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

Genes of the Major Histocompatibility Complex (MHC) have recently been shown to have neuronal functions in the thalamus and hippocampus. Common genetic variants in the Human Leukocyte Antigens (HLA) region, human homologue of the MHC locus, are associated with small effects on susceptibility to schizophrenia, while volumetric changes of the thalamus and hippocampus have also been linked to schizophrenia. We therefore investigated whether common variants of the HLA would affect volumetric variation of the thalamus and hippocampus. We analyzed thalamus and hippocampus volumes, as measured using structural magnetic resonance imaging, in 1.265 healthy participants. These participants had also been genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. We imputed genotypes for single nucleotide polymorphisms at high density across the HLA locus, as well as HLA allotypes and HLA amino acids, by use of a reference population dataset that was specifically targeted to the HLA region. We detected a significant association of the SNP rs17194174 with thalamus volume (nominal P=0.0000017, corrected P=0.0039), as well as additional SNPs within the same region of linkage disequilibrium. This effect was largely lateralized to the left thalamus and is localized within a genomic region previously associated with schizophrenia. The associated SNPs are also clustered within a potential regulatory element, and a region of linkage disequilibrium that spans genes expressed in the thalamus, including HLA-A. Our data indicate that genetic variation within the HLA region influences the volume and asymmetry of the human thalamus. The molecular mechanisms underlying this association may relate to HLA influences on susceptibility to schizophrenia

Abstract

Lateralizations of brain structure and motor behavior have been observed in humans as early as the first trimester of gestation, and are likely to arise from asymmetrical genetic–developmental programs, as in other animals. Studies of gene expression levels in postmortem tissue samples, comparing the left and right sides of the human cerebral cortex, have generally not revealed striking transcriptional differences between the hemispheres. This is likely due to lateralization of gene expression being subtle and quantitative. However, a recent re-analysis and meta-analysis of gene expression data from the adult superior temporal and auditory cortex found lateralization of transcription of genes involved in synaptic transmission and neuronal electrophysiology. Meanwhile, human subcortical mid- and hindbrain structures have not been well studied in relation to lateralization of gene activity, despite being potentially important developmental origins of asymmetry. Genetic polymorphisms with small effects on adult brain and behavioral asymmetries are beginning to be identified through studies of large datasets, but the core genetic mechanisms of lateralized human brain development remain unknown. Identifying subtly lateralized genetic networks in the brain will lead to a new understanding of how neuronal circuits on the left and right are differently fine-tuned to preferentially support particular cognitive and behavioral functions.

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.

Abstract

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10-33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction

Abstract

Lateralization is an important aspect of the functional brain architecture for language and other cognitive faculties. The molecular genetic basis of human brain lateralization is unknown, and recent studies have suggested that gene expression in the cerebral cortex is bilaterally symmetrical. Here we have re-analyzed two transcriptomic datasets derived from post mortem human cerebral cortex, with a specific focus on superior temporal and auditory language cortex in adults. We applied an empirical Bayes approach to model differential left-right expression, together with gene ontology analysis and meta-analysis. There was robust and reproducible lateralization of individual genes and gene ontology groups that are likely to fine-tune the electrophysiological and neurotransmission properties of cortical circuits, most notably synaptic transmission, nervous system development and glutamate receptor activity. Our findings anchor the cerebral biology of language to the molecular genetic level. Future research in model systems may determine how these molecular signatures of neurophysiological lateralization effect fine-tuning of cerebral cortical function, differently in the two hemispheres.

Abstract

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

Abstract

We previously reported an association with a putative functional variant in the ADAMTSL3 gene, just below genome-wide significance in a genome-wide association study of schizophrenia. As variants impacting the function of ADAMTSL3 (a disintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3) could illuminate a novel disease mechanism and a potentially specific target, we have used complementary approaches to further evaluate the association. We imputed genotypes and performed high density association analysis using data from the HapMap and 1000 genomes projects. To review all variants that could potentially cause the association, and to identify additional possible pathogenic rare variants, we sequenced ADAMTSL3 in 92 schizophrenics. A total of 71 ADAMTSL3 variants were identified by sequencing, many were also seen in the 1000 genomes data, but 26 were novel. None of the variants identified by re-sequencing was in strong linkage disequilibrium (LD) with the associated markers. Imputation analysis refined association between ADAMTSL3 and schizophrenia, and highlighted additional common variants with similar levels of association. We evaluated the functional consequences of all variants identified by sequencing, or showing direct or imputed association. The strongest evidence for function remained with the originally associated variant, rs950169, suggesting that this variant may be causal of the association. Rare variants were also identified with possible functional impact. Our study confirms ADAMTSL3 as a candidate for further investigation in schizophrenia, using the variants identified here. The utility of imputation analysis is demonstrated, and we recommend wider use of this method to re-evaluate the existing canon of suggestive schizophrenia associations.

Abstract

Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35 079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P=0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.