Presentations

Abstract

White matter tracts form the structural basis of large-scale functional networks in the human brain. We applied brain-wide tractography to diffusion images from 30,810 adult participants (UK Biobank), and found significant heritability for 90 regional connectivity measures and 851 fiber tracts. Multivariate genome-wide association analyses identified 355 independently associated lead SNPs across the genome, of which 77% were not previously associated with human brain metrics. Enrichment analyses implicated neurodevelopmental processes including neurogenesis, neural differentiation, neural migration, neural projection guidance, and axon development, as well as prenatal brain expression especially in stem cells, astrocytes, microglia and neurons. We used the multivariate association profiles of lead SNPs to identify 26 genomic loci implicated in structural connectivity between core regions of the left-hemisphere language network, and also identified 6 loci associated with hemispheric left-right asymmetry of structural connectivity. Polygenic scores for schizophrenia, bipolar disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, reading ability, left-handedness, Alzheimer’s disease, amyotrophic lateral sclerosis, and epilepsy showed significant multivariate associations with structural connectivity, each implicating specific sets of brain regions with trait-relevant functional profiles. This large-scale mapping study revealed common genetic contributions to the human brain's structural connectome in the general adult population, and its links with polygenic disposition to brain disorders and behavioral traits.

Abstract

Dyslexia is a common learning disability with a known genetic component. Several candidate genes have been implicated in dyslexia susceptibility, such as ROBO1, KIAA0319, and DCDC2. Associations with variants in these genes have also been reported for a variety of psychometric measures that tackle underlying processes that might be impaired in dyslexic people. In this study, we first conducted a literature review to select single nucleotide polymorphisms (SNPs) in dyslexia candidate genes that had been repeatedly implicated in multiple studies. We then assessed the selected SNPs for association in a well-phenotyped longitudinal dataset: the Dutch Dyslexia Program longitudinal sample. We tested for association with several quantitative traits, including word and nonword reading fluency, rapid naming, phoneme deletion and nonword repetition, and took advantage of the longitudinal nature of the sample to examine if associations were stable across four developmental time-points (from 7 to 12 years). Two SNPs in the KIAA0319 gene were found to be nominally associated with rapid naming, and further analysis revealed that these associations were stable across different ages.

Abstract

A degree of functional lateralization is characteristic of various aspects of human cognition, including aspects of language processing, which show left hemisphere dominance in most people. Left-right asymmetries of the human brain and behaviour are likely to arise from lateralized genetic-developmental programs that originate in the early embryo. In adults, a recent study of gene expression data from superior temporal and auditory cortex found subtle, quantitative lateralization of genes involved in synaptic transmission and neuronal electrophysiology. These observations are consistent with functional lateralization of this cortical region for language. Genetic polymorphisms that may have small, modifying effects on brain and behavioral asymmetries are starting to be identified through association studies, although core genetic mechanisms of asymmetrical brain development are not known. A major challenge will be to understand how neuronal circuits of the left and right hemisphere become differently fine-tuned, at the molecular level, to preferentially support particular cognitive functions. Through analyzing the inter-hemispheric genetic contrast, powerful insights may be gained into the exact properties of the left hemisphere's architecture which are particularly supportive of language-related functions

Abstract

Combining approaches at multiple scales, including gene, protein, brain and behavior, would provide a comprehensive picture of brain functions and individual differences. In this project, we will focus on the human language system, combining post mortem analysis of the transcriptome with genotyping in large datasets, functional mapping, and behavioral tasks, as well as receptor mapping via collaboration with Human Brain Project (HBP) investigators.