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Study Description

Although schizophrenia is a highly heritable disease, relatively little progress had been made in securely identifying the genetic causes of this disorder, and most instances of schizophrenia in the general population remain unexplained. One avenue of explanation for the genetic basis of schizophrenia, however, has been effectively closed by recent research. Genome-wide association studies (GWAS) have now shown that common variation makes at most a modest contribution to the risk of schizophrenia. At the same time that the role of common variation has been circumscribed by GWAS, however, the analysis of copy number variants that are detectable on a genome-wide scale has revealed and replicated a number of very rare variants that associate with schizophrenia. These rare copy number variants that have been implicated in schizophrenia, however, have one striking feature in common: they are all risk factors for other brain related disorders beyond schizophrenia such as mental retardation, autism and epilepsy. These findings argue that genetic risk factors may confer a highly penetrant vulnerability to neuropsychiatric disorder, which is then further modified by interacting genetic or environmental factors to determine the ultimate manifestation. Most schizophrenia collections that are being studied today, however, have been selected precisely for their homogeneity: including only schizophrenia patients with no comorbidities, or schizophrenia patients with relatives who have schizophrenia but no other neuropsychiatric conditions. These selection criteria are inconsistent with what we now know about the bulk of the genetic differences that have been associated with disease. The central hypothesis of this project is that there are rare genetic variants that strongly elevate the risk of various neuropsychiatric diseases, and that these risk factors can be identified most readily in families segregating multiple neuropsychiatric conditions.

  • Study Type: Multiplex Families
  • dbGaP estimated ancestry components using GRAF-pop
  • Number of study subjects that have individual level data available through Authorized Access: 162

Authorized Access
Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

This study initially aimed to sequence 100 probands. A supplement was later submitted to sequence an additional 125 individuals, including affected children and their families. The inclusion and exclusion criteria for both sections of the study are listed below.

Our patient selection criteria was based on two hypotheses: first, that patients with rare highly penetrant genetic contributors to schizophrenia also have affected family members, and second, that because all known genes contributing to schizophrenia also contribute to other disorders such as mental retardation, epilepsy and autism, families that segregate more than one of these conditions will be most likely to contain highly penetrant genetic contributors. For this research, in order to maximize the chances of selecting patients with genetic variants with high penetrance, we recruited only schizophrenia or schizoaffective patients who manifest other serious neuropsychiatric problems in themselves or their close relatives. The following inclusion criteria was therefore used: (i) DSM-IV diagnosis of schizophrenia or schizoaffective disorder; (ii) at least one first or second degree relative (parent, child or sibling OR grandparent, grandchild, half-sibling, aunt, uncle, nephew or niece) with schizophrenia or schizoaffective disorder and (iii) EITHER (i) one of the following co-morbid conditions: mental retardation, seizure disorder, pervasive developmental disorder (PDD) in the proband OR (ii) at least two first, second or third degree relatives with mental retardation, seizure disorder or PDD. In addition to the proband, we also recruited at least one affected and one non-affected first or second degree relative with schizophrenia per proband, and as many other first, second or third degree relatives as were accessible and willing to enroll in the study. For each relative, we collected blood, administered the SCID to screen for mental disorders and collected information on other aspects of their medical history, education and employment history.

Inclusion criteria (for the supplement study):

  1. Proband is under 18 years of age and meets an axis I DSM-IV-TR criteria for one of the following disorders: Obsessive-compulsive disorder, Schizophrenia, Bipolar Disorder, Attention-Deficient and Hyperactivity Disorder, Major Depression, or Sensory Integration Disorder.
  2. Proband must have two or more affected first or second degree relatives with at least one of the above listed Axis I qualifying disorders and/or co-morbidities of developmental delay, mental retardation, or seizures.
  3. Proband does not have a known diagnosis of genetic syndrome or disorder.
  4. Proband has negative karyotype and/or clinical chromosome microarray, negative newborn screen (if applied), negative basic metabolic screen including plasma amino acid, urine organic acid, and acylcarnitine profile, negative FMR1 DNA test or other genetic tests if apply.
  5. Parents, unaffected siblings, and other extended family members indicated are available for the study.

Exclusion criteria

  1. Proband has a significant history of prematurity (birth weight <1500g).
  2. Proband has a history of brain injury including hypoxia, CNS infection, accident, and toxin, etc.
  3. Proband is confirmed or strongly suspected for a known genetic syndrome.
  4. Abnormal molecular or genetic study such as finding of known pathologic CNVs or abnormal biochemical profile of unclear significance.
  5. Proband has severe and profound mental retardation.
  6. Immediate and extended family members are not available for study.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Sequencing Illumina HiSeq 2000 N/A N/A
Selected publications
Diseases/Traits Related to Study (MESH terms)
Links to Related Resources
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Study Attribution