The androgen receptor gene: A major modifier of speed of neuronal transmission and intelligence?

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Summary

Humans show considerable additive genetic variance in cognitive ability or general intelligence (g) but the genes that influence this variation are largely unknown. It is suggested here that the X-linked androgen receptor gene (AR) has a major modifying effect on speed of neuronal transmission and thus on g. The AR is polymorphic in its N-terminal transactivation domain which encodes a polyglutamine tract (CAGn) with a parametric mean of n = 21 CAG repeats and normal variation between n = 11 and n = 30 repeats . Very low repeat numbers are associated with mental retardation, repeat numbers above 30 with reduced cognitive function, and CAGn greater than 40 with spinal and bulbar muscular atrophy. Within the range of 11–30 repeats short CAG chains are associated with high androgen sensitivity and high sperm counts. Despite this, all human populations contain many individuals with n > 21 repeats. I suggest that within the range of 11–30 repeats there is a positive association with speed of neuronal transmission and values of g. The advantage of high g and the consequent spread of alleles for high CAGn will be countered by the negative effects on sperm production. Below CAGn = 11 and above CAGn = 30 neuronal speed may reduce, thus leading to reductions in g and loss of function of neurons. In support of the model I discuss the link between the X-chromosome and g, the comparative structure of the AR gene in the primates, and the variation in CAGn and g in human ethnic groups.

Introduction

Intelligence may be measured in a number of ways but all measures show considerable intra-population variation and evidence that genes have a significant influence on this variation [1], [2], [3]. There is a high genotypic correlation between tests of cognitive ability, and this has led to the belief that all intelligence comes from one general factor (g) [4], [5]. However, despite this strong association, the loci that are responsible for a large proportion of the variance in g have not yet been identified [6]. Genes that, when mutated, cause mental impairment are found on the X-chromosome at higher incidence than expected, and a large X-chromosome effect for cognitive abilities has been suggested for humans [7]. Therefore the X-chromosome is a likely place to find genes that influence g in a substantial way. One X-linked gene that has been implicated in mental retardation is the androgen receptor gene (AR). A link between variation in the AR, speed of neuronal transmission and g is the theme of this paper.

Section snippets

The androgen receptor gene

The AR is highly polymorphic in its N-terminal transactivation domain. This domain encodes a polyglutamine tract (CAGn) in the AR protein with a parametric mean of 21 CAGn and normal variation between 11 and 30 repeats [8]. In addition to sites such as the reproductive system and bone, the AR is strongly expressed in the CNS [9]. Loss-of-function mutations of the AR do not result in mental impairment, but a very short CAG chain in the AR is associated with mental retardation [10]. At the higher

The androgen receptor gene in human populations

CAGn is polymorphic in humans but it also shows variation in mean CAGn between populations. Furthermore, the population differences in CAGn appear to map on to population differences in g.

A consideration of over 1000 X-chromosomes from Africa, North America and Asia has shown that men of African descent have mean CAGn of between 16.7 to 17.8 repeats, those of European descent a mean of 19.7 repeats, and of Asian descent a mean of 20.1 repeats [18]. In contrast to many genes these differences

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