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The genetic validation of heterogeneity in schizophrenia.

Tsutsumi A, Glatt SJ, Kanazawa T, Kawashige S, Uenishi H, Hokyo A, Kaneko T, Moritani M, Kikuyama H, Koh J, Matsumura H, Yoneda H - Behav Brain Funct (2011)

Bottom Line: To aggregate the vulnerability of the disorder based on the participants' genetic information, we calculated the "risk-index" by adding the number of genetic risk factors.No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms.It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuropsychiatry, Osaka Medical College, Osaka, Japan.

ABSTRACT

Introduction: Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV.

Methods: Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p < 0.0005) were selected from DRD2, DRD4, GRIN2B, TPH1, MTHFR, and DTNBP1 (February, 2007). 407 Schizophrenia cases and 384 controls participated in this study. To aggregate the vulnerability of the disorder based on the participants' genetic information, we calculated the "risk-index" by adding the number of genetic risk factors.

Results: No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57) was slightly lower than among controls (6.6+/-1.39).

Conclusion: The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

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Related in: MedlinePlus

Numbers of the samples with each Risk-Index. X-axis is "Risk Index", and Y-axis is the Numbers of the samples. The average and standard deviation of "Risk Index" for schizophrenia was 6.5 ± 1.57, while 6.6 ± 1.39 for normal controls. Abbreviation: SCZ = Schizophrenia, NCs = Normal Controls
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Figure 1: Numbers of the samples with each Risk-Index. X-axis is "Risk Index", and Y-axis is the Numbers of the samples. The average and standard deviation of "Risk Index" for schizophrenia was 6.5 ± 1.57, while 6.6 ± 1.39 for normal controls. Abbreviation: SCZ = Schizophrenia, NCs = Normal Controls

Mentions: The distribution of no single polymorphism was significantly different between schizophrenia and control groups at a p-value less than 0.05 (Fisher's exact test for each variant and t-test for aggregated seven variants, Table 3). Moreover, no statistically significant deviation in the genetic vulnerability index derived from all seven variants was found within the seven top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5 ± 1.57) was slightly lower than among controls (6.6 ± 1.39) (Figure 1). This is consistent with the negative results from the logistic regression analysis of the risk-index score, which found a non-significant (p = 0.783) and slightly negative (β = -0.02) effect of increments in the risk-index on likelihood of being in the schizophrenia group. Our failure to find a higher-order genetic effect of these seven variants on vulnerability to schizophrenia persisted when we reanalyzed the data after assigning a weight to each risk allele proportional to its odds ratio as indicated in SZGene. Again, a negative result was obtained when risk-allele carriers (risk-allele homozygotes and risk-allele heterozygotes) were pooled, suggesting that neither an additive nor a dominant model of the joint effects of these seven variants could be supported.


The genetic validation of heterogeneity in schizophrenia.

Tsutsumi A, Glatt SJ, Kanazawa T, Kawashige S, Uenishi H, Hokyo A, Kaneko T, Moritani M, Kikuyama H, Koh J, Matsumura H, Yoneda H - Behav Brain Funct (2011)

Numbers of the samples with each Risk-Index. X-axis is "Risk Index", and Y-axis is the Numbers of the samples. The average and standard deviation of "Risk Index" for schizophrenia was 6.5 ± 1.57, while 6.6 ± 1.39 for normal controls. Abbreviation: SCZ = Schizophrenia, NCs = Normal Controls
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198897&req=5

Figure 1: Numbers of the samples with each Risk-Index. X-axis is "Risk Index", and Y-axis is the Numbers of the samples. The average and standard deviation of "Risk Index" for schizophrenia was 6.5 ± 1.57, while 6.6 ± 1.39 for normal controls. Abbreviation: SCZ = Schizophrenia, NCs = Normal Controls
Mentions: The distribution of no single polymorphism was significantly different between schizophrenia and control groups at a p-value less than 0.05 (Fisher's exact test for each variant and t-test for aggregated seven variants, Table 3). Moreover, no statistically significant deviation in the genetic vulnerability index derived from all seven variants was found within the seven top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5 ± 1.57) was slightly lower than among controls (6.6 ± 1.39) (Figure 1). This is consistent with the negative results from the logistic regression analysis of the risk-index score, which found a non-significant (p = 0.783) and slightly negative (β = -0.02) effect of increments in the risk-index on likelihood of being in the schizophrenia group. Our failure to find a higher-order genetic effect of these seven variants on vulnerability to schizophrenia persisted when we reanalyzed the data after assigning a weight to each risk allele proportional to its odds ratio as indicated in SZGene. Again, a negative result was obtained when risk-allele carriers (risk-allele homozygotes and risk-allele heterozygotes) were pooled, suggesting that neither an additive nor a dominant model of the joint effects of these seven variants could be supported.

Bottom Line: To aggregate the vulnerability of the disorder based on the participants' genetic information, we calculated the "risk-index" by adding the number of genetic risk factors.No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms.It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuropsychiatry, Osaka Medical College, Osaka, Japan.

ABSTRACT

Introduction: Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV.

Methods: Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p < 0.0005) were selected from DRD2, DRD4, GRIN2B, TPH1, MTHFR, and DTNBP1 (February, 2007). 407 Schizophrenia cases and 384 controls participated in this study. To aggregate the vulnerability of the disorder based on the participants' genetic information, we calculated the "risk-index" by adding the number of genetic risk factors.

Results: No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57) was slightly lower than among controls (6.6+/-1.39).

Conclusion: The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

Show MeSH
Related in: MedlinePlus