The genes that turn 'three' red
The first-ever genome-wide scan of synesthesia may illuminate how genetics drives complex cognitive traits
Researchers have completed the first-ever genome-wide scan of synesthesia, a condition in which sensory stimuli cross wires and combine such that people "see" sounds or "taste" shapes, according to a study published online today in the American Journal of Human Genetics.
Investigators at the Wellcome Trust Centre for Human Genetics at the University of Oxford pinpointed four areas of the genome associated with the disorder. Those regions contain genes that have been associated with autism and dyslexia, as well as genes involved in different aspects of brain development, and further analysis could illuminate how genetics drives complex cognitive traits, the authors say.
"It's exciting that we have a study about the genetic basis of synesthesia -- finally," said Noam Sagiv, a cognitive neuroscientist at Brunel University in the UK, who was not involved in the research. Until now "we've just been guessing," he said, by "using data based on prevalence estimates."
Francis Galton, best known as one of the founders of eugenics, first pointed out in the 19th century that synesthesia runs in families, suggesting it has a genetic component. "Based on pedigree analysis, many people thought that [synesthesia] was a simple Mendelian disorder," said Julian Asher, now at Imperial College, London, the study's lead author and himself a synesthete. The study, however, demonstrated that the condition is multigenic. Which makes sense, Asher noted: "The clinical phenotype is so complex, it's hard to believe all of that can be caused by a single gene."
Consequently, "now we're looking at gene-gene interactions, with multiple genes contributing," Asher said.
The condition comes in several forms, but Asher and his colleagues conducted their genetic analysis on individuals with what's known as known as auditory-visual synesthesia -- the classical form, in which individuals strongly associate sounds with specific colors.
The region of the genome most strongly linked to synesthesia was on chromosome 2, and has also been strongly linked to autism. That doesn't mean that the two conditions are related, per se, explained Ed Hubbard, a cognitive neuroscientist at Vanderbilt University in Tennessee who was not involved in the study. Instead, the common gene or genes are likely "more generally involved in how the brain gets built."
The study also pulled out a region on chromosome 6 that contains genes linked to dyslexia -- especially interesting, "seeing as phonemes [the units of sound in language] and letters are two of the strongest synesthetic triggers," Asher said. One possibility, he said, is that mutations in those genes lead people to process those stimuli differently. "Maybe some people [with those mutations] end up with dyslexia, and some with synesthesia."
The genetic analysis also dispelled the long-held assumption that synesthesia was an X-linked disorder, an idea that stemmed from the fact that researchers had never before seen synesthetic fathers who had synesthetic sons. In their subject pool, the researchers identified two cases of such male-to-male transmission, demonstrating that the condition is almost certainly autosomal.
Asher and his colleagues are following up their study with higher-density screening, to narrow down their list of candidate genes. "Next, we want to home in on what these genes are and what they do," he said.
At least two other labs, one at Baylor College of Medicine in Houston, and the other Trinity College, Dublin, have been working on similar genetic studies, but the subject database of those groups differs from that used in the current study, said Hubbard. The Irish group includes fewer families, but with more individuals from each family, and the Houston group focuses on people with a form of the condition called sequence-to-color synesthesia.
The differences in the populations "could make a huge difference," said Sagiv. Asher and his colleagues were wise to choose a very specific population of synesthetes for the field's first genetic study, he said, but broadening the inclusion criteria to different forms of the disorder may identify additional genes.
Hubbard agreed that the results of all three genetic studies together will further flesh out the picture. "Once we start to identify genes that are involved, we can start to look at what function they play in a mouse or monkey brain," he said, and then "come up with ways of studying what they do experimentally" in animal models.
Abstract ot the Asher article
A Whole-Genome Scan and Fine-Mapping Linkage Study of Auditory-Visual Synesthesia Reveals Evidence of Linkage to Chromosomes 2q24, 5q33, 6p12, and 12p12
Julian E. Asher,1,2,* Janine A. Lamb,3 Denise Brocklebank,1 Jean-Baptiste Cazier,1 Elena Maestrini,4 Laura Addis,1 Mallika Sen,1 Simon Baron-Cohen,2 and Anthony P. Monaco1
Synesthesia, a neurological condition affecting between 0.05%–1% of the population, is characterized by anomalous sensory perception and associated alterations in cognitive function due to interference from synesthetic percepts. A stimulus in one sensory modality triggers an automatic, consistent response in either another modality or a different aspect of the same modality. Familiality studies show evidence of a strong genetic predisposition; whereas initial pedigree analyses supported a single-gene X-linked dominant mode of inheritance with a skewed F:M ratio and a notable absence of male-to-male transmission, subsequent analyses in larger samples indicated that the mode of inheritance was likely to be more complex. Here, we report the results of a whole-genome linkage scan for auditory-visual synesthesia with 410 microsatellite markers at 9.05 cM density in 43 multiplex families (n 1/4 196) with potential candidate regions fine-mapped at 5 cM density. Using NPL and HLOD analysis, we identified four candidate regions. Significant linkage at the genome-wide level was detected to chromosome 2q24 (HLOD 1/4 3.025, empirical genome-wide p 1/4 0.047). Suggestive linkage was found to chromosomes 5q33, 6p12, and 12p12. No support was found for linkage to the X chromosome; furthermore, we have identified two confirmed cases of male-to-male transmission of synesthesia. Our results demonstrate that auditory-visual synesthesia is likely to be an oligogenic disorder subject to multiple modes of inheritance and locus heterogeneity. This study comprises a significant step toward identifying the genetic substrates underlying synesthesia, with important implications for our understanding of the role of genes in human cognition and perception.
1 Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK;
2 Department of Psychiatry, Section of Developmental Psychiatry, Douglas House, 18B Trumpington Road, University of Cambridge, Cambridge CB2 8AH, UK;
3 Centre for Integrated Genomic Medical Research, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK;
4 Department of Biology, University of Bologna, Via Selmi 3, Bologna, Italy
*Correspondence: j.asher@imperial.ac.uk
DOI 10.1016/j.ajhg.2009.01.012. a2009 by The American Society of Human Genetics. All rights reserved. |
