Analysis of 94 Candidate Genes and 12 Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia

Harvard University, Cambridge, Massachusetts, United States
American Journal of Psychiatry (Impact Factor: 13.56). 04/2011; 168(9):930-46. DOI: 10.1176/appi.ajp.2011.10050723
Source: PubMed

ABSTRACT The authors used a custom array of 1,536 single-nucleotide polymorphisms (SNPs) to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes in data collected by the Consortium on the Genetics of Schizophrenia.
Variance-component association analyses of 534 genotyped subjects from 130 families were conducted by using Merlin software. A novel bootstrap total significance test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate significant associations in the context of complex family data and possible population stratification effects.
Associations with endophenotypes were observed for 46 genes of potential functional significance, with three SNPs at p<10(-4), 27 SNPs at p<10(-3), and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded that expected by chance alone, with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes (e.g., NRG1 and ERBB4) displayed evidence for pleiotropy, revealing associations with four or more endophenotypes. The results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility.
This study supports use of relevant endophenotypes and the bootstrap total significance test for identifying genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others suggests alternative, independent pathways mediating pathogenesis in the "group of schizophrenias."

  • American Journal of Psychiatry 02/2015; 172(2):105-107. DOI:10.1176/appi.ajp.2014.14111452 · 13.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sensory processing deficits, first investigated by Kraepelin and Bleuler as possible pathophysiological mechanisms in schizophrenia, are now being recharacterized in the context of our current understanding of the molecular and neurobiological brain mechanisms involved. The National Institute of Mental Health Research Domain Criteria position these deficits as intermediaries between molecular and cellular mechanisms and clinical symptoms of schizophrenia, such as hallucinations. The prepulse inhibition of startle responses by a weaker preceding tone, the inhibitory gating of response to paired sensory stimuli characterized using the auditory P50 evoked response, and the detection of slight deviations in patterns of sensory stimulation eliciting the cortical mismatch negativity potential demonstrate deficits in early sensory processing mechanisms, whose molecular and neurobiological bases are increasingly well understood. Deficits in sensory processing underlie more complex cognitive dysfunction and are in turn affected by higher-level cognitive difficulties. These deficits are now being used to identify genes involved in familial transmission of schizophrenia and to monitor potentially therapeutic drug effects for both treatment and prevention. This research also provides a clinical reminder that patients' sensory perception of the surrounding world, even during treatment sessions, may differ considerably from others' perceptions. A person's ability to understand and interact effectively with the surrounding world ultimately depends on an underlying sensory experience of it.
    American Journal of Psychiatry 01/2015; 172(1):17-31. DOI:10.1176/appi.ajp.2014.13121691 · 13.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Childhood-onset schizophrenia (COS) is a rare, chronic mental illness that is diagnosed in children prior to the age of 13. COS is a controversial diagnosis among clinicians and can be very difficult to diagnose for a number of reasons. Schizophrenia is a psychotic disorder characterized by hallucinations, delusions, flat affect, limited motivation and anhedonia. The psychotic nature of this disorder is quite disruptive to the child's emotional regulation, behavioural control and can reduce the child's ability to perform daily tasks that are crucial to adaptive functioning. Prior to the onset of schizophrenia, children often develop premorbid abnormalities, which are disturbances to a child's functioning that may serve as warning signs. These disturbances can manifest in a variety of behavioural ways and may include introversion, depression, aggression, suicidal ideation and manic-like behaviours. This article will review the clinical presentation of schizophrenia in children and examine the existing knowledge around aetiology, treatment approaches, assessment techniques and differential diagnostic considerations. Gaps in the literature are identified and directions for future research are discussed.
    01/2014; 2(1):735-747. DOI:10.1080/21642850.2014.927738


Available from
Oct 17, 2014