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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    • "Changes in psychosocial functioning over time can be used as a measure of outcome or functional recovery from episodes of mental disorders (Jobe and Harrow, 2005; Lieberman et al., 2008). The sex-specific genetic architecture of mental disorders has gained attention lately (Ober et al., 2008), sparked by a finding in the Reelin gene that increases the risk to develop SZspec in females but not males (Shifman et al., 2008). Subsequent investigation by Goes et al. (2009) also implicated Reelin as a sex-specific genetic risk factor in BDs, pointing to a sex-specific cross-disorder vulnerability locus. "
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    ABSTRACT: Sex is a powerful modulator of disease susceptibility, course and outcome. The gene CACNA1C is among the best replicated vulnerability genes of bipolar disorder and schizophrenia. The aim of the present study was to investigate whether sex and a variant in CACNA1C (rs10774035 as a proxy for the well-acknowledged risk variant rs1006737) influence psychosocial adaptation in a large German patient sample with schizophrenia-spectrum (n=297) and bipolar (n=516) disorders. We analyzed Global Assessment of Functioning (GAF) scores, retrospectively collected for different time points during disease course. We investigated whether CACNA1C sex-dependently modulates longitudinal GAF scores and recovery from episodes of psychiatric disturbance in the above mentioned disorders. Psychosocial recovery was measured as difference score between the current GAF score (assessing the last remission) and the worst GAF score ever during an illness episode. Covariate- adjusted association analyses revealed a sex × rs10774035 genotype interaction on longitudinal GAF and recovery from illness episodes only in schizophrenia-spectrum but not in bipolar disorders. In schizophrenia-spectrum affected males, rs10774035 minor allele (T) carriers had higher GAF scores at three time points (premorbid, worst ever, current). In contrast, females carrying rs10774035 minor alleles had impaired recovery from schizophrenia-spectrum episodes. These results encourage further investigations of gene × sex interactions and longitudinal quantitative phenotypes to unravel the rich variety of behavioral consequences of genetic individuality.
    Preview · Article · Oct 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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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). "

    Full-text · Dataset · Dec 2014
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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.
    Full-text · Article · Jul 2014 · Brain and Behavior
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