Francks, C. et al. Parent-of-origin effects on handedness and schizophrenia susceptibility on chromosome 2p12-q11. Hum. Mol. Genet. 12, 3225-3230

Wellcome Trust Centre for Human Genetics, University of Oxford, UK.
Human Molecular Genetics (Impact Factor: 6.39). 12/2003; 12(24):3225-30. DOI: 10.1093/hmg/ddg362
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Schizophrenia and non-right-handedness are moderately associated, and both traits are often accompanied by abnormalities of asymmetrical brain morphology or function. We have found linkage previously of chromosome 2p12-q11 to a quantitative measure of handedness, and we have also found linkage of schizophrenia/schizoaffective disorder to this same chromosomal region in a separate study. Now, we have found that in one of our samples (191 reading-disabled sibling pairs), the relative hand skill of siblings was correlated more strongly with paternal than maternal relative hand skill. This led us to re-analyse 2p12-q11 under parent-of-origin linkage models. We found linkage of relative hand skill in the RD siblings to 2p12-q11 with P=0.0000037 for paternal identity-by-descent sharing, whereas the maternally inherited locus was not linked to the trait (P>0.2). Similarly, in affected-sib-pair analysis of our schizophrenia dataset (241 sibling pairs), we found linkage to schizophrenia for paternal sharing with LOD=4.72, P=0.0000016, within 3 cM of the peak linkage to relative hand skill. Maternal linkage across the region was weak or non-significant. These similar paternal-specific linkages suggest that the causative genetic effects on 2p12-q11 are related. The linkages may be due to a single maternally imprinted influence on lateralized brain development that contains common functional polymorphisms.

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    • "Given the unusual strength of the affect-sib-pair linkage at this locus that was previously reported in these sib pairs (LOD ¼ 4.72, [Francks et al., 2003]), the current study was sufficiently powered to detect an effect mediated by methylation that was hypothesized to drive this linkage, even if such an effect may be relatively unusual and specific to these families. However, our use of the New York/ Oxford sibs also meant that we were limited to studying DNA extracted from blood, and also to a reduced number of subjects from whom sufficient DNA was still available from this valuable collection. "
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    ABSTRACT: Epigenetic effects on psychiatric traits remain relatively under-studied, and it remains unclear what the sizes of individual epigenetic effects may be, or how they vary between different clinical populations. The gene LRRTM1 (chromosome 2p12) has previously been linked and associated with schizophrenia in a parent-of-origin manner in a set of affected siblings (LOD = 4.72), indirectly suggesting a disruption of paternal imprinting at this locus in these families. From the same set of siblings that originally showed strong linkage at this locus, we analyzed 99 individuals using 454-bisulfite sequencing, from whole blood DNA, to measure the level of DNA methylation in the promoter region of LRRTM1. We also assessed seven additional loci that would be informative to compare. Paternal identity-by-descent sharing at LRRTM1, within sibling pairs, was linked to their similarity of methylation at the gene's promoter. Reduced methylation at the promoter showed a significant association with schizophrenia. Sibling pairs concordant for schizophrenia showed more similar methylation levels at the LRRTM1 promoter than diagnostically discordant pairs. The alleles of common SNPs spanning the locus did not explain this epigenetic linkage, which can therefore be considered as largely independent of DNA sequence variation and would not be detected in standard genetic association analysis. Our data suggest that hypomethylation at the LRRTM1 promoter, particularly of the paternally inherited allele, was a risk factor for the development of schizophrenia in this set of siblings affected with familial schizophrenia, and that had previously showed linkage at this locus in an affected-sib-pair context. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2014; 165(7). DOI:10.1002/ajmg.b.32258 · 3.42 Impact Factor
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    • "), autism spectrum condition (ASC) (Arking et al., 2008; Ashley-Koch et al., 1999; Cook et al., 1997; Lamb et al., 2005; Repetto, White, Bader, Johnson, & Knoll, 1998), bipolar disorder (Dick et al., 2003; McInnis et al., 2003; Schultze et al., 2004), Prader–Willi syndrome (Gallagher, Pils, Albalwi, & Francke, 2002; Glenn, Driscoll, Yang, & Nicholls, 1997; Runte, Varon, Horn, Horsthemke, & Buiting, 2005; Sahoo et al., 2008) and schizophrenia (DeLisi et al., 2002; Francks et al., 2003; Seal et al., 2006). There have been many theories regarding the evolution of imprinting, but as more imprinted genes are discovered and their function becomes better understood, few theories have retained any credibility as they struggle to accommodate the data (Day & Bonduriansky, 2004; Moore & Mills, 2008; Weisstein, Feldman, & Spencer, 2002; Weisstein & Spencer, 2003). "
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    ABSTRACT: Genomic imprinting is a violation of Mendel's laws that enables selection to act on genes, depending on parent of origin, but, even more controversially, on the sex of the offspring. This study tested whether there are parent-of-origin effects on the heritability of empathy and systemizing in the general population as part of a larger question concerning the role of imprinted genes in the evolution of human cognition and behaviour. The measures tested were the Empathy and Systemizing Quotients as proxies for the related terms mentalistic and mechanistic cognition in the imprinted brain theory. To test genomic imprinting hypotheses, correlations in behavioural scores between pairs of full, maternal and paternal siblings were compared. Where scores are influenced by imprinted genes, the actual correlations between pairs of siblings will differ from those expected following classical Mendelian inheritance in a predictable way depending on what kind of imprinting is influencing the trait. These theoretical predictions were used to test the fit of the data against Mendelian and imprinting models using structural equation modeling. The imprinted brain theory proposes a trade-off between maternally influenced mentalistic cognition and paternally influenced mechanistic cognition. However, the results of this study support a model of contrasting maternal and paternal influences on strong and weak empathizing and a maternal influence on systemizing. Although the sample size was insufficient to comprehensively analyse sex-limitation models, there is some evidence that heritability of systemizing is stronger in females than in males.
    Evolution and Human Behavior 07/2012; 33(4):402-410. DOI:10.1016/j.evolhumbehav.2011.12.002 · 3.13 Impact Factor
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    • "Mental and neurological disorders are often influenced by deregulation of the imprinting processes. For example, genomic imprinting has been implicated in bipolar disorder, schizophrenia and autism.61-63 Interestingly, imprinted genes are frequently associated with antisense transcripts,64 which might play a role in gene silencing and could be causal factor in neurological disorders.3,4 "
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    ABSTRACT: DNA sequences associated with protein-coding genes have been the primary focus of most genetic analyses of complex human diseases. Although we are rapidly gaining a comprehensive view of the etiology of certain central nervous system disorders, major gaps in our understanding persist. Recent studies have uncovered that many human genomic sequences are transcribed but not translated, generating an astounding diversity of noncoding RNAs (ncRNAs). This awareness should be taken into account when studying human diseases and may have profound implications on the development of novel biomarkers as well as therapies.
    RNA biology 06/2012; 9(6):860-70. DOI:10.4161/rna.20482 · 4.97 Impact Factor
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