| 1 | Mol. Psychiatry 2012 Sep 17: 906-17 |
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| PMID | 21747397 |
| Title | Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe. |
| Abstract | Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture ofschizophrenia(SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genesAMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n=11?540; P=3.89 � 10(-9), odds ratio (OR)=1.25). This finding was replicated in 23?206 independent samples of European ancestry (P=0.0029, OR=1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder. |
| SCZ Keywords | schizophrenia |
| 2 | Eur. J. Neurosci. 2013 Sep 38: 2941-5 |
| PMID | 23551272 |
| Title | From gene to brain to behavior: schizophrenia-associated variation in AMBRA1 alters impulsivity-related traits. |
| Abstract | Recently, genome-wide association betweenschizophreniaand an intronic variant inAMBRA1(rs11819869) was reported. Additionally, in a reverse genetic approach in adult healthy subjects, risk allele carriers showed a higher medial prefrontal cortex blood oxygen level-dependent (BOLD) response during a flanker task examining motor inhibition as an aspect of impulsivity. To test whether this finding can be expanded to further aspects of impulsivity, we analysed the effects of the rs11819869 genotype on impulsivity-related traits on a behavioral, temperament and neural level in a large sample of healthy adolescents. We consider this reverse genetic approach specifically suited for use in a healthy adolescent sample, as these individuals comprise those who will eventually develop mental disorders in which impulsivity is implicated. Healthy adolescents from the IMAGEN study were included in the neuropsychological analysis (n�=�848) and a functional magnetic resonance imaging (fMRI) task (n�=�512). Various aspects of impulsivity were assessed using the Temperament and Character Inventory-Revised, the Substance Use Risk Profile Scale, the Cambridge Cognition Neuropsychological Test Automated Battery, and the Stop Signal Task (SST) in the fMRI paradigm. On a behavioral level, increased delay aversion was observed in risk allele carriers. Furthermore, risk allele carriers showed a higher BOLD response in an orbito-frontal target region during the SST, which declined to trend status after Family Wise Error correction. Our findings support the hypothesis that theschizophrenia有关的风险rs11819869的变体involved in various aspects of impulsivity, and that this involvement occurs on a behavioral as well as an imaging genetics level. |
| SCZ Keywords | schizophrenia |