Publications

Abstract

Lateralization is a defining characteristic of the human brain, often studied through localized approaches that focus on interhemispheric differences between homologous pairs of regions. It is also important to emphasize an integrative perspective of global brain asymmetry, in which hemispheric differences are understood through global patterns across the entire brain.

Abstract

Hemispheric brain asymmetry is a basic organizational principle of the human brain and has been implicated in various psychiatric conditions, including autism spectrum disorder. Brain asymmetry is not a uniquely human feature and is observed in other species such as the mouse. Yet, asymmetry patterns are generally nuanced, and substantial sample sizes are required to detect these patterns. In this pre-registered study, we use a mouse dataset from the Province of Ontario Neurodevelopmental Network, which comprises structural MRI data from over 2000 mice, including genetic models for autism spectrum disorder, to reveal the scope and magnitude of hemispheric asymmetry in the mouse. Our findings demonstrate the presence of robust hemispheric asymmetry in the mouse brain, such as larger right hemispheric volumes towards the anterior pole and larger left hemispheric volumes toward the posterior pole, opposite to what has been shown in humans. This suggests the existence of species-specific traits. Further clustering analysis identified distinct asymmetry patterns in autism spectrum disorder models, a phenomenon that is also seen in atypically developing participants. Our study shows potential for the use of mouse models in studying the biological bases of typical and atypical brain asymmetry but also warrants caution as asymmetry patterns seem to differ between humans and mice.

Abstract

Left-right asymmetry is an important aspect of human brain organization for functions including language and hand motor control, which can be altered in some psychiatric traits. The last five years have seen rapid advances in the identification of specific genes linked to variation in asymmetry of the human brain and/or handedness. These advances have been driven by a new generation of large-scale genome-wide association studies, carried out in samples ranging from roughly 16,000 to over 1.5 million participants. The implicated genes tend to be most active in the embryonic and fetal brain, consistent with early developmental patterning of brain asymmetry. Several of the genes encode components of microtubules, or other microtubule-associated proteins. Microtubules are key elements of the internal cellular skeleton (cytoskeleton). A major challenge remains to understand how these genes affect, or even induce, the brain’s left-right axis. Several of the implicated genes have also been associated with psychiatric or neurological disorders, and polygenic dispositions to autism and schizophrenia have been associated with structural brain asymmetry. Knowledge of developmental mechanisms that lead to hemispheric specialization may ultimately help to define etiologic subtypes of brain disorders.

Abstract

OBJECTIVE: Recent research has provided evidence for a genetically mediated association between language or reading-related cognitive deficits and impaired motor coordination. Other studies have identified relationships between lateralization of hand skill and cognitive abilities. With a large sample, the authors aimed to investigate genetic relationships between measures of reading-related cognition, hand motor skill, and hand skill lateralization.

METHOD: The authors applied univariate and bivariate correlation and familiality analyses to a range of measures. They also performed genomewide linkage analysis of hand motor skill in a subgroup of 195 sibling pairs.

RESULTS: Hand motor skill was significantly familial (maximum heritability=41%), as were reading-related measures. Hand motor skill was weakly but significantly correlated with reading-related measures, such as nonword reading and irregular word reading. However, these correlations were not significantly familial in nature, and the authors did not observe linkage of hand motor skill to any chromosomal regions implicated in susceptibility to dyslexia. Lateralization of hand skill was not correlated with reading or cognitive ability.

CONCLUSIONS: The authors confirmed a relationship between lower motor ability and poor reading performance. However, the genetic effects on motor skill and reading ability appeared to be largely or wholly distinct, suggesting that the correlation between these traits may have arisen from environmental influences. Finally, the authors found no evidence that reading disability and/or low general cognitive ability were associated with ambidexterity.

Abstract

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.

Abstract

Replication of linkage results for complex traits has been exceedingly difficult, owing in part to the inability to measure the precise underlying phenotype, small sample sizes, genetic heterogeneity, and statistical methods employed in analysis. Often, in any particular study, multiple correlated traits have been collected, yet these have been analyzed independently or, at most, in bivariate analyses. Theoretical arguments suggest that full multivariate analysis of all available traits should offer more power to detect linkage; however, this has not yet been evaluated on a genomewide scale. Here, we conduct multivariate genomewide analyses of quantitative-trait loci that influence reading- and language-related measures in families affected with developmental dyslexia. The results of these analyses are substantially clearer than those of previous univariate analyses of the same data set, helping to resolve a number of key issues. These outcomes highlight the relevance of multivariate analysis for complex disorders for dissection of linkage results in correlated traits. The approach employed here may aid positional cloning of susceptibility genes in a wide spectrum of complex traits.

Abstract

Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is a common, highly heritable neurobehavioral disorder of childhood onset, characterized by hyperactivity, impulsivity, and/or inattention. As part of an ongoing study of the genetic etiology of ADHD, we have performed a genomewide linkage scan in 204 nuclear families comprising 853 individuals and 270 affected sibling pairs (ASPs). Previously, we reported genomewide linkage analysis of a “first wave” of these families composed of 126 ASPs. A follow-up investigation of one region on 16p yielded significant linkage in an extended sample. The current study extends the original sample of 126 ASPs to 270 ASPs and provides linkage analyses of the entire sample, using polymorphic microsatellite markers that define an ∼10-cM map across the genome. Maximum LOD score (MLS) analysis identified suggestive linkage for 17p11 (MLS=2.98) and four nominal regions with MLS values >1.0, including 5p13, 6q14, 11q25, and 20q13. These data, taken together with the fine mapping on 16p13, suggest two regions as highly likely to harbor risk genes for ADHD: 16p13 and 17p11. Interestingly, both regions, as well as 5p13, have been highlighted in genomewide scans for autism.

Abstract

Family and twin studies consistently demonstrate a significant role for genetic factors in the aetiology of the reading disorder dyslexia. However, dyslexia is complex at both the genetic and phenotypic levels, and currently the nature of the core deficit or deficits remains uncertain. Traditional approaches for mapping disease genes, originally developed for single-gene disorders, have limited success when there is not a simple relationship between genotype and phenotype. Recent advances in high-throughput genotyping technology and quantitative statistical methods have made a new approach to identifying genes involved in complex disorders possible. The method involves assessing the genetic similarity of many sibling pairs along the lengths of all their chromosomes and attempting to correlate this similarity with that of their phenotypic scores. We are adopting this approach in an ongoing genome-wide search for genes involved in dyslexia susceptibility, and have already successfully applied the method by replicating results from previous studies suggesting that a quantitative trait locus at 6p21.3 influences reading disability.