LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia

University of Helsinki, Helsinki, Uusimaa, Finland
Molecular Psychiatry (Impact Factor: 14.5). 01/2008; 12(12):1129-39, 1057. DOI: 10.1038/
Source: PubMed


Left-right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P=0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P=0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.

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Available from: Anthony P Monaco
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    • "A number of environmental factors such as season of birth (Stoyanov et al., 2011), cultural influences (Fagard and Dahmen, 2004), differential visual experience of the hands (Ocklenburg and Güntürkün, 2009; Ocklenburg et al., 2010), parental influence (Laland, 2008) and others (Schaafsma et al., 2009) have been shown to influence handedness. Moreover, several genes such as LRRTM1 (Francks et al., 2007), PCSK6 (Scerri et al., 2011; Arning et al., 2013), and AR (Medland et al., 2005; Hampson and Sankar, 2012) have been related to handedness . However, the variance in individual handedness explained by any single one of these factors is typically low, and it is not uncommon that findings in one sample cannot be replicated in others (for example see: Bloss et al., 2010; Hubacek et al., 2013). "

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    • "To understand whether and how our results generalize to a broader patient population, future studies will need to incorporate more diverse approaches to patient recruitment, particularly targeting sporadic patients rather than families with multiple affected individuals, and also using an updated version of the DSM. LRRTM1 was previously associated in a paternal-specific manner with handedness (relative hand skill) in a set of families affected by dyslexia [Francks et al., 2007]. Unfortunately the handedness data are sparse for the New York/Oxford siblings. "
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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.
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    • "Various other studies have shown fetal and infant asymmetries in the perisylvian region, sylvian fissure, and superior temporal sulcus (Dubois et al., 2008; Dubois et al., 2010; Habas et al., 2012; Kasprian et al., 2011; Li et al., 2013). These early developmental asymmetries clearly indicate a role for genetic mechanisms, but very few individual genes have so far been implicated in any aspect of lateralization of the human brain (Francks et al., 2007; Ocklenburg et al., 2013; Scerri et al., 2011; Sun et al., 2005; Sun and Walsh, 2006). Language lateralization appears to develop largely independently of early embryonic mechanisms that pattern left-right asymmetry of the viscera (heart, lungs etc.; Tanaka et al., 1999). "
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    ABSTRACT: The genetic determinants of cerebral asymmetries are unknown. Sex differences in asymmetry of the planum temporale, that overlaps Wernicke’s classical language area, have been inconsistently reported. Meta-analysis of previous studies has suggested that publication bias established this sex difference in the literature. Using probabilistic definitions of cortical regions we screened over the cerebral cortex for sexual dimorphisms of asymmetry in 2337 healthy subjects, and found the planum temporale to show the strongest sex-linked asymmetry of all regions, which was supported by two further datasets, and also by analysis with the Freesurfer package that performs automated parcellation of cerebral cortical regions. We performed a genome-wide association scan meta-analysis of planum temporale asymmetry in a pooled sample of 3095 subjects, followed by a candidate-driven approach which measured a significant enrichment of association in genes of the ´steroid hormone receptor activity´ and 'steroid metabolic process' pathways. Variants in the genes and pathways identified may affect the role of the planum temporale in language cognition.
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