Is synaesthesia an X-linked trait with lethality in males?

In previous research the inheritance patterns of synaesthesia (eg experiencing colours from graphemes) has been studied and it was concluded that synaesthesia is most likely to be the outcome of a single gene passed on the X chromosome in a dominant fashion. In addition, it has been reported that the female ^male ratio of synaesthetes is as high as 6 : 1 and the families of synaesthetes contain more female than male members. This raises the possibility that the gene may be associated with lethality in males. In this study we replicate and extend previous research by investigating the female ^male ratio and inheritance patterns in a large sample of synaesthetic families (N ˆ 85).We were able to verify the authenticity of grapheme ^ colour associates in at least one proband from each family using internal consistency. As before, our results show a female ^ male bias and are broadly consistent with an X-linked dominant mode of inheritance. However, there was no evidence of male lethality (eg synaesthetes are just as likely to give birth to sons as to daughters). Moreover, our female ^male ratio of synaesthetes within families was 2 : 1öconsiderably lower than previous estimates. We speculate that men may be more reluctant to disclose synaesthesia than women (indeed, our female ^male ratio based on self-referral was 3:7 : 1). Finally, we discuss how the genotype may give rise to the phenotype in terms of changes in synaptogenesis or plasticity extending into childhood, to be subsequently shaped by the environment. DOI:10.1068/p5250 Different terminology has been used in the literature to describe synaesthetic manifestations, and this has raised questions whether these might reflect more substantive differences in kind. We have adopted the nomenclature of placing the inducing stimulus before the synaesthetic experience, separated by a dash (eg grapheme ^ colour). We use the term grapheme to denote the minimal functional distinctive unit of a writing system (Henderson 1985). This implies abstract entities corresponding to single letters and digits. of colour. The colour of each grapheme is apparent in the word overall, but one particular grapheme (usually the initial letter or initial vowel) dominates. The synaesthetes in our sample experience colour both when hearing speech (also called c̀oloured hearing') and when reading words, and so resemble other cases reported in the literature (eg Baron-Cohen et al 1996). While some synaesthetes state that the colours may be more vivid or automatic when elicited in a particular way (reading versus hearing), the colours themselves tend not to depend on the mode of input (see Simner et al, in press, for an in-depth description of this variant). Synaesthesia is normally defined in phenomenological terms, although a number of different methods provide converging objective evidence for these phenomenological reports. People with synaesthesia show greater internal consistency than nonsynaesthetes given memory/imagery instruction (eg Baron-Cohen et al 1993); they may show facilitation on tasks of perception (Palmeri et al 2002; Ramachandran and Hubbard 2001) or memory (Smilek et al 2002a); and they show Stroop-like interference when the elicited synaesthetic colour differs from the veridical colour of a stimulus (Mills et al 1999). Moreover, functional imaging has suggested that some of the neural resources that, in other individuals, support normal colour perception, are used in synaesthesia (Nunn et al 2002). That synaesthesia may advance our understanding of genetic influences on perception was first recognised by polymath Sir Francis Galton (Galton 1990; Galton 1883/1997). Galton noted that synaesthesia tends to cluster in families and is more common in women. However, it was not until the seminal work of Baron-Cohen and colleagues, 100 years later, that this suggestion appeared in a well-developed model (Baron-Cohen 1996; Baron-Cohen et al 1987, 1993, 1996). Synaesthesia may be an ideal system for neurogenetics in a number of respects. First, a relatively simple pattern of inheritance has been put forward. Baron-Cohen et al (1996) postulate that synaesthesia could result from a single dominant gene inherited via the X chromosome. Second, a neurodevelopmental mechanism has also been advanced. Synaesthesia may reflect aberrant connections between two unimodal perceptual regions, or between polymodal and unimodal regions. Baron-Cohen (1996) suggests that synaesthesia is something that we all possess in the first few months of life, but which is lost through programmed cell death (apoptosis). Synaesthetes, because of a genetic modification, may retain these pathways (see also Maurer 1997). Third, the phenotype appears to be relatively restricted and is unlikely to have been subjected to direct external intervention (eg remediation). Synaesthesia is not harmful or disruptive either in terms of physical health or cognitive ability (eg Cytowic 2002), and many synaesthetes remain unaware that their experiences are unusual until quite late in life (ie they may be unaware that other people do not experience, say, coloured numbers). Finally, the phenotype itself is intrinsically interesting. It may, for example, shed light on the neural substrate of conscious perceptual experiences, and colour in particular (Gray 2003; Gray et al 2002). In synaesthesia, people report conscious perceptual experiences in the absence of stimulation of the normal sensory pathways (eg from the eye to the visual cortex) as is evidenced by the fact that colourselective regions can be activated from spoken input (eg Nunn et al 2002). The aim of the present study is to replicate and extend the findings of BaronCohen et al (1996) and, as such, their study will be considered in some detail. Their first aim was to establish the prevalence and female ^male ratio of synaesthesia within the general population. An advert was placed in two local newspapers in the city of Cambridge (UK), aimed at tapping the separate student and town populations. The advert described the phenomenon of synaesthesia and asked potential synaesthetes to contact the researchers. There were 26 confirmed cases: 22 had coloured words (related to graphemes within the words), and 4 had coloured music. The female ^male ratio was 5:5 : 1 (22 women, 4 men). Baron-Cohen et al estimated the prevalence of synaesthesia to be a minimum of 1 in 2000, based on newspaper circulation figures of 55 000. 612 J Ward, J Simner