Ross, C. J. D. | bioRxiv Science

bioRxiv2019

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

Huntington disease (HD) is a neurodegenerative disorder that is caused by a CAG repeat expansion in the HTT gene. In an attempt to identify genomic modifiers that contribute towards the age of onset of HD, we performed a transcriptome wide association study assessing heritable differences in genetically determined expression in diverse tissues, employing genome wide data from over 4,000 patients. This identified genes that showed evidence for colocalization and replication, with downstream functional validation being performed in isogenic HD stem cells and patient brains. Enrichment analyses detected associations with various biologically-relevant gene sets and striatal coexpression modules that are mediated by CAG length. Further, cortical coexpression modules that are relevant for HD onset were also associated with cognitive decline and HD-related traits in a longitudinal cohort. In summary, the combination of population-scale gene expression information with HD patient genomic data identified novel modifier genes for the disorder.

genomics↗

bioRxiv2018

Affectively-biased Competition Favoring Rewarding Expressions is Not Modulated by Common Variation in Norepinephrine Receptor Function

It is well established that emotionally salient stimuli evoke greater visual cortex activation than neutral ones, and can distract attention from competing tasks. Yet less is known about underlying neurobiological processes. As a proxy of population level biased competition, EEG steady-state visual evoked potentials are sensitive to competition effects from salient stimuli. Here we wished to examine whether individual differences in norepinephrine activity play a role in emotionally-biased competition.\n\nOur previous research has found robust effects of a common variation in the ADRA2B gene, coding for alpha2B norepinephrine (NE) receptors, on emotional modulation of attention and memory. In the present study, EEG was collected while 87 carriers of the ADRA2B deletion variant and 95 non-carriers (final sample) performed a change detection task in which target gratings (gabor patches) were superimposed directly over angry, happy, and neutral faces. Participants indicated the number of phase changes (0-3) in the target. Overlapping targets and distractors were flickered at a distinct driving frequencies. Relative EEG power for faces vs. targets at the driving frequency served as an index of cortical resources allocated to each of the competing stimuli. Deletion carriers and non-carriers were randomly assigned to Discovery and Replication samples and reliability of results across samples was assessed before the groups were combined for greater power.\n\nOverall happy faces evoked higher competition than angry or neutral faces; however, we observed no hypothesized effects of ADRA2B. Increased competition from happy faces was not due to the effect of low-level visual features or individuals low in social anxiety. Our results indicate that emotionally biased competition during sustained attention, while reliably observed in young adults, is not influenced by commonly observed individual differences linked to NE receptor function. They further indicate an overall pattern of affectively-biased competition for happy faces, which we interpret in relation to previously observed boundary conditions.

neuroscience↗