Reference
Complete the bibliographic reference for the article according to AJE format.

Van Den Bogaert A, et al. The DTNBP1 (Dysbindin) gene contributes to schizophrenia, depending on family history of the disease. Am J Hum Genet 2003 Dec; 73(6): 1438-43.

Category of HuGE information
Specify the types of information (from the list below) available in the article:

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

1. Prevalence of gene variant
2. Gene-disease association

DTNBP1 is expressed in many tissues, including the brain. Previous studies using Irish schizophrenic-dense pedigrees have found association with several specific SNPs in DTNBP1. This study attempts to verify those findings in German, Polish, and Swedish populations.

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

1. Gene name: DTNBP1
2. Chromosome location: 6p22.3
3. Gene product/function: Dysbindin, a widely expressed protein that has been briefly studied in rat muscle and brain tissues. In the brain it localizes to the axons of nerve cells and may play a role in signal transduction.
4. Alleles: P1635 (A/G), P1325 (C/T), P1757 (G/A), P1320 (C/T), P1578 (C/T)
5. OMIM#: 607145

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

N/A

Health outcome(s)
Identification of the major health outcome(s) studied

Schizophrenia

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

1. Case-control

1. Disease case definition
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants (% of total eligible)

1. Disease case definition: Schizophrenia as diagnosed by a psychiatrist after interview, considering both medical records and family history of the disorder. Criteria for diagnoses were the DSM-IV (German and Polish), and DSM-III-R (Swedish).
2. Exclusion criteria: none mentioned
3. Gender:                cases                controls
   German:        418 (47.6% male)        285 (60.3%)
   Polish:              294 (59.2%)             113 (37.2%)
   Swedish:           142 (62.0%)             272 (54.8%)
4. Race/ethnicity: German, Polish, and Swedish analyzed separately
5. Age: not specified
6. Time period: not specified
7. Geographic location: not specified
8. Number of participants: 854 cases, 670 controls

1. Control selection criteria
2. Matching variables
3. Exclusion criteria
4. Gender
5. Race/ethnicity
6. Age
7. Time period
8. Geographic location
9. Number of participants (% of total eligible)

No mention of control selection process.

Polish: 113 (37.2% men)
German: 285 (60.3% men)
Swedish: 272 (54.8% men)

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (% of total eligible)

None examined

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

1. Gene: DTNBP1
2. DNA source: not stated
3. Methodology: sequenced using pyrosequencing technique
4. Number of participants genotyped: 100%

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

1. German: between 7.8% and 24.9% among controls, depending on SNP
   Polish: between 2.7% and 15.2%
   Swedish: between 6.1% and 19.9%
2. Found several statistically significant associations with haplotypes in the Swedish population. After restricting cases to those with a family history of disease (n=32), additional haplotype associations were significant. A particular haplotype, ACATT, had an OR of 6.75 among family history cases. No such associations were seen in the German or Polish populations.

• Table 1: tests the distributions of the individual SNPs in cases and controls. No significant results were seen.
• Table 2: displays global p-values (all Ors equal) for combinations of the SNPs in a ‘sliding-window’ fashion. Significant results seen for the Swedish subgroup, particularly those cases having a family history of the disease.
• Table 3: again examines the distributions of the different SNPs amongst cases and controls, this time restricting the analysis to those cases with a family history of disease. No statistically significant results.
• Table 4: displays distributions amongst cases and controls for specific 5 marker haplotypes, restricted to family history cases. Haplotype ACATT is found in 17.8% of cases and 3.1% of controls, OR = 6.75.

The DTNBP1 gene appears to have a relationship with schizophrenia in the Swedish population. Future studies should be enriched for family history cases.

This study supports previous work that claims a genetic predisposition for schizophrenia in some populations. A direct result of this work may be experiments in biochemistry and genetics seeking the role of dysbindin in nerve cells, particularly in those with schizophrenia and those without. The fact that the findings were limited to the Swedish group may suggest a distinct form of the disease with its own genetic and environmental risk-factors. Another illness believed to result from an interplay of genetic and environmental causes, type I diabetes, shows great variation of incidence around the Baltic sea . Incidence rates differ by over 5 fold between Sweden and Poland , implying a different distribution of causative factors for that disease, and setting a precedent of genetic and environmental heterogeneity in the region (1). The Baltic Sea may isolate Sweden from the other countries, while Germany and Poland would mix relatively freely, the result being a distinct form of the disease across the sea. More importantly, different diagnosis criteria in the Swedish group may also explain the discrepancy, as theirs was less restrictive. DSM-III-R requires continuous symptoms for a week, while DSM-IV requires the same symptoms for at least a month. It is therefore conceivable that DTNBP1 has only been linked to a ‘type III’ schizophrenia, rather than ‘type IV’, with DSM-III-R referring to a lesser psychosis on the diagnostic spectrum of schizophrenia.

It is unfortunate that little information was given about the participants in this study. Data on confounders was not collected making it impossible to assess what role other risk-factors may have played in generating the outcome described. Similarly, an assessment of gene-environment in tera ction was impossible--an unfortunate drawback considering the etiology of schizophrenia involves environmental stressors that bring about psychotic episodes. A nice feature of the study, however, is the separation of the German, Polish, and Swedish cohorts, minimizing the effect of population stratification. Future studies should heed the lopsided distribution of significant results in this study and similarly stratify their data.

The authors’ conclusion to enrich future studies with family history cases is plausible and may help find a genetic link to schizophrenia. However, care must be taken in such studies to ensure that results are not extrapolated to all schizophrenia cases, rather only to the subset of schizophrenia cases with family history; the two groups may have distinct forms of the disease with different biological origins.

1. Tuomilehto J, et al. (1996). Epidemiology of Insulin-Dependent Diabetues Mellitus Around the Baltic Sea . Horm Metab Res 28: 340-343.