madman
Super Moderator
As the mediator of androgen actions, the androgen receptor (AR) plays a central role in establishing both physical and behavioral sex differences. The AR gene contains a CAG repeat polymorphism that is related to the strength of androgen actions on target tissues and that is correlated with various health-related conditions, especially prostate cancer and infertility. Some studies have also linked the number of AR CAG repeats with behavioral and mental health factors. The present study provides a tabulated summary of the average number of AR CAG repeats for males according to the countries in which each study was conducted, thereby allowing future research to correlate national average AR CAG repeats with national variations in physical, medical, and behavioral traits. Findings are summarized in two tables. The first table lists results from each of 187 studies of a total of 57,826 research participants according to the country in which each study was conducted. In the second table, the results from the first table are condensed down to the average number of AR CAG repeats for each of the 78 countries from which samples were drawn.
Androgens, and in particular the hormone testosterone produced by the testes, are major actors in sexually dimorphic developmental processes. In addition to the development of male genitalia and other physical sex differences, they also produce behavioral sex differences in animals (Ligon et al., 1990; Preston et al., 2012) and humans (Josephs et al., 2006; Sellers, Mehl & Josephs, 2007). The cellular actions of testosterone and other androgens are mediated by the androgen receptor (AR), a protein that binds to regulatory sites of many genes and either stimulates or, sometimes, represses the transcription of the genes when testosterone or some other androgen is bound to it (Chamberlain, Driver & Miesfeld, 1994). Without androgen receptors, testosterone cannot regulate gene expression and therefore cannot have effects on bodily functioning. Males whose androgen receptor gene is non-functional do not develop male genitalia. Their physical appearance and psychosocial development are female. In other words, regardless of how much testosterone an individual may produce, the AR gene determines the extent to which testosterone is able to actually alter intracellular activity (Batrinos, 2012; Ding et al., 2004; Meyer et al., 2010).
In humans, the AR gene comes in many forms, called alleles. The best-studied alleles are those involving a CAG repeat sequence that encodes a polyglutamine tract near the amino end of the androgen receptor. This CAG repeat has different lengths in different people. In humans, the number of AR CAG repeats ranges from as few as 9 to as many as 36, but population averages are typically between 17 and 24 (Chamberlain et al., 1994; Hsiao et al., 1999; Irvine et al., 2000; La Spada et al., 1991). Individuals with higher numbers of AR CAG repeats will normally have diminished testosterone action on cellular functioning, effectively making males with high AR CAG repeats less masculine regarding most sexually dimorphic traits when compared to males with fewer AR CAG repeats (Loehlin et al., 2004; Simanainen et al., 2011)
Why Study AR CAG Repeats?
Several diseases have been found to be statistically associated with the number of AR CAG repeats. In men, these primarily include prostate cancer, which appears to be inversely correlated with the number of repeats (meta-analyses: Gu et al., 2012; Qin et. al., 2017; Weng et al., 2017), and infertility which is positively correlated (meta-analysis: Mobasseri et al., 2018; Xiao et al., 2016). Also, some research has found an inverse relationship between the number of AR CAG repeats and male pattern baldness (Ellis et al., 2007; Hillmer et al., 2005).
Among women, associations with the number of AR CAG repeats are more difficult to assess because females have two X chromosomes, and therefore two AR genes (albeit one of which is usually non-functional). Despite this qualification, inverse correlations have been found between AR CAG repeats and the incidence of breast cancer (Hao et al., 2010), at least among women of European descent (Mao et al., 2015).
For both sexes, AR CAG repeats have also been implicated as causing skin-related illnesses such as acne and hirsutism (Sawaya & Shalita 1998; Yang et al., 2009). Other diseases that are possibly associated with the number of AR CAG repeats are migraines, Alzheimer’s disease, and spinal muscular atrophy (Kennedy’s disease) (review: Singh, Singh & Thangaraj, 2007).
Complexity in research findings on relationships between AR CAG repeats and various health-related traits have come from evidence of a substantially increased risk of gallbladder cancer among men with high AR CAG repeats, while women with the greatest number of repeats had a significantly lower risk of the same form of cancer (meta-analysis: Meyer et al., 2010). Furthermore, research on the association between AR CAG repeats and male testicular cancer suggests that the relationship is curvilinear (meta-analysis: Jiang et al., 2016).
Behavioral and mental health factors have also received research attention in connection with AR CAG repeats. For example, relatively short AR CAG repeat numbers have been found associated with psychoticism (Turakulov et al., 2004). Another study confirmed this pattern for adolescent females but not for adolescent males (Loehlin et al., 2005). Along similar lines, one study indicated that short AR CAG repeats were associated with impulsive-disinhibited personality traits (Aluja et al., 2011), and another found short AR CAG repeats associated with extraversion (Lukaszewski & Roney, 2011). AR CAG repeat numbers were recently found positively correlated with sexual jealousy (Lewis et al., 2018).
Along experimental lines, a study of college students reported that low AR CAG repeat males exhibited a rise in testosterone within a half hour or so after socially interacting with a young woman. This pattern did not occur among males with high numbers of repeats, and no AR CAG-related differences were found when males interacted with other males (Roney, Simmons & Lukaszewski, 2010). These findings coincide with evidence that adding AR CAG repeats seems to curtail the body’s ability to synthesize and release testosterone (Campbell et al., 2009; Chamberlain, Driver & Miesfeld, 1994).
Some research has also implicated AR CAG repeats in the study of criminality, especially violent forms. One study of imprisoned males reported that conviction for violent offenses was inversely correlated with AR CAG repeat length (Rajender et al., 2008). Another study found no significant difference between the AR CAG repeats among violent criminals and control males but did report a higher incidence of unusually short AR CAG repeats among the violent offenders in their sample (Cheng et al., 2006).
The Present Investigation
The above leads one to suspect that AR CAG repeats could play a substantial role in influencing many aspects of human health and well-being. Studies of behavioral effects are much less numerous than those dealing with health, but these studies also point toward the potential for valuable insights to be gained by linking AR CAG functioning with behavior.
All of the studies conducted so far on male AR CAG repeats have been limited to comparing samples of individuals. We are inclined to suspect that relationships at ecological levels of analysis may also be worth pursuing. In other words, countries that have males with unusually high or low AR CAG repeats could, as a result, also exhibit unusually high or low rates of certain diseases or behavioral patterns.
To make it possible to conduct ecological-level analyses, the present investigation was undertaken to compile all of the national data on average AR CAG repeats for males that could be located. Our search was limited to males for three inter-related reasons: First, most AR CAG repeat studies conducted so far have been among males. Second, AR CAG repeats appear to primarily affect testosterone, a hormone that is much higher in males than in females. And, third, males have just one X chromosome whereas females have two.
Results
Based on a total sample of 57,826 males occupying 78 countries, the overall average number of AR CAG repeats was found to be 21.40. National averages ranged from 17.00 to 23.16. Five countries had averages in the 17.00s; they were Swaziland (17.00), Zambia (17.00), Sierra Leone (17.30), Nigeria (17.58), and Senegal (17.90). Five countries had averages of 23.00 or higher; they were Lithuania (23.00), Mongolia (23.00), Ireland (23.07), Thailand (23.10), and Romania (23.16).
Conclusions
This study was undertaken to obtain estimates of national averages in male AR CAG repeats. The overall average repeat numbers for all 78 countries for which data were obtained from a total of 57,826 research participants was 21.40. Country-by-country average repeats ranged from 17.00 for Swaziland and Zambia to 23.16 for Romania.
We wish to underscore that few if any of the national samples can be considered representative of an entire country, although the averages are likely to be close estimates. This is partly because many of the sample sizes were small (often below 200 per study), and partly because most of the samples were drawn from regions within countries. Therefore, as research on AR CAG repeats continues to be published, the findings presented here should be updated.
In rough geographic terms, Table 2 indicates that males from Sub-Saharan African countries have the fewest average numbers of repeats, all in the 17-20 range, with the exception of Kenya’s 22.51. AR CAG repeats for males in the northern African and Middle Eastern countries were generally in the 19-21 range. The countries where our analysis found the highest AR CAG repeats were in the Eurasian continent; these countries were generally in the 22-23 range (Scotland’s average of 19.00, based on a sample of 20 individuals, being an exception). Finally, most samples drawn from both North and South American countries were in the 21-22 range.
Researchers interested in conducting ecological analyses of how male AR CAG repeats vary by country may find Table 2 useful. Both health-related and behavior-related traits influenced by AR CAG repeats are likely to vary from country to country in accordance with the average AR CAG repeats shown in Table 2.
Finally, it is worth stating that, even though we limited our sampling to males, the national variations shown in Table 2 are equally valid for females. This is because males have just one androgen receptor gene that they inherit from their mothers. Presumably, which of the two X chromosomes a mother contributes to her male offspring is randomly determined.
Androgens, and in particular the hormone testosterone produced by the testes, are major actors in sexually dimorphic developmental processes. In addition to the development of male genitalia and other physical sex differences, they also produce behavioral sex differences in animals (Ligon et al., 1990; Preston et al., 2012) and humans (Josephs et al., 2006; Sellers, Mehl & Josephs, 2007). The cellular actions of testosterone and other androgens are mediated by the androgen receptor (AR), a protein that binds to regulatory sites of many genes and either stimulates or, sometimes, represses the transcription of the genes when testosterone or some other androgen is bound to it (Chamberlain, Driver & Miesfeld, 1994). Without androgen receptors, testosterone cannot regulate gene expression and therefore cannot have effects on bodily functioning. Males whose androgen receptor gene is non-functional do not develop male genitalia. Their physical appearance and psychosocial development are female. In other words, regardless of how much testosterone an individual may produce, the AR gene determines the extent to which testosterone is able to actually alter intracellular activity (Batrinos, 2012; Ding et al., 2004; Meyer et al., 2010).
In humans, the AR gene comes in many forms, called alleles. The best-studied alleles are those involving a CAG repeat sequence that encodes a polyglutamine tract near the amino end of the androgen receptor. This CAG repeat has different lengths in different people. In humans, the number of AR CAG repeats ranges from as few as 9 to as many as 36, but population averages are typically between 17 and 24 (Chamberlain et al., 1994; Hsiao et al., 1999; Irvine et al., 2000; La Spada et al., 1991). Individuals with higher numbers of AR CAG repeats will normally have diminished testosterone action on cellular functioning, effectively making males with high AR CAG repeats less masculine regarding most sexually dimorphic traits when compared to males with fewer AR CAG repeats (Loehlin et al., 2004; Simanainen et al., 2011)
Why Study AR CAG Repeats?
Several diseases have been found to be statistically associated with the number of AR CAG repeats. In men, these primarily include prostate cancer, which appears to be inversely correlated with the number of repeats (meta-analyses: Gu et al., 2012; Qin et. al., 2017; Weng et al., 2017), and infertility which is positively correlated (meta-analysis: Mobasseri et al., 2018; Xiao et al., 2016). Also, some research has found an inverse relationship between the number of AR CAG repeats and male pattern baldness (Ellis et al., 2007; Hillmer et al., 2005).
Among women, associations with the number of AR CAG repeats are more difficult to assess because females have two X chromosomes, and therefore two AR genes (albeit one of which is usually non-functional). Despite this qualification, inverse correlations have been found between AR CAG repeats and the incidence of breast cancer (Hao et al., 2010), at least among women of European descent (Mao et al., 2015).
For both sexes, AR CAG repeats have also been implicated as causing skin-related illnesses such as acne and hirsutism (Sawaya & Shalita 1998; Yang et al., 2009). Other diseases that are possibly associated with the number of AR CAG repeats are migraines, Alzheimer’s disease, and spinal muscular atrophy (Kennedy’s disease) (review: Singh, Singh & Thangaraj, 2007).
Complexity in research findings on relationships between AR CAG repeats and various health-related traits have come from evidence of a substantially increased risk of gallbladder cancer among men with high AR CAG repeats, while women with the greatest number of repeats had a significantly lower risk of the same form of cancer (meta-analysis: Meyer et al., 2010). Furthermore, research on the association between AR CAG repeats and male testicular cancer suggests that the relationship is curvilinear (meta-analysis: Jiang et al., 2016).
Behavioral and mental health factors have also received research attention in connection with AR CAG repeats. For example, relatively short AR CAG repeat numbers have been found associated with psychoticism (Turakulov et al., 2004). Another study confirmed this pattern for adolescent females but not for adolescent males (Loehlin et al., 2005). Along similar lines, one study indicated that short AR CAG repeats were associated with impulsive-disinhibited personality traits (Aluja et al., 2011), and another found short AR CAG repeats associated with extraversion (Lukaszewski & Roney, 2011). AR CAG repeat numbers were recently found positively correlated with sexual jealousy (Lewis et al., 2018).
Along experimental lines, a study of college students reported that low AR CAG repeat males exhibited a rise in testosterone within a half hour or so after socially interacting with a young woman. This pattern did not occur among males with high numbers of repeats, and no AR CAG-related differences were found when males interacted with other males (Roney, Simmons & Lukaszewski, 2010). These findings coincide with evidence that adding AR CAG repeats seems to curtail the body’s ability to synthesize and release testosterone (Campbell et al., 2009; Chamberlain, Driver & Miesfeld, 1994).
Some research has also implicated AR CAG repeats in the study of criminality, especially violent forms. One study of imprisoned males reported that conviction for violent offenses was inversely correlated with AR CAG repeat length (Rajender et al., 2008). Another study found no significant difference between the AR CAG repeats among violent criminals and control males but did report a higher incidence of unusually short AR CAG repeats among the violent offenders in their sample (Cheng et al., 2006).
The Present Investigation
The above leads one to suspect that AR CAG repeats could play a substantial role in influencing many aspects of human health and well-being. Studies of behavioral effects are much less numerous than those dealing with health, but these studies also point toward the potential for valuable insights to be gained by linking AR CAG functioning with behavior.
All of the studies conducted so far on male AR CAG repeats have been limited to comparing samples of individuals. We are inclined to suspect that relationships at ecological levels of analysis may also be worth pursuing. In other words, countries that have males with unusually high or low AR CAG repeats could, as a result, also exhibit unusually high or low rates of certain diseases or behavioral patterns.
To make it possible to conduct ecological-level analyses, the present investigation was undertaken to compile all of the national data on average AR CAG repeats for males that could be located. Our search was limited to males for three inter-related reasons: First, most AR CAG repeat studies conducted so far have been among males. Second, AR CAG repeats appear to primarily affect testosterone, a hormone that is much higher in males than in females. And, third, males have just one X chromosome whereas females have two.
Results
Based on a total sample of 57,826 males occupying 78 countries, the overall average number of AR CAG repeats was found to be 21.40. National averages ranged from 17.00 to 23.16. Five countries had averages in the 17.00s; they were Swaziland (17.00), Zambia (17.00), Sierra Leone (17.30), Nigeria (17.58), and Senegal (17.90). Five countries had averages of 23.00 or higher; they were Lithuania (23.00), Mongolia (23.00), Ireland (23.07), Thailand (23.10), and Romania (23.16).
Conclusions
This study was undertaken to obtain estimates of national averages in male AR CAG repeats. The overall average repeat numbers for all 78 countries for which data were obtained from a total of 57,826 research participants was 21.40. Country-by-country average repeats ranged from 17.00 for Swaziland and Zambia to 23.16 for Romania.
We wish to underscore that few if any of the national samples can be considered representative of an entire country, although the averages are likely to be close estimates. This is partly because many of the sample sizes were small (often below 200 per study), and partly because most of the samples were drawn from regions within countries. Therefore, as research on AR CAG repeats continues to be published, the findings presented here should be updated.
In rough geographic terms, Table 2 indicates that males from Sub-Saharan African countries have the fewest average numbers of repeats, all in the 17-20 range, with the exception of Kenya’s 22.51. AR CAG repeats for males in the northern African and Middle Eastern countries were generally in the 19-21 range. The countries where our analysis found the highest AR CAG repeats were in the Eurasian continent; these countries were generally in the 22-23 range (Scotland’s average of 19.00, based on a sample of 20 individuals, being an exception). Finally, most samples drawn from both North and South American countries were in the 21-22 range.
Researchers interested in conducting ecological analyses of how male AR CAG repeats vary by country may find Table 2 useful. Both health-related and behavior-related traits influenced by AR CAG repeats are likely to vary from country to country in accordance with the average AR CAG repeats shown in Table 2.
Finally, it is worth stating that, even though we limited our sampling to males, the national variations shown in Table 2 are equally valid for females. This is because males have just one androgen receptor gene that they inherit from their mothers. Presumably, which of the two X chromosomes a mother contributes to her male offspring is randomly determined.
