• The concept of target features in schizophrenia research

      Tsuang, M. T.; Faraone, S. V. (Wiley, 1999-05)
      Target features are clinical or neurobiological characteristics that arc expressions of the underlying predisposition to an illness. They comprise a wide range of phenomena, from thc classic signs and symptoms of psychopathology to sophisticated measures of brain structure and function. For schizophrenia, many target features have been identified. These include eye tracking dysfunction, attentional impairment, allusive thinking, neurological signs, thought disorder, characteristic auditory evoked potentials, neuropsychological impairment, structural brain abnormalities and functional brain abnormalities. In their most pathological forms, thcse features are present among many schizophrenic patients, yet it is their presence among their non-psychotic relatives that shows them to be target features. We discuss the theoretical background for target features, present examples and describe how the discovery of target features has implications I for schizophrenia research.
    • Pediatric mania: a developmental subtype of bipolar disorder?

      Biederman, Joseph; Mick, Eric; Faraone, Stephen V; Spencer, Thomas; Wilens, Timothy E; Wozniak, Janet (Elsevier BV, 2000-09)
    • Linkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample

      Faraone, Stephen V.; Skol, Andrew D.; Tsuang, Debby W.; Bingham, Stephen; Young, Keith A.; Prabhudesai, Sarita; Haverstock, Susan L.; Mena, Felicitas; Menon, Aerath Sri Kumar; Bisset, Darren; et al. (Wiley, 2002-07-29)
      Several prior reports have suggested that chromosomal region 13q32 may harbor a schizophrenia susceptibility gene. In an attempt to replicate this finding, we assessed linkage between chromosome 13 markers and schizophrenia in 166 families, each with two or more affected members. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Studies Program, included 392 sampled affected subjects and 216 affected sib pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizoaffective disorder, depressed. The families had mixed ethnic backgrounds. The majority were northern European-American families (n = 62, 37%), but a substantial proportion were African-American kindreds (n = 60, 36%). Chromosome 13 markers, spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the 13q32 region were genotyped and the data analyzed using semi-parametric affected only linkage analysis. For the combined sample (with race broadly defined and schizophrenia narrowly defined) the maximum LOD score was 1.43 (Z-score of 2.57; P = 0.01) at 79.0 cM between markers D13S1241 (76.3 cM) and D13S159 (79.5 cM). Both ethnic groups showed a peak in this region. The peak is within 3 cM of the peak reported by Brzustowicz et al.
    • Linkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample

      Faraone, Stephen V.; Skol, Andrew D.; Tsuang, Debby W.; Bingham, Stephen; Young, Keith A.; Prabhudesai, Sarita; Haverstock, Susan L.; Mena, Felicitas; Menon, Aerath Sri Kumar; Bisset, Darren; et al. (Wiley, 2002-07-29)
      Several prior reports have suggested that chromosomal region 13q32 may harbor a schizophrenia susceptibility gene. In an attempt to replicate this finding, we assessed linkage between chromosome 13 markers and schizophrenia in 166 families, each with two or more affected members. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Studies Program, included 392 sampled affected subjects and 216 affected sib pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizoaffective disorder, depressed. The families had mixed ethnic backgrounds. The majority were northern European-American families (n¼62, 37%), but a substantial proportion were African- American kindreds (n¼60, 36%). Chromosome 13 markers, spaced at intervals of approximately 10cMover the entire chromosome and 2–5 cM for the 13q32 region were genotyped and the data analyzed using semiparametric affected only linkage analysis. For the combined sample (with race broadly defined and schizophrenia narrowly defined) the maximum LOD score was 1.43 (Z-score of 2.57; P¼0.01) at 79.0 cM between markers D13S1241 (76.3 cM) and D13S159 (79.5 cM). Both ethnic groups showed a peak in this region. The peak is within 3 cMof the peak reported by Brzustowicz et al. [1999: Am J Hum Genet 65:1096–1103].
    • Evidence for the multigenic inheritance of schizophrenia

      Freedman, Robert; Leonard, Sherry; Olincy, Ann; Kaufmann, Charles A.; Malaspina, Dolores; Cloninger, C. Robert; Svrakic, Dragan; Faraone, Stephen V.; Tsuang, Ming T. (Wiley, 2002-08-21)
      Schizophrenia is assumed to have complex inheritance because of its high prevalence and sporadic familial transmission. Findings of linkage on different chromosomes in various studies corroborate this assumption. It is not known whether these ®endings represent heterogeneous inheritance, in which various ethnic groups inherit illness through different major gene effects, or multigenic inheritance, in which affected individuals inherit several common genetic abnormalities. This study therefore examined inheritance of schizophrenia at different genetic loci in a nationally collected European American and African American sample. Seventy-seven families were previously genotyped at 458 markers for the NIMH Schizophrenia Genetics Initiative. Initial genetic analysis tested a dominant model, with schizophrenia and schizoaffective disorder, depressed type, as the affected phenotype. The families showed one genome-wide significant linkage (Z ¼ 3.97) at chromosome 15q14, which maps within 1 cM of a previous linkage at the a7-nicotinic receptor gene. Chromosome 10p13 showed suggestive linkage (Z ¼ 2.40). Six others (6q21, 9q32, 13q32, 15q24, 17p12, 20q13) were positive, with few differences between the two ethnic groups. The probability of each family transmitting schizophrenia through two genes is greater than expected from the combination of the independent segregation of each gene. Two trait-locus linkage analysis supports a model in which genetic alleles associated with schizophrenia are relatively common in the general population and affected individuals inherit risk for illness through at least two different loci.
    • Treatment of nonpsychotic relatives of patients with schizophrenia: Six case studies

      Tsuang, Ming T.; Stone, William S.; Tarbox, Sarah I.; Faraone, Stephen V. (Wiley, 2002-11-27)
      There is growing support for the notion that the genetic liability for schizophrenia could be manifested in brain dysfunction, even without the full manifestations of schizophrenia [Meehl, 1962, 1989; Seidman, 1997; Faraone et al., 2001]. This liability is characterized clinically by neurologic, neurobiological, psychiatric, neuropsychological, and psychosocial impairments in nonpsychotic, first-degree relatives of people with schizophrenia and includes eye tracking dysfunction [Levy et al., 1994], allusive thinking [Catts et al., 1993], neurologic signs [Erlenmeyer-Kimling et al., 1982], biochemical abnormalities [Callicott et al., 1998], char acteristic auditory evoked potentials [Friedman and Squires-Wheeler, 1994], neuroimaging assessed brain abnormalities [Seidman et al., 1997], and neuropsycho logical impairment [Kremen et al., 1994]. Paul Meehl introduced the term ‘‘schizotaxia’’ in 1962 to describe the genetic predisposition to schizophrenia [Meehl, 1962], and we have modified the concept to take account of subsequent research [Faraone et al., 2000]. The concept of schizotaxia raises at least three fundamental issues: 1) What is the conceptual basis of schizotaxia? 2) Is it a valid syndrome? and 3) perhaps most importantly from the point of view of the eventual prevention of schizo phrenia, is it treatable? In this paper, we review the model of schizotaxia by focusing first on its nature and extent. We then describe preliminary research criteria for its diagnosis in nonpsychotic relatives of schizo phrenic patients, followed by a presentation of our initial attempts to treat schizotaxia. Finally, prospects for the future focus on the need to validate the proposed syndrome further and on the clinical implications of treating schizotaxia.
    • Long-term outcome of pediatric obsessive-compulsive disorder: a meta-analysis and qualitative review of the literature

      Stewart, S. E.; Geller, D. A.; Jenike, M.; Pauls, D.; Shaw, D.; Mullin, B.; Faraone, S. V. (Wiley, 2004-07)
      Objective: To review the extant literature on the long-term outcome of child/adolescent-onset obsessive–compulsive disorder (OCD). Method: Medline and Psychlit databases were systematically searched for articles regarding long-term outcomes of child/adolescent-onset OCD. Meta-analysis regression was applied to evaluate predictors and persistence of OCD. Results: Sixteen study samples (n ¼ 6–132; total ¼ 521 participants) in 22 studies had follow-up periods ranging between 1 and 15.6 years. Pooled mean persistence rates were 41% for full OCD and 60% for full or subthreshold OCD. Earlier age of OCD onset (z ¼ )3.26, P ¼ 0.001), increased OCD duration (z ¼ 2.22, P ¼ 0.027) and inpatient vs. out-patient status (z ¼ 2.94, P ¼ 0.003) predicted greater persistence. Comorbid psychiatric illness and poor initial treatment response were poor prognostic factors. Although psychosocial function was frequently compromised, most studies lacked comprehensive outcome measures. Conclusion: Long-term persistence of pediatric OCD may be lower than believed. Future studies should include broader measures of outcome including symptomatic persistence and functional impairment in multiple domains.
    • ADHD Symptoms vs. Impairment: Revisited

      Barkley, Russell A.; Cunningham, Charles E.; Gordon, Michael; Faraone, Stephen V.; Lewandowski, Larry; Murphy, Kevin R. (Guilford Publications, 2006-04)
    • Family based association analysis of statistically derived quantitative traits for drug use in ADHD and the dopamine transporter gene

      Lasky-Su, Jessica; Biederman, Joseph; Doyle, Alysa E.; Wilens, Timothy; Monuteaux, Michael; Smoller, Jordan W.; Faraone, Stephen (Elsevier BV, 2006-06)
      Objective To determine whether SNPs within the dopamine transporter gene (DAT) are associated with quantitative phenotypes generated from drug frequency variables in an ADHD sample. Method 35 SNPs were genotyped in and around DAT. We developed a quantitative phenotype at each SNP by weighting the drug frequency variables. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, a screening procedure was used to select and test the SNPs with the greatest power to detect an association in DAT. Results No SNPs in DAT were associated with the quantitative phenotypes generated from the drug frequency variables after the multiple comparisons adjustment; however, some SNPs achieved nominal significance. A sliding window of analysis of 3 SNPs also resulted in only nominal associations. Conclusions SNPs in DAT do not appear to be associated with the phenotypes generated from drug frequency variables among individuals with ADHD.
    • Investigation of parent-of-origin effects in ADHD candidate genes

      Kim, Jang Woo; Waldman, Irwin D.; Faraone, Stephen V.; Biederman, Joseph; Doyle, Alysa E.; Purcell, Shaun; Arbeitman, Lori; Fagerness, Jesen; Sklar, Pamela; Smoller, Jordan W. (Wiley, 2007)
    • Environmental risk factors for attention‐deficit hyperactivity disorder

      Banerjee, Tania Das; Middleton, Frank; Faraone, Stephen V. (Wiley, 2007-06-15)
      Attention-deficit hyperactivity disorder (ADHD) is the most common cognitive and behavioural disorder diagnosed among school children. It is characterized by deficient attention and problem solving, along with hyperactivity and difficulty withholding incorrect responses. This highly prevalent disorder is estimated to affect 5–10% of children and in many cases, persists into adulthood, leading to 4% prevalence among adults. Converging evidence from epidemiologic, neuropsychology, neuroimaging, genetic and treatment studies shows that ADHD is a valid medical disorder. The majority of studies performed to assess genetic risk factors in ADHD have supported a strong familial nature of this disorder. Family studies have identified a 2- to 8-fold increase in the risk for ADHD in parents and siblings of children with ADHD. Various twin and adoption studies have also highlighted the highly genetic nature of ADHD. In fact the mean heritability of ADHD was shown to be 0.77, which is comparable to other neuropsychiatric disorders such as schizophrenia or bipolar disorder. However, several biological and environmental factors have also been proposed as risk factors for ADHD, including food additives/diet, lead contamination, cigarette and alcohol exposure, maternal smoking during pregnancy, and low birth weight. Many recent studies have specifically examined the relationships between ADHD and these extraneous factors. This review describes some of these possible risk factors.
    • Stability of executive function deficits into young adult years: a prospective longitudinal follow-up study of grown up males with ADHD

      Biederman, J.; Petty, C. R.; Fried, R.; Doyle, A. E.; Spencer, T.; Seidman, L. J.; Gross, L.; Poetzl, K.; Faraone, S. V. (Wiley, 2007-08)
      Objective: Although individuals with attention deficit‐hyperactivity disorder (ADHD) commonly exhibit deficits in executive functions that greatly increase the morbidity of the disorder, all available information on the subject is cross sectional. Method: Males (n = 85) 9–22 years with ADHD followed over 7 years into young adulthood were assessed on measures of sustained attention/vigilance, planning and organization, response inhibition, set shifting and categorization, selective attention and visual scanning, verbal and visual learning, and memory. A binary definition of executive function deficits (EFDs) was defined based on a subject manifesting at least two abnormal tests 1.5 standard deviations from controls. Results: The majority of subjects maintained EFDs over time (kappa: 0.41, P < 0.001; sensitivity: 55%, specificity: 85%, positive predictive value: 69%, and negative predictive value: 75%). Conclusion: Considering the morbidity of EFDs, these findings stress the importance of their early recognition for prevention and early intervention strategies. EFDs are stable over time.
    • The new neuropsychiatric genetics

      Faraone, S.V.; Smoller, J.W.; Pato, C.N.; Sullivan, P.; Tsuang, M.T. (Wiley, 2008-01-05)
    • Disorder Versus Disability: The Challenge of ADHD in the Context of a High IQ

      Antshel, Kevin M.; Hendricks, Kaitlin; Faraone, Stephen V.; Gordon, Michael (Guilford Publications, 2011-04)
    • DRAMS: A tool to detect and re-align mixed-up samples for integrative studies of multi-omics data

      Jiang, Yi; Giase, Gina; Grennan, Kay; Shieh, Annie W.; Xia, Yan; Han, Lide; Wang, Quan; Wei, Qiang; Chen, Rui; Liu, Sihan; et al. (Public Library of Science (PLoS), 2020-04-13)
    • Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure

      Hoogman, Martine; Rooij, Daan; Klein, Marieke; Boedhoe, Premika; Ilioska, Iva; Li, Ting; Patel, Yash; Postema, Merel C.; Zhang‐James, Yanli; Anagnostou, Evdokia; et al. (Wiley, 2020-05-18)
      Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case–control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case–control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.
    • Agonal factors distort gene-expression patterns in human postmortem brains

      Dai, Jiacheng; Chen, Yu; Chen, Chao; Liu, Chunyu (Cold Spring Harbor Laboratory, 2020-07-12)
      Agonal factors, the conditions that occur just prior to death, can impact the molecular quality of postmortem brains, influencing gene expression results. Nevertheless, study designs using postmortem brain tissue rarely, if ever, account for these factors, and previous studies had not documented nor adjusted for agonal factors. Our study used gene expression data of 262 samples from ROSMAP with the following terminal states recorded for each donor: surgery, fever, infection, unconsciousness, difficulty breathing, and mechanical ventilation. Performed differential gene expression and weighted gene co-expression network analyses (WGCNA), fever and infection were the primary contributors to brain gene expression changes. Fever and infection also contributed to brain cell-type specific gene expression and cell proportion changes. Furthermore, the gene expression patterns implicated in fever and infection were unique to other agonal factors. We also found that previous studies of gene expression in postmortem brains were confounded by variables of hypoxia or oxygen level pathways. Therefore, correction for agonal factors through probabilistic estimation of expression residuals (PEER) or surrogate variable analysis (SVA) is recommended to control for unknown agonal factors. Our analyses revealed fever and infection contributing to gene expression changes in postmortem brains and emphasized the necessity of study designs that document and account for agonal factors.
    • Agonal factors distort gene-expression patterns in human postmortem brains

      Dai, Jiacheng; Chen, Yu; Chen, Chao; Liu, Chunyu (Cold Spring Harbor Laboratory, 2020-07-12)
      Agonal factors, the conditions that occur just prior to death, can impact the molecular quality of postmortem brains, influencing gene expression results. Nevertheless, study designs using postmortem brain tissue rarely, if ever, account for these factors, and previous studies had not documented nor adjusted for agonal factors. Our study used gene expression data of 262 samples from ROSMAP with the following terminal states recorded for each donor: surgery, fever, infection, unconsciousness, difficulty breathing, and mechanical ventilation. Performed differential gene expression and weighted gene co-expression network analyses (WGCNA), fever and infection were the primary contributors to brain gene expression changes. Fever and infection also contributed to brain cell-type specific gene expression and cell proportion changes. Furthermore, the gene expression patterns implicated in fever and infection were unique to other agonal factors. We also found that previous studies of gene expression in postmortem brains were confounded by variables of hypoxia or oxygen level pathways. Therefore, correction for agonal factors through probabilistic estimation of expression residuals (PEER) or surrogate variable analysis (SVA) is recommended to control for unknown agonal factors. Our analyses revealed fever and infection contributing to gene expression changes in postmortem brains and emphasized the necessity of study designs that document and account for agonal factors.