal network. This might increase the risk of developing unusual ideas, perceptions and disorganized language that characterize schizotypal traits, potentially predicting which individuals are at greater risk to develop a psychotic disorder.
    Schizophrenia Research 10/2013; · 4.59 Impact Factor
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    ABSTRACT: Smaller hippocampal volumes similar to those found in schizophrenia (SZ) are frequently observed to a lesser extent in non-psychotic first-degree relatives of patients with the illness, compared to control subjects. In this study, subdivisions of the hippocampal formation and their association with verbal and visual learning and memory were assessed in persons at familial high risk (FHR) for SZ. MRI scans were acquired using a 3T Siemens scanner of young adult (ages 19-32) FHR subjects (N=46) and controls with no family history of illness (i.e., at low genetic risk LRC; N=31) were processed using FreeSurfer 5.0. Subfields of the hippocampal formation were evaluated using the van Leemput method (Van Leemput et al., 2010). Learning and memory measures were collected by standardized neurocognitive tests. Controlling intracranial volume, significantly reduced left (p<0.025), and right hippocampus (p<0.024) volumes were observed in FHR subjects. Among the subfields, the left (p<0.01) and right subicula (p<0.005) were significantly reduced in the FHR group. Immediate verbal recall of stories was significantly impaired and was significantly correlated with the left and right subicula within the FHR group. Reduced subiculum volume and its association with verbal memory refines further the association with left and right hippocampus reported in previous FHR studies of schizophrenia. Further research is needed to determine the specific genetic and environmental risk factors that may be related to hippocampal subfield alterations.
    Schizophrenia Research 10/2013; · 4.59 Impact Factor
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    ABSTRACT: Siblings of patients diagnosed with schizophrenia are at elevated risk for developing this disorder. The nature of such risk associated with brain abnormalities, and whether such abnormalities are similar to those observed in schizophrenia, remain unclear. Deficits in language processing are frequently reported in increased risk populations. Interestingly, white matter pathology involving fronto-temporal language pathways, including arcuate fasciculus (AF), uncinate fasciculus (UF), and inferior occipitofrontal fasciculus (IOFF), are frequently reported in schizophrenia. In this study, high spatial and directional resolution diffusion MRI data was obtained on a 3T magnet from 33 subjects with increased familial risk for developing schizophrenia, and 28 control subjects. Diffusion tractography was performed to measure white matter integrity within AF, UF, and IOFF. To understand these abnormalities, Fractional Anisotropy (FA, a measure of tract integrity) and Trace (a measure of overall diffusion), were combined with more specific measures of axial diffusivity (AX, a putative measure of axonal integrity) and radial diffusivity (RD, a putative measure of myelin integrity). Results revealed a significant decrease in Trace within IOFF, and a significant decrease in AX in all tracts. FA and RD anomalies, frequently reported in schizophrenia, were not observed. Moreover, AX group effect was modulated by age, with increased risk subjects demonstrating a deviation from normal maturation trajectory. Findings suggest that familial risk for schizophrenia may be associated with abnormalities in axonal rather than myelin integrity, and possibly associated with disruptions in normal brain maturation. AX should be considered a possible biomarker of risk for developing schizophrenia.
    Schizophrenia Research 06/2013; · 4.59 Impact Factor
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    ABSTRACT: Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets. To identify SCZ susceptibility genes. We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1,085,772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs. Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases. We included 11,185 cases and 10,768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families. Case-control status for SCZ. Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P.01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 x 10(-16) and 93% in subjects of European ancestry only (P < 2.20 < 10(-16)). Our results supported the major histocompatibility complex region showing a3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 x 10(-10)) and NOTCH4 (P = 3.16 x 10(-7)) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 x 10(-7)), AS3MT (P = 9.01 x 10(-7)), CNNM2 (P = 6.07 = 10(-7)), and NT5C2(P = 4.09 x 10(-7)). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction)and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse). We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.
    Archives of General Psychiatry 06/2013; 70(6):573-81. · 13.77 Impact Factor
  • Molecular psychiatry 01/2013; · 15.05 Impact Factor
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    ABSTRACT: The XXth World Congress of Psychiatric Genetics (WCPG), sponsored by The International Society of Psychiatric Genetics (ISPG) took place in Hamburg, Germany on October 14-18, 2012. Approximately 600 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned sessions as rapporteurs. This manuscript represents topics covered in most, but not all, oral presentations during the conference, and some of the major notable new findings reported at this 2012 WCPG. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2013; · 3.23 Impact Factor
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  • Henry A Nasrallah, Lynn E Delisi
    Schizophrenia Research 12/2012; · 4.59 Impact Factor
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    ABSTRACT: Schizophrenia is a severe and heritable brain disorder. Language impairment has been hypothesized to spur its onset and underlie the characteristic symptoms. In this study, we investigate whether altered topological pattern of the language processing brain network exists and could be a potential biomarker of schizophrenia. We hypothesized that both patients with schizophrenia and the genetic high risk population would show significantly weakened efficiencies of the network hubs for normal language processing, especially at left inferior frontal and bilateral temporal lobes. Language task-based fMRI data from 21 patients with schizophrenia, 22 genetic high risk subjects and 36 controls were analyzed. Graph theoretic and post hoc analyses of the fMRI data, and correlations between the functional network features and scores of language tests were carried out. Compared to controls, patients with schizophrenia and the high risk subjects showed significantly weakened network hubs in left inferior frontal and right fusiform gyri. A unique topology of super active and intercommunicating network hubs at left fusiform gyrus and right inferior/middle frontal gyri, which were associated with the behavioral language impairment was found in the patient group, compared to the high risk and control groups. Aberrant systems-level topology of language processing network, especially significantly weakened network hubs in left inferior frontal and right fusiform gyri, may serve as a candidate biomarker of schizophrenia. Supported by existing findings, the hyperactive left fusiform gyrus communicating with right frontal lobe might be the key neurophysiological component causing hallucinations in schizophrenia. These findings provided a new systems-level diagnostic target for the disorder.
    Schizophrenia Research 08/2012; 141(2-3):128-36. · 4.59 Impact Factor
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    ABSTRACT: The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012 and this year had as its emphasis, "The Globalization of Research". Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.
    Schizophrenia Research 08/2012; 141(1):e1-e24. · 4.59 Impact Factor
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    ABSTRACT: Neuroanatomical and cognitive alterations typical of schizophrenia (SZ) patients are observed to a lesser extent in their adolescent and adult first-degree relatives, likely reflecting neurodevelopmental abnormalities associated with genetic risk for the illness. The anatomical pathways for language are hypothesized to be abnormal and to underlie the positive symptoms of schizophrenia. Examining non-psychotic relatives at high familial risk (FHR) for schizophrenia may clarify if these deficits represent trait markers associated with genetic vulnerability, rather than specific markers resulting from the pathological process underlying schizophrenia. T1 MRI scans from a 3T Siemens scanner of young adult FHR subjects (N=46) and controls with no family history of illness (i.e. at low genetic risk LRC; N=31) were processed using FreeSurfer 5.0. We explored volumetric and lateralization alterations in regions associated with language processing. An extensive neuropsychological battery of language measures was administered. No significant differences were observed between groups on any language measures. Controlling intracranial volume, significantly smaller left pars triangularis (PT) (p<0.01) and right pars orbitalis (PO) (p<0.01) volumes and reversal of the L>R pars orbitalis (p<0.001) lateralization were observed in FHR subjects. In addition, the L pars triangularis and R pars orbitalis correlated with performance on tests of linguistic function in the FHR group. Reduced volume and reversed structural asymmetry in language-related regions hypothesized to be altered in SZ are also found in first degree relatives at FHR, despite normal language performance. To clarify if these findings are endophenotypes for Sz, future studies would need to be performed of ill and well family members no longer within the age range of risk for illness to show these deficits segregate with schizophrenia within families. Moreover, measures of complex language need to be studied to determine if FHR individuals manifest impairments in some aspects of language function.
    Schizophrenia Research 08/2012; 141(1):65-71. · 4.59 Impact Factor
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    ABSTRACT: The intrusion of associations into speech in schizophrenia disrupts coherence and comprehensibility, a feature of formal thought disorder referred to as loosened associations. We have previously proposed that loosened associations may result from hyperactivity in semantic association networks, leading to an increased frequency of associated words appearing in speech. Using Computed Associations in Sequential Text (CAST) software to quantify the frequency of such associations in speech, we have reported more frequent normative associations in language samples from patients with schizophrenia and in individuals with schizotypal characteristics. The present study further examined this deviance in schizophrenia by studying normative associations in those who share genes with an individual with schizophrenia, (i.e. first-degree relatives of probands with schizophrenia; HR) but who do not have an illness. Familial high-risk participants (n=22), and controls (n=24) provided verbal responses to cards from the Thematic Apperception Test. CAST analysis revealed that HR used more associated words in their speech compared to controls. Furthermore, the frequency of normative word associations was positively correlated with dimensional and total scores of schizotypy derived from ratings of the structured interview for schizotypy, which confirms past research showing a relationship between schizotypy and hyperassociations. Our results suggest that some language disturbances in schizophrenia likely arise from an underlying psychopathological mechanism, hyperactivity of semantic associations.
    Schizophrenia Research 07/2012; 140(1-3):99-103. · 4.59 Impact Factor
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    ABSTRACT: Several studies have associated cannabis use with the development of schizophrenia. However, it has been difficult to disentangle the effects of cannabis from that of other illicit drugs, as previous studies have not evaluated pure cannabis users. To test whether the onset of cannabis use had an effect on the initiation of psychosis, we examined the time relationship between onset of use and onset of psychosis, restricting our analysis to a cohort of individuals who only used cannabis and no other street drugs. Fifty-seven subjects with non-affective psychoses who used cannabis prior to developing a psychosis were interviewed using the Diagnostic Interview for Genetic Studies (DIGS). The Family Interview for Genetic Studies (FIGS) was also used to interview a family informant about psychiatric illness in the patient and the entire family. Multiple linear regression techniques were used to estimate the association between variables. After adjusting for potential confounding factors such as sex, age, lifetime diagnosis of alcohol abuse or dependence, and family history of schizophrenia, the age at onset of cannabis was significantly associated with age at onset of psychosis (β=0.4, 95% CI=0.1-0.7, p=0.004) and age at first hospitalization (β=0.4, 95% CI=0.1-0.8, p=0.008). The mean time between beginning to use cannabis and onset of psychosis was 7.0±4.3. Age at onset of alcohol use was not associated with age at onset of psychosis or age at first hospitalization. Age at onset of cannabis is directly associated with age at onset of psychosis and age at first hospitalization. These associations remain significant after adjusting for potential confounding factors and are consistent with the hypothesis that cannabis could cause or precipitate the onset of psychosis after a prolonged period of time.
    Schizophrenia Research 06/2012; 139(1-3):157-60. · 4.59 Impact Factor
  • W Wolfgang Fleischhacker, Lynn E DeLisi
    Current opinion in psychiatry 05/2012; 25(4):327-8. · 3.57 Impact Factor
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    ABSTRACT: Schizophrenia is a severe psychiatric disorder with a strong genetic predisposition. Structural and functional brain deficits throughout the cerebral cortex, particularly in the language-processing associated brain regions, are consistently reported. Recently, increasing evidence from magnetic resonance imaging (MRI) studies suggests that healthy relatives of schizophrenia patients also show structural brain abnormalities in cortical gray matter (GM) volume and thickness, suggesting that this may be associated with an unexpressed genetic liability for the disorder. Unfortunately, the findings are not consistent, which may be caused by different age ranges of the cohorts studied. In the present study, we examined the voxel-based whole brain cortical thickness, area, GM volume densities, and regional cortical thickness-related laterality indices in 14 bilateral regions of interest (ROIs) from known language-processing circuits in 20 schizophrenia patients, 21 young non-psychotic subjects with heightened genetic risk for schizophrenia at the peak ages for development of the disorder, and 48 matched controls. The results showed widespread significant reductions in cortical thickness, cortical GM volume density, and scattered decreases in cortical surface area in the schizophrenia patients compared with those in the high-risk subjects and normal controls. Moreover, the genetic high-risk subjects showed significantly increased regional cortical thickness in 7 of the 14 ROIs in the language-processing pathway when compared with controls. They also had increased GM volume density in scattered regions associated with language-processing when compared with the normal controls. Laterality analyses showed that the spatial distribution of abnormal cortical thickness in the schizophrenia patients, as well as in the high-risk subjects, contributes to a decrease of the normal left-greater-than-right anatomical asymmetry in the inferior orbital frontal area, and a increased left-greater-than-right pattern in the inferior parietal and occipital regions. Together with the existing findings in the literature, the results of the present study suggest that developmental disruption of the anatomical differentiation of the hemispheres provides a basis for understanding the language impairment and symptoms of psychosis, and that these may arise because of abnormal left-right hemispherical communications that interrupt the normal flow of information processing. The early structural deficits in language-processing circuits may precede the appearance of psychotic symptoms and may be an indicator of an increased risk of developing schizophrenia.
    Psychiatry Research 04/2012; 201(3):182-9. · 2.46 Impact Factor
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    ABSTRACT: Cannabis use can frequently have adverse affects in those that use it and these can be amplified by various characteristics of an individual, from demographic and environmental variations to familial predisposition for mental illnesses. The current study of 100 individuals, who were cannabis users during their adolescence and may still be users, was a survey of the self perceived effects of cannabis and their correlates. A reliable family member was also interviewed for determination of family history of various major mental illnesses and substance use. As many as 40% of cannabis users had paranoid feelings (suspiciousness) when using cannabis, although the most frequent effect was feeling relaxed (46%). Having a familial background for mental illnesses such as depression or schizophrenia did not determine the effects of cannabis nor its pattern of use, although the number of subjects with such a history was small. An age at which an individual began using cannabis did have an effect on how heavily it was used and the heavier the cannabis use, the more likely the individual was also to have had psychotic symptoms after use. There were no sex differences in effects of cannabis. These results are tempered by the reliance on self-report for many of the variables ascertained. Cannabis can frequently have negative effects in its users, which can be amplified by certain demographic and/or psychosocial factors. Thus, users with a specific profile may be at a higher risk of unpleasant effects from cannabis use and caution should be noted when cannabis is administered to young people for medicinal purposes.
    Harm Reduction Journal 03/2012; 9(1):15. · 1.26 Impact Factor
  • American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2012; 159B(1):128-9. · 3.23 Impact Factor

Publication Stats

8k Citations
1,570.49 Total Impact Points

Institutions

  • 2010–2014
    • Harvard Medical School
      • Department of Psychiatry
      Boston, Massachusetts, United States
    • Université de Montréal
      • Department of Medicine
      Montréal, Quebec, Canada
    • McGill University
      • Department of Psychiatry
      Montréal, Quebec, Canada
    • King's College London
      • Institute of Psychiatry
      London, ENG, United Kingdom
  • 2012–2013
    • Beth Israel Deaconess Medical Center
      • Department of Psychiatry
      Boston, Massachusetts, United States
    • University of Cincinnati
      Cincinnati, Ohio, United States
    • University of Western Australia
      • School of Psychiatry and Clinical Neurosciences
      Perth, Western Australia, Australia
    • Harvard University
      Cambridge, Massachusetts, United States
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 1989–2013
    • University of California, Irvine
      • • Department of Psychiatry & Human Behavior
      • • Department of Medicine
      Irvine, California, United States
  • 2010–2012
    • Yeshiva University
      • Department of Radiology
      New York City, New York, United States
  • 2011
    • Broad Institute of MIT and Harvard
      Cambridge, Massachusetts, United States
  • 2003–2010
    • Nathan Kline Institute
      Orangeburg, New York, United States
  • 1987–2010
    • National Institute of Mental Health (NIMH)
      • Clinical Brain Disorders Branch
      Bethesda, MD, United States
    • Vanderbilt University
      Nashville, Michigan, United States
  • 2009
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
    • Virginia Commonwealth University
      • Department of Human and Molecular Genetics
      Richmond, VA, United States
  • 2002–2009
    • CUNY Graduate Center
      New York City, New York, United States
    • Mount Sinai School of Medicine
      • Department of Psychiatry
      Manhattan, NY, United States
  • 2008
    • Morehouse School of Medicine
      Atlanta, Georgia, United States
    • Hadassah Medical Center
      Yerushalayim, Jerusalem District, Israel
  • 2001–2008
    • New York University
      • Department of Psychiatry
      New York City, NY, United States
  • 2006
    • New York State Psychiatric Institute
      New York City, New York, United States
  • 2003–2006
    • University of Oxford
      • Department of Psychiatry
      Oxford, ENG, United Kingdom
  • 2000–2005
    • SUNY Ulster
      Kingston, New York, United States
    • Johns Hopkins University
      • Department of Psychiatry and Behavioral Sciences
      Baltimore, MD, United States
  • 1991–2005
    • Napa State Hospital
      Napa, California, United States
  • 1992–2001
    • State University of New York
      New York City, New York, United States
  • 1993–2000
    • Stony Brook University
      • • Department of Psychiatry and Behavioral Science
      • • Health Sciences Center
      • • Department of Medicine
      Stony Brook, NY, United States
  • 1997
    • VA Palo Alto Health Care System
      Palo Alto, California, United States
  • 1996–1997
    • Public Health Agency
      Béal Feirste, N Ireland, United Kingdom