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BY GINA SHAW

Synesthesia — a neurological phenomenon that causes unusual connections between senses or cognitive pathways, like "tasting" colors or "hearing" letters —has been described in literature dating back to the ancient Greeks, with the first medical description appearing in a German physician's thesis from 1812. In 1880, Charles Darwin's cousin Francis Galton, published a paper in Nature on the phenomenon

Imaging studies have demonstrated increased structural and functional connectivity in a number of regions of the brain among people with synesthesia, but any molecular basis for the condition has eluded scientists, with previous linkage studies searching for shared genetic loci across multiple families yielding limited success.

But now a new study from researchers at the Max Planck Institute and Raboud University in the Netherlands and the UK's Cambridge University has, for the first time, identified specific genes that are linked to synesthesia.

Because of a lack of candidate genes, lead author Simon Fisher, DPhil, director of the Max Planck Institute for Psycholinguistics and professor of language and genetics at the Donders Institute for Brain, Cognition and Behaviour, and his colleagues applied whole-exome sequencing to three families who all have sound-color synesthesia affecting multiple relatives across at least three generations.

Published in Proceedings of the National Academy of Sciences on March 20, the analysis identified rare genetic variants that align with synesthesia in each family — a total of 37 genes of interest — on six genes: COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2. These genes are all associated with axonogenesis and expressed during early childhood when synesthetic associations are formed.

"These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences," the authors wrote.

STUDY DESIGN

The families in the study were selected from an existing cohort of 43 sound-color synesthesia families, who had been originally recruited by Simon Baron-Cohen, and colleagues at the University of Cambridge.

"The bigger cohort was used for an earlier genetic mapping study using older methods, before next-generation DNA sequencing was available," said Dr. Fisher. "This larger cohort included families of a range of sizes; quite a number of them only had two synesthestic members, for example. Since the main message from the prior work was that there is a lot of genetic heterogeneity, in our new study we wanted to focus on the largest of the families with sufficient DNA left to allow high-quality exome sequencing. The larger the individual family, the more power we have to reliably identify if there is a rare risk variant that segregates with the trait. We were able to zero in on three families with five synesthetic relatives, across three or four successive generations of the pedigree, as the most promising from the available cohort."

"Although the causative variants identified in this paper appear to be rare —none are shared across families — they may yield unique insights into the biological processes involved in synesthesia. There were just a few biological themes that were significantly enriched across the candidate genes identified, and one of those was axonogenesis, a crucial process helping neurons get wired up to each other in the developing brain," Dr. Fisher explained.

"This is fascinating, because it is consistent with well-established prior findings of altered connectivity in neuroimaging of synesthesia, and so the pattern fits with a prominent hypothesis about how synesthesia develops," he continued. "This means that, although we confirm the genetic heterogeneity of synesthesia, we at the same time show that the candidate genes cluster in shared pathways that are well aligned with neurobiological accounts, offering us potential entry points into the relevant mechanisms."

Synesthesia comes in many varieties: in grapheme-color synesthesia, numbers and letters trigger a color experience, although the color associations differ from person to person. With ordinal-linguistic personification, numbers or words have personalities. Individuals with conceptual synesthesia may see abstract concepts, such as units of time or mathematical operations, as shapes. Many people with synesthesia experience more than one form of the condition. ​

EXPERT COMMENTARY

For a long time, however, people with synesthesia were thought to have some form of mental illness, the after effects of drug use, or just to be making the whole thing up or speaking metaphorically.

Vilyanur Ramachandran, MBBS, FRCP (London), PhD, director of the Center for Brain and Cognition at the University of California, San Diego, was one of the first scientists to theorize that synesthesia arises from a cross-activation between brain regions.

"In experiments that we published about 15 years ago, we proposed the neural basis for synesthesia," Dr. Ramachandran said. "We discovered that the condition occurs early in perceptual processing and is tractable scientifically."

For example, he said, on a "pop-out" test in which a triangular pattern of twos is embedded in a large field of fives — all in black and white — non-synesthetes must look carefully to find the twos, while for those with synesthesia, it pops out faster, like a bright red triangle in a forest of greens.

This amenability to "test genuineness" is why Dr. Fisher's research focuses primarily on forms of synesthesia that induce perceptions of color. "An inherent feature of studying synesthesia is that it needs us to somehow get insights into people's internal experiences of the outside world, quite a challenge," he said. "In particular, for genetic analyses, we want to have as objective an assessment of the phenotype as possible, so we can't depend solely on asking for a self-report. For sound-color and grapheme-color forms there are robust well-accepted methods for validating whether someone is indeed synesthetic, by presenting them with many different primary stimuli and assessing the consistency of their color responses over repeated presentations."

Neuroimaging studies such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scans have also documented differences in brain region activation among synesthetes compared to non-synesthetes, but those studies have yielded somewhat inconsistent results —perhaps because of the differing forms that synesthesia takes. Overall, however, there is some consistent evidence suggesting that color-selective region V4 of the posterior-inferior temporal cortex and parieto-occipital junction is involved with word-color synesthesia.

"It is possible that genetic mutations, such as the ones identified in this paper cause connections to emerge between brain areas that are usually segregated," said Dr. Ramachandran. "Or a mutation may lead to defective pruning of early connections between areas that are normally connected only sparsely."

FROM SYNESTHESIA TO SHAKESPEARE?

Synesthesia appears to be much more common than had previously been thought; some studies have suggested that as many as one in 50 people have this quirk. "Why would a gene that makes excess connections survive in the population such that it is so common?" Dr. Ramachandran asked.

"Perhaps a clue comes from the fact that it's about eight times more common in artists and poets. Synesthesia may not just be a quirky color-number thing, but a broader sign of connections linking far-flung brain regions," he said. "If it's expressed diffusely, then perhaps you are more metaphorical and tend to think of unrelated, creative ideas in general. Synesthesia may be a manifestation of abstract and metaphorical thinking in general."

Think of Shakespeare, and Romeo's famous line: "It is the East, and Juliet is the sun," Dr. Ramachandran suggested. "Isaac Newton associated wavelengths with colors for his famous discovery of the spectrum of light, at a time when the wavelengths of sound had long been known but that hadn't been thought about yet with color. It makes me wonder if he had it, especially since he made a toy musical instrument which would flash colors corresponding to tones."

Rates of synesthesia are also elevated in both autism spectrum disorder and savantism. "While it's important to realize that synesthesia (and associated hyperconnectivity) often occurs in people without any kind of neurological diagnosis, there are reports suggesting that atypical sensory sensitivity may be a shared feature seen in synesthesia and in autism," said Dr. Fisher. "Our data don't point to any simple link, because the candidate genes we identified are not enriched for genes known to be involved in autistic traits. On the other hand, there is overlap in terms of biological pathways, and that is something that we would want to investigate more systematically in our future work."

He noted that the literature is unclear on connectivity differences in autism. "While some studies find that autism involves reduced connectivity, others have actually claimed hyperconnectivity ."

Dr. Fisher cautioned that there are limitations to the study's conclusions, given that the numbers and sizes of families studied with these next-generation techniques are relatively small. "We are now running whole genome sequencing of other large families with different forms of synesthesia, including grapheme-color and sequence-color," he said. "The approach there is similar to the current study, trying to find rare variants with potential large effects on the trait. We hope to test whether the same pathways from the current study emerge in additional multigenerational families, as well as if the patterns are convergent for different types of synesthesia."

There may be other inheritance pathways for synesthesia beyond these rare gene variants as well, such as the combined action of many common polymorphisms, each with a small effect. To search for those, Dr. Fisher and his group are using web- and app-based testing to recruit hundreds of independent unrelated cases of grapheme-color synesthesia and using DNA chips to characterize common polymorphisms across the genome.

"The community of synesthesia researchers is a nicely interactive one, so we have colleagues helping us spread the word and identify participants, and we already have nearly 1,000 cases enrolled in our study, and we are happy for more to join!" he said.

"With more of the genetic data in hand in the coming years, including both rare and common variation, we hope to be able to robustly address the issues of overlaps with other cognitive traits and disorders, and bring a new molecular perspective on the biological pathways, as well as connecting to brain imaging and neuropsychological findings."

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Tilot AK, Kucera K, Vino, et al. Rare variants in axogenesis genes connect three families with sound-color synesthesia​. Proc Natl Acad Sci USA 2018;115(12):3168-3173.​