Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kindgdom.
PLoS Genetics (Impact Factor: 8.17). 03/2008; 4(2):e28. DOI: 10.1371/journal.pgen.0040028
Source: PubMed

ABSTRACT Sex differences in schizophrenia are well known, but their genetic basis has not been identified. We performed a genome-wide association scan for schizophrenia in an Ashkenazi Jewish population using DNA pooling. We found a female-specific association with rs7341475, a SNP in the fourth intron of the reelin (RELN) gene (p = 2.9 x 10(-5) in women), with a significant gene-sex effect (p = 1.8 x 10(-4)). We 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 (p = 2.1 x 10(-3) in women; p = 4.2 x 10(-3) for gene-sex interaction). Based on all populations the estimated relative risk of women carrying the common genotype is 1.58 (p = 8.8 x 10(-7); p = 1.6 x 10(-5) for gene-sex interaction). The female-specific association between RELN and schizophrenia is one of the few examples of a replicated sex-specific genetic association in any disease.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Reelin has recently attracted attention because of its connection to several neuropsychiatric diseases. We previously reported the finding that prior transplantation of GABAergic neuron precursor cells into the medial prefrontal cortex (mPFC) of mice significantly prevented the induction of cognitive and sensory-motor gating deficits induced by phencyclidine (PCP). The majority of the precursor cells transplanted into the mPFC of the recipient mice differentiated into members of a somatostatin/Reelin-expressing class of GABAergic interneurons. These findings raised the possibility that Reelin secreted by the transplanted cells plays an important role in preventing the deficits induced by PCP. In this study, we investigated whether Reelin itself has a preventive effect on PCP-induced behavioral phenotypes by injecting conditioned medium containing Reelin into the lateral ventricle of the brains of 6- to 7-week-old male mice before administrating PCP. Behavioral analyses showed that the prior Reelin injection had a preventive effect against induction of the cognitive and sensory-motor gating deficits associated with PCP. Moreover, one of the types of Reelin receptor was found to be expressed by neurons in the mPFC. The results of this study point to the Reelin signaling pathway as a candidate target for the pharmacologic treatment of neuropsychiatric diseases.
    Neuroscience Research 01/2015; DOI:10.1016/j.neures.2014.12.013 · 2.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A biochip was developed to examine the polymorphisms of genes associated with schizophrenia risk, including DISC1, RELN, ZNF804A, PLXNA2, COMT, SLC18A1, CACNA1C, ANK2, TPH1, PLAA, and SNAP-25. Allele and genotype frequencies of the genes were determined in 198 schizophrenics and 192 healthy subjects from Bashkortostan (ethnic Russians and Tatars). The frequencies of allele A (p = 0.007) and genotype AA (p = 0.002) of the rs2270641 A > C polymorphism of SLC18A1 in the patients with paranoid schizophrenia was lower than in the healthy subjects. The frequency of genotype AA of the rs1800532 C > A polymorphism of TPH1 in the schizophrenics was higher than in the healthy subjects (p = 0.036). Compared with the healthy subjects, the ethnic Tatar patients with paranoid schizophrenia had a lower frequency of allele C of the rs7341475 C > T polymorphism of RELN (p = 0.039) and a higher frequency of genotype AA of the rs1800532 C > A polymorphism of TPH1 (p = 0.019, OR = 2.52, CI 1.18-5.38). The frequency of allele C (p = 0.0001) and genotype GC (p = 0.0001) of the rs1327175 G > C polymorphism of PLXNA2 was elevated in the patients with a family history of paranoid schizophrenia. Based on the results, the SLC18A1, TPH1, and RELN polymorphisms were associated with risk of schizophrenia.
    Molecular Biology 07/2014; 48(4):546-555. DOI:10.1134/S0026893314030042 · 0.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with schizophrenia are at an increased risk for the development of depression. Overlap in the symptoms and genetic risk factors between the two disorders suggests a common etiological mechanism may underlie the presentation of comorbid depression in schizophrenia. Understanding these shared mechanisms will be important in informing the development of new treatments. Rodent models are powerful tools for understanding gene function as it relates to behavior. Examining rodent models relevant to both schizophrenia and depression reveals a number of common mechanisms. Current models which demonstrate endophenotypes of both schizophrenia and depression are reviewed here, including models of CUB and SUSHI multiple domains 1, PDZ and LIM domain 5, glutamate Delta 1 receptor, diabetic db/db mice, neuropeptide Y, disrupted in schizophrenia 1, and its interacting partners, reelin, maternal immune activation, and social isolation. Neurotransmission, brain connectivity, the immune system, the environment, and metabolism emerge as potential common mechanisms linking these models and potentially explaining comorbid depression in schizophrenia.
    Frontiers in Psychiatry 02/2015; 6:13. DOI:10.3389/fpsyt.2015.00013

Full-text (2 Sources)

Available from
May 21, 2014