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Schizophrenia Genetic Studies

What Is Schizophrenia?

Schizophrenia is a chronic, disabling brain disorder that affects about 1% of Americans. It may cause people to hear voices, see imaginary sights, or believe other people are controlling their thoughts. These sensations can be frightening and often lead to erratic behavior. There is no cure, but treatment can usually control the most serious symptoms.


What Causes Schizophrenia?

The exact cause is not known, but scientists suspect genes and environment both play a role. Inside the brain, levels of the chemical messengers dopamine and glutamate may be out of balance. And brain structures may be abnormal, too. For example, brain scans of identical twins show that the fluid-filled "ventricles" can be larger in a twin with schizophrenia, compared with a twin who does not have the illness. Activity levels can also be higher or lower than normal in some areas of the schizophrenic brain.

Schizophrenia Study examines 8 Genes

In 2000, Lichterman et al was able to extend the spectrum concept to include neuropsychologically, neurophysiologically and neuroradiologically measurable familial traits as subclinical endophenotypes of schizophrenia that may be more fundamental to the development of the disease than overt psychopathology.


Replicable linkage findings have emerged from genome scans that imply at least seven chromosomal regions to harbor schizophrenia susceptibility genes.


They strengthen the conviction that schizophrenia is indeed a genetically complex disorder, based on a larger number of susceptibility genes with risk-increasing alleles that are common in the population and exert a limited effect on the individual level.


They mentioned several schizophrenia susceptibility genes: 1q, 5q, 6p, 8p, 10p, 13q, 18p, 22q


Lichtermann, D., Karbe, E., & Maier, W. (2000). The genetic epidemiology of schizophrenia and of schizophrenia spectrum disorders. European Archives Of Psychiatry & Clinical Neuroscience, 250(6), 304.

Schizophrenia Study examines Biological Markers
In 2004, Joseph detailed that biological markers in psychiatry (also known as "endophenotypes," "subclinical traits,“ "intermediate phenotypes," and "vulnerability markers" ) have been defined as "any neurobiological measure related to the underlying molecular genetics of the illness, including biochemical, endocrinological, neurophysiological, neuroanatomical, or neuropsychological markers “


Characteristics researchers require for a biological marker are

1.that it can be reliably measured
2.that it be manifest among all people with a susceptibility locus (independent of state)
3.that it is specific to the disorder under study
4.that it is inherited


Joseph, J. (2004). The fruitless search for schizophrenia genes. Ethical Human Psychology and Psychiatry, 6(3), 167-181.

Schizophrenia Study examined Reelen Gene risk for Women only

In 2008, Shifman et al performed a genome-wide association scan for schizophrenia in an Ashkenazi Jewish population using DNA pooling.


They found a female-specific association with rs7341475, a SNP in the fourth intron of the reelin (RELN) gene (p ¼ 2.9 3 105 in women), with a significant gene-sex effect (p ¼ 1.8 3 104).


They also studied rs7341475 in four additional populations, totaling 2,274 cases and 4,401 controls. A significant effect was observed only in women, replicating the initial result (p¼2.13103 in women; p¼4.23103 for gene-sex interaction).


Based on all populations the estimated relative risk of women carrying the common genotype is 1.58 (p ¼ 8.8 3 107; p ¼ 1.6 3 105 for gene-sex interaction).


They concluded that the female specific association between RELN and schizophrenia is one of the few examples of a replicated sex-specific genetic association in any disease.


Shifman, S., Johannesson, M., Bronstein, M., Chen, S. X., Collier, D. A., Craddock, N. J., & ... Darvasi, A. (2008). Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. Plos Genetics, 4(2), 1-7. doi:10.1371/journal.pgen.0040028

Schizophrenia Study examined ERBB3

Li et al (2009) stated that: Schizophrenia is a common psychiatric disorder with a complex genetic aetiology.


Their evidence shows that the oligodendrocyte and myelin-related genes including ERBB3 are closely related to schizophrenia.


They presented findings of the first association study between ERBB3 and schizophrenia in the Caucasian population


Li, D., Feng, G. & He, L. (2009) Case-control study of association between the functional candidate gene ERBB3 and schizophrenia in Caucasian population. World Journal Of Biological Psychiatry, 10(4_2), 595-598. doi:10.1080/15622970903304442.

Schizophrenia Study examines Various Research Efforts
In 2011, Haraldsson et al reviewed current literature on schizophrenia genetics with special emphasis on new developments such as genome-wide association studies (GWAS), associations of copy number variations (CNVs) with schizophrenia and the role of endophenotypes in genetic research

They reported that the first GWAS of schizophrenia had identified new putative candidate risk genes and opened avenues for investigating how multiple genes may act in functional biological pathways forming the genetic basis of schizophrenia and other complex diseases. There is growing evidence that rare de novo CNVs as well as some inherited CNVs contribute to the susceptibility to several neuropsychiatric disorders including schizophrenia.

They concluded that Schizophrenia endophenotypes which possibly better represent biological phenomena than the complex clinical phenotype, are turning out to be helpful for investigating neurobiological pathways of putative risk genes

Haraldsson, H., Ettinger, U., & Sigurdsson, E. (2011). Developments in schizophrenia genetics: From linkage to microchips, deletions and duplications. Nordic Journal Of Psychiatry, 65(2), 82-88. doi:10.3109/08039488.2011.552734

Schizophrenia Study examined SNPs

Lee et al in 2012, estimated that 23% (s.e. = 1%) of variation in liability to schizophrenia is captured by SNPs. Schizophrenia is a complex disorder caused by both genetic and environmental factors. They used 9,087 affected individuals, 12,171 controls and 915,354 imputed SNPs from the Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (PGC-SCZ).


They showed that a substantial proportion of this variation must be the result of common causal variants, that the variance explained by each chromosome is linearly related to:

  • its length (r = 0.89, P = 2.6 × 10−8)
  • that the genetic basis of schizophrenia is the same in males and females
  • that a disproportionate proportion of variation is attributable to a set of 2,725 genes expressed in the central nervous system (CNS; P = 7.6 × 10−8)

These results are consistent with a polygenic genetic architecture and imply more individual SNP associations will be detected for this disease as sample size increases.



Lee, S., DeCandia, T., Ripke, S., Yang, J., Sullivan, P., Goddard, M., & ... Wray, N. (2012). Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nature Genetics, 44(3), 247-250. doi:10.1038/ng.1108

SCHIZOPHRENIA GENETIC STUDY REFERENCES

 

Haraldsson, H., Ettinger, U., & Sigurdsson, E. (2011). Developments in schizophrenia

genetics: From linkage to microchips, deletions and duplications. Nordic Journal Of Psychiatry65(2), 82-88. doi:10.3109/08039488.2011.552734

 

Joseph, J. (2004). The fruitless search for schizophrenia genes. Ethical Human

Psychology and Psychiatry, 6(3), 167-181.

 

Lee, S., DeCandia, T., Ripke, S., Yang, J., Sullivan, P., Goddard, M., & ... Wray, N.

(2012). Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nature Genetics44(3), 247-250. doi:10.1038/ng.1108

 

Li, D., Feng, G. & He, L. (2009) Case-control study of association between the

functional candidate gene ERBB3 and schizophrenia in Caucasian population. World Journal Of Biological Psychiatry10(4_2), 595-598. doi:10.1080/15622970903304442.

 

Lichtermann, D., Karbe, E., & Maier, W. (2000). The genetic epidemiology of

schizophrenia and of schizophrenia spectrum disorders. European Archives Of Psychiatry & Clinical Neuroscience250(6), 304.

 

Shifman, S., Johannesson, M., Bronstein, M., Chen, S. X., Collier, D. A., Craddock, N.

J., & ... Darvasi, A. (2008). Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. Plos Genetics4(2), 1-7. doi:10.1371/journal.pgen.0040028