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: 7.53). 03/2008; 4(2):e28. DOI: 10.1371/journal.pgen.0040028
Source: PubMed


Author Summary

Schizophrenia is a complex mental disease, which includes symptoms of delusions, hallucinations, disorganized speech, aberrant behavior, lack of emotional expression, diminished motivation, and social withdrawal. The cause of schizophrenia is unknown, but there is extensive evidence that genetics play a significant role in its aetiology. We studied the genetic basis of schizophrenia by analyzing around 500,000 genetic variants distributed across the whole human genome in DNA from schizophrenic patients and controls. We analyzed separately the DNA from men and women, and identified a genetic variant that increases the risk of developing schizophrenia in women only. The genetic variant is estimated to increase the risk of schizophrenia for women carrying the risk variant by 1.4-fold. The genetic variant is in a gene called reelin, which is known to play a part in brain development. However, it is still unclear how this genetic variant predisposes to schizophrenia nor why it is specific to women only.

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    • "The reelin gene has been proposed as a candidate gene in neurodevelopmental disorders such as schizophrenia and autism (Keller and Persico, 2003; Fatemi et al., 2005; Eastwood and Harrison, 2006; Abrahams and Geschwind, 2008). Interestingly, a common variant of the reelin gene has been found to increase schizophrenia risk only in women (Shifman et al., 2008), confirming that gene–sex interactions can be important for neurodevelopmental disorders. Reelin is a large secreted protein that is critical for neuron positioning during brain development (D'Arcangelo et al., 1995; Tissir and Goffinet, 2003). "

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    • "P < 0.001), and had a smaller univariable F score than did TAS score. Sensation-seeking tendencies, similar to other behavioral traits such as depressive symptoms, anger traits, and sensitivity to stress (Mizuno et al. 2006; Baud et al. 2007; Shifman et al. 2008; Guo and Tillman 2009), vary by gender (Russo et al. 1993; Wilkinson et al. 2011, 2012). Because gender differences are seen across all aspects of sensation seeking, and because social disinhibition score differed significantly by gender in our univariable analysis (Table 1), we completed an exploratory stratified analysis by gender. "
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    ABSTRACT: IntroductionThe genetic heritability for sensation-seeking tendencies ranges from 40 to 60%. Sensation-seeking behaviors typically manifest during adolescence and are associated with alcohol and cigarette experimentation in adolescents. Social disinhibition is an aspect of sensation-seeking that is closely tied to cigarette and alcohol experimentation.Methods We examined the contribution of candidate genes to social disinhibition among 1132 Mexican origin youth in Houston, Texas, adjusting for established demographic and psychosocial risk factors. Saliva samples were obtained at baseline in 2005–06, and social disinhibition and other psychosocial data were obtained in 2008–09. Participants were genotyped for 672 functional and tagging SNPs potentially related to sensation-seeking, risk-taking, smoking, and alcohol use.ResultsSix SNPs were significantly associated with social disinhibition scores, after controlling for false discovery and adjusting for population stratification and relevant demographic/psychosocial characteristics. Minor alleles for three of the SNPs (rs1998220 on OPRM1; rs9534511 on HTR2A; and rs4938056 on HTR3B) were associated with increased risk of social disinhibition, while minor alleles for the other three SNPs (rs1003921 on KCNC1; rs16116 downstream of NPY; and rs16870286 on LINC00518) exhibited a protective effect. Age, linguistic acculturation, thrill and adventure-seeking, and drug and alcohol-seeking were all significantly positively associated with increased risk of social disinhibition in a multivariable model (P < 0.001).Conclusions These results add to our knowledge of genetic risk factors for social disinhibition. Additional research is needed to verify whether these SNPs are associated with social disinhibition among youth of different ethnicities and nationalities, and to elucidate whether and how these SNPs functionally contribute to social disinhibition.
    Brain and Behavior 07/2014; 4(4). DOI:10.1002/brb3.236 · 2.24 Impact Factor
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    • "Reelin abnormalities and schizophrenia risk ( Shifman et al . 2008 ) and with bipolar disorder ( Goes et al . 2010 ) . These studies , combined with our data , may suggest that women with a Reelin deficiency may be more susceptible to psychiatric illnesses , such as schizophrenia or bipolar disorder , than men and that ovarian hormones may be involved in this sex difference . Several rodent studies hav"
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    ABSTRACT: Neurodevelopmental psychiatric disorders such as schizophrenia may be caused by a combination of gene x environment, gene x gene and/or gene x sex interactions. Reduced expression of both Reelin and Brain-Derived Neurotrophic factor (BDNF) has been associated with schizophrenia in human post-mortem studies. However, it is unclear how Reelin and BDNF interact (gene x gene) and whether this is sex-specific (gene x sex). This study investigated BDNF-TrkB signaling in the hippocampus of male and female Reelin heterozygous (Rln(+/-) ) mice. We found significantly increased levels of BDNF in the ventral hippocampus (VHP) of female, but not male Rln(+/-) compared to wildtype (WT) controls. While levels of TrkB were not significantly altered, phosphorylated TrkB (pTrkB) levels were significantly lower, again only in female Rln(+/-) compared to WT. This translated to downstream effects with a significant decrease in phosphorylated ERK1 (pERK1). No changes in BDNF, TrkB, pTrkB or pERK1/2 were observed in the dorsal hippocampus of Rln(+/-) mice. Ovariectomy (OVX) had no effect in WT controls, but caused a significant decrease in BDNF expression in the VHP of Rln(+/-) mice to the levels of intact WT controls. The high expression of BDNF was restored in OVX Rln(+/-) mice by 17β-estradiol treatment, suggesting that Rln(+/-) mice respond differently to an altered estradiol state than WT controls. In addition, while OVX had no significant effect on TrkB or ERK expression/phosphorylation, OVX + estradiol treatment markedly increased TrkB and ERK1 phosphorylation in Rln(+/-) and, to a lesser extent in WT controls, compared to intact genotype-matched controls. These data may provide a better understanding of the interaction of Reelin and BDNF in the hippocampus, which may be involved in schizophrenia. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12205.
    Journal of Neurochemistry 02/2013; 126(3). DOI:10.1111/jnc.12205 · 4.28 Impact Factor
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