Publications

Abstract

Rhythm and language-related traits are phenotypically correlated, but their genetic overlap is largely unknown. Here, we leveraged two large-scale genome-wide association studies performed to shed light on the shared genetics of rhythm (N=606,825) and dyslexia (N=1,138,870). Our results reveal an intricate shared genetic and neurobiological architecture, and lay groundwork for resolving longstanding debates about the potential co-evolution of human language and musical traits.

Abstract

Apolipoprotein E ε4 is a major genetic risk factor for Alzheimer’s disease, and some apolipoprotein E ε4 carriers show Alzheimer’s disease–related neuropathology many years before cognitive changes are apparent. Therefore, studying healthy apolipoprotein E genotyped individuals offers an opportunity to investigate the earliest changes in brain measures that may signal the presence of disease-related processes. For example, subtle changes in functional magnetic resonance imaging functional connectivity, particularly within the default mode network, have been described when comparing healthy ε4 carriers to ε3 carriers. Similarly, very mild impairments of episodic memory have also been documented in healthy apolipoprotein E ε4 carriers. Here, we use a naturalistic activity (movie watching), and a marker of episodic memory encoding (transient changes in functional magnetic resonance imaging activity and functional connectivity around so-called ‘event boundaries’), to investigate potential phenotype differences associated with the apolipoprotein E ε4 genotype in a large sample of healthy adults. Using Bayes factor analyses, we found strong evidence against existence of differences associated with apolipoprotein E allelic status. Similarly, we did not find apolipoprotein E-associated differences when we ran exploratory analyses examining: functional system segregation across the whole brain, and connectivity within the default mode network. We conclude that apolipoprotein E genotype has little or no effect on how ongoing experiences are processed in healthy adults. The mild phenotype differences observed in some studies may reflect early effects of Alzheimer’s disease–related pathology in apolipoprotein E ε4 carriers.

Abstract

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Abstract

Familial hemiplegic migraine type 1 (FHM1) is a
rare monogenic subtype of migraine with aura caused by mutations
in CACNA1A that encodes the α1A subunit of voltagegated
CaV2.1 calcium channels. Transgenic knock-in mice
that carry the human FHM1 R192Q missense mutation
(‘FHM1 R192Q mice’) exhibit an increased susceptibility to
cortical spreading depression (CSD), the mechanism underlying
migraine aura. Here, we analysed gene expression profiles
from isolated cortical tissue of FHM1 R192Q mice 24 h after
experimentally induced CSD in order to identify molecular
pathways affected by CSD. Gene expression profiles were
generated using deep serial analysis of gene expression sequencing.
Our data reveal a signature of inflammatory signalling
upon CSD in the cortex of both mutant and wild-type
mice. However, only in the brains of FHM1 R192Q mice
specific genes are up-regulated in response to CSD that are
implicated in interferon-related inflammatory signalling. Our
findings show that CSD modulates inflammatory processes in
both wild-type and mutant brains, but that an additional
unique inflammatory signature becomes expressed after
CSD in a relevant mouse model of migraine.

Abstract

Cluster headache is a relatively rare headache disorder, typically characterized by multiple daily, short-lasting attacks of excruciating, unilateral (peri-)orbital or temporal pain associated with autonomic symptoms and restlessness. To better understand the pathophysiology of cluster headache, we used RNA sequencing to identify differentially expressed genes and pathways in whole blood of patients with episodic (n = 19) or chronic (n = 20) cluster headache in comparison with headache-free controls (n = 20). Gene expression data were analysed by gene and by module of co-expressed genes with particular attention to previously implicated disease pathways including hypocretin dysregulation. Only moderate gene expression differences were identified and no associations were found with previously reported pathogenic mechanisms. At the level of functional gene sets, associations were observed for genes involved in several brain-related mechanisms such as GABA receptor function and voltage-gated channels. In addition, genes and modules of co-expressed genes showed a role for intracellular signalling cascades, mitochondria and inflammation. Although larger study samples may be required to identify the full range of involved pathways, these results indicate a role for mitochondria, intracellular signalling and inflammation in cluster headache