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Defining the genetics of grapheme-colour synaesthesia

Periodic Reporting for period 1 - SynGenes (Defining the genetics of grapheme-colour synaesthesia)

Reporting period: 2016-06-01 to 2018-05-31

Synaesthesia is a neurological phenomenon that causes the boundaries between the senses to become blurred. Approximately 4% of the population experiences synaesthesia, most commonly in the form of colour associations with the days of the week (“Mondays are red”) or months. Most individuals with synaesthesia have no other neurological issues, and many are completely unaware that their perceptions are unusual. This aspect of synaesthesia makes it a compelling window into how natural variation in sensory perception is established.

Although reports of synaesthesia running in families date to the late 1800s, the genetic basis of such perceptual differences remains unknown and there are no candidate genes associated with the trait. Our understanding of how the brain generates synaesthetic associations is held back by our inability to study synaesthesia at a cellular or molecular level. Knowing which genes or molecular processes to target in such studies would unlock new opportunities to examine the molecular basis of perception.

The scientific objective of this action was to define the genetics of synaesthesia through studies focused on both rare and common genetic variation. Dr. Tilot made significant progress toward this goal during the length of the action, publishing the first set of robust candidate genes for the trait in 2018. Her research suggests that synaesthesia may arise from variants in genes involved in how neurons form connections across the brain during development. This provides direct support for a prominent hypothesis generated from studies in neuroimaging and psychology, that synaesthesia is caused by hyperconnectivity between brain regions. Further studies into whether individuals with synaesthesia have increased genetic risk for other neuropsychological conditions will be completed in the autumn of 2018, utilizing the cohort recruited by Dr. Tilot in combination with additional participants from the Generation Scotland project.

The action also provided Dr. Tilot with extensive training opportunities in project management and neurogenetics research, including statistical analysis and writing for scientific and lay audiences. A highlight of the training component of the action was the successful competition for a multidisciplinary Discussion Meeting on synaesthesia, hosted by the Royal Society, which will be held in London in October, 2018. Dr. Tilot is a co-organizer of the meeting and will serve as a guest editor for a special issue of Philosophical Transactions of the Royal Society, Part B that will follow the meeting.
Work Package 1 (WP1) used next generation sequencing to identify rare variants associated with synaesthesia in three multi-generational families. Dr. Tilot found that the resulting list of variants was enriched in genes that were involved in axonogenesis, the process by which neurons connect with each other during development. She then integrated the resulting list of genes with data on where (which brain regions, what cell types) and when (early development through adulthood) they were active in the brain (WP3). These results were presented at the 2017 Society for Neuroscience meeting and published in Tilot et al., Proc. Nat. Acad. Sci., 2018. The paper generated a large amount of international media coverage, including print, web, and radio reports in outlets like the US public radio program Science Friday, the magazine Newsweek, and the Spanish newspaper El Pais.

WP2 centered on how common variation contributes to synaesthesia and included development of the world’s largest cohort of verified synaesthetes with DNA samples available for research (over 800 as of May 2018). Dr. Tilot also managed a new collaboration with the Generation Scotland project, which involved recontacting over 6000 individuals with existing genotype data and inviting them to complete a synaesthesia testing battery. Data analysis is ongoing and will include synaesthetes from the Max Planck Institute cohort as well as Generation Scotland. Dr. Tilot will present the results at the Royal Society Discussion Meeting and publish the report in the special issue of Phil. Trans. Roy. Soc. B.

WP4 made dissemination of the results and public outreach a core component of the action, and Dr. Tilot made such activities a regular part of her agenda. Highlights from this effort include a popular “Ask Me Anything” hosted by Reddit’s r/Science, interviews with students in the Netherlands, Spain, and the USA, a lay audience article on synaesthesia for the journal Science in School, and an invited talk at the International Association for Synaesthetes Artists and Scientists’ inaugural symposium.
At the start of the action there were no candidate genes for synaesthesia, and prior genetic studies had approached the trait using older, relatively imprecise methods. Dr. Tilot advanced the state-of-the-art substantially during the action, using the latest genetic sequencing technology to identify rare mutations in six genes with clear relevance for a major hypothesis in the field. Publishing the results in a widely read journal maximized the opportunity to recruit new participants for further synaesthesia genetics research and spark new investigations into the molecular basis of variation in sensory perception.

Further results are expected from WP2, that will clarify previous reports on the relationship between synaesthesia and autism by identifying what (if any) increased genetic risks synaesthetes experience for this and other neurological disorders in comparison to the general population. The wider societal impact of these studies can be seen in the press coverage of the first publication from the action – around the globe, people are fascinated by perception and these results offer a new opportunity to address the biology behind the question “Do you see what I see?”
Summary of the proposal