New Genetic Findings in Schizophrenia: Is there Still Room for the Dopamine Hypothesis of Schizophrenia?
paper
Cited
Public
- Authors
- Nieratschker, Vanessa; Nöthen, Markus M; Rietschel, Marcella
- Year
- 2010
- Journal
- Frontiers in behavioral neuroscience
- PMID
- 20485477
- DOI
- 10.3389/fnbeh.2010.00023
- PMCID
- PMC2871716
Schizophrenia is a highly heritable disorder, but the identification of specific genes has proven to be a difficult endeavor. Genes involved in the dopaminergic system are considered to be major candidates since the "dopamine hypothesis" of impairment in dopaminergic neurotransmission is one of the most widely accepted hypotheses of the etiology of schizophrenia. The overall findings from candidate studies do provide some support for the "dopamine hypothesis." However, results from the first systematic genome-wide association (GWA) studies have implicated variants within ZNF804A, NRGN, TCF4, and variants in the MHC region on chromosome 6p22.1. Although these genes may not immediately impact on dopaminergic neurotransmission, it remains possible that downstream impairments in dopaminergic function are caused. Furthermore, only a very small fraction of all truly associated genetic variants have been detected and many more associated variants will be identified in the future by GWA studies and alternative approaches. The results of these studies may allow a more comprehensive re-evaluation of the dopamine hypothesis.
Linkage analyses have proven to be successful in identifying genetic variants underlying monogenic disorders caused by rare variants with large effects. Association studies aim to detect common variants that make only a small contribution to the disorder. The detection of rare variants with only small phenotypic effects is difficult since sequencing of large numbers of patients and controls is necessary and (prohibitively) large samples sizes are required for association testing (adapted from McCarthy et al., 2008). *SNPs with a minor allele frequency <1% are typically not included in arrays used for genome-wide association studies.
LLM interpretation
This conceptual diagram illustrates the relationship between the population frequency of genetic variants (x-axis) and their phenotypic effect size (y-axis). It categorizes "rare variants" (<1% frequency) and "common variants" (>1% frequency), associating rare variants with large effects to monogenic disorders (detected via linkage studies) and common variants with small effects to complex disorders (detected via association studies). A region of rare variants with small effects is labeled as "not yet detectable."
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In this knowledge base
| Title | Year | PMID |
|---|---|---|
| Replication of ZNF804A gene variant associations with risk of heroin addiction. | 2015 | 26382569 |
External
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| BCL9 and C9orf5 are associated with negative symptoms in schizophrenia: meta-analysis of two genome-wide association studies. | Xu C et al. | — | 2013 | → |
| Does the dopamine hypothesis explain schizophrenia? | Lau CI et al. | — | 2013 | → |
| Genetic evidence for the association between the early growth response 3 (EGR3) gene and schizophrenia. | Zhang R et al. | — | 2012 | → |
| Is lead exposure in early life an environmental risk factor for Schizophrenia? Neurobiological connections and testable hypotheses. | Guilarte TR et al. | — | 2012 | → |
| PKNOX2 is associated with formal thought disorder in schizophrenia: a meta-analysis of two genome-wide association studies. | Wang KS et al. | — | 2012 | → |
| Schizophrenia shows a unique metabolomics signature in plasma. | He Y et al. | — | 2012 | → |