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Genetics of Why Finns Are Less Anxious Than Italians
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A happy Finn

A happy Finn

This morning my attention was brought to an interesting piece in The New York Times, The Feel-Good Gene. It marshals an impressive array of scientific disciplines, genetics, biochemistry, and psychiatry. Concurrently Linda Avey on her Facebook page pointed to where you could find your genoptype for the SNP in question in 23andMe . Because it is geared toward a popular audience without scientific training the original article in The New York Times is a bit vague about the allele and SNP code. But Avey seems correct in her inferences, because the piece does cite an article in Nature Communications, ​FAAH genetic variation enhances fronto-amygdala function in mouse and human. So as the article notes the gene is FAAH, but it makes clear that the SNP is Rs324420. If you look up this variant you see that it is associated with many variations in phenotype. The results for the recent paper from last week, cited in the article, indicate that the mutant/derived allele, A, confers a reduction in anxiety in both humans and mice (the gist of the article). In certain contexts because of the reduced anxiety in individuals who carry the A allele they are better at learning, because they more rapidly “update” to conditions where their initial fear response was an overreaction. At this point I will tell you that I am “wild type.” In other words, I carry the ancestral allele, C, and am of homozygous genotype for that allele. In fact both my parents are homozygotes for the C allele. Since this is the majority allele in most populations that is not entirely surprising.

Mutant/derived allele orange

Mutant/derived allele orange

In passing the author of The New York Times piece observes that “roughly 21 percent of Americans of European descent, 14 percent of Han Chinese living in China and 45 percent of Yoruban Nigerians have been found to carry this gene variant.” These data are from the HapMap. According to them 45 percent of the Yoruba Nigerians in the sample carry the A allele, which means that presumably they are less anxious, on average, than the Chinese. Perhaps this aligns with some expectations or stereotypes you might have?

Well, I decided to check a wider range of populations, because it literally takes about 2 minutes. First, I looked in the HGDP browser. You can see that there is wide variation in African populations. The Mbuti Pygmies of Central Africa have a far lower proportion of the A allele than most European groups, in line with a few East Asian groups, as well as Papuans. Across much of Western Eurasia you see many populations at intermediate frequencies, but it looks as if in Europe there is a cline of A from north to south. One can confirm this with the much larger sample sizes of the 1000 Genomes browser. The highest proportion of A, which purports to be associated with reduced anxiety, is found among Finns, at 29 percent. Then there is the British sample at 24 percent. Finally, both the Spanish and Italian (Tuscan) samples return 16 percent. The South Asian groups all exhibit frequencies of A between 15 and 25 percent (at 18 percent for Bangladeshis, it makes sense why my family would be homozygote for C).

download What about the phenotype in question? I’ll skip over the biochemistry, though it isn’t too difficult in terms of pathways. The original article states that “one community-based study of almost 2,100 healthy volunteers found that people with two copies of the mutant gene had roughly half the rate (11 percent) of cannabis dependence than those with one or no mutant gene (26 percent).” That’s not a trivial sample size, but it’s one study. But, it dovetails with the overall thesis, that the biochemical priors of individuals with the AA genotype might allow them to avoid addictions to “abused drugs, like cocaine, opiates and alcohol.” I’m a little confused about this assertion because I looked up the SNPedia page for this variant, and the first major association of an AA genotype is with alcoholism and drug use! Additionally, I did not mention one thing when surveying populations earlier: the groups with the highest frequency of the A allele are Amerindians. This is clear in the HGDP and the 1000 Genomes results.

AA genotype odds ratio

AA genotype odds ratio

The point of this post is not to suggest that variation within the FAAH locus is not relevant to phenotypic differences in individuals or populations. There’s a lot of epidemiological, and now molecular, biochemical, and neurological, evidence that this missense mutation is important in a functional sense. It is likely to make a difference in outcomes. In The New York Times piece the author speculatively suggests that variation at this SNP somehow perpetuates personality heterogeneity in our species, and is a boon to a society. Granted, this doesn’t seem to be true in all cases, as the Mbuti Pygmies and Papuans may lack polymorphism here. But, it is interesting to me that the derived mutation is found at variable frequencies all across the world. There’s probably a evolutionary and biomedical story here to be told about some sort of balancing selection. But, as with many narratives which are fixated upon endophenotypes, the scientific conclusions aren’t quite cut and dried, and rather are still developing, because the endophenotypes themselves are at the end of a long causal chain.

 
• Category: Science • Tags: Behavior Genetics, FAAH, Genetics 
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  1. Robert Ford says: • Website

    very, very cool. i’m an AC and i’ll send that article to my family cuz it seems quite relevant. i like this new era of science reporting where you can see how it applies directly to you. however, like you said, it seems a little fuzzy – similar to how 23andMe recently sent out results for liking sugar. supposedly, i should not be likely to like sweets but the truth couldn’t be more opposite. i understand we’re in the early stages of this stuff but it’s a little disappointing when your reality doesn’t agree with their prediction at all.

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  2. AC, me.

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    • Replies: @Robert Ford
    am i correct to assume that an AC would be a "middle ground" between "anxious" and not? or does it not work that way?
  3. Long-term fear must be a double-edged sword, essentially helpful in the situations where the danger is real, persistent, and uncontrolled? So it’s easy to come up with a hypothesis that the balance between the two alleles may have been maintained in evolution, either through distinct advantages of each allele, or through heterozygous advantage coupled with homozygous fitness loss?

    I would also expect the complex phenotypes such as anxiety or substance abuse to be regulated by multiple loci, some of which may be more important in the populations where rs324420 is fixed…

    Read More
    • Replies: @Razib Khan
    re: het advantage. i doubt that. the segregation load problem with overdominance makes me skeptical of any given case of het advantage. it does exist (see: some malaria stuff), but it has to be rare to make any sense. so the chances that this is one of those rare cases is unlikely. but some sort of spatial or frequency dynamics balancing seem feasible.
  4. Robert Ford says: • Website
    @Sandgroper
    AC, me.

    am i correct to assume that an AC would be a “middle ground” between “anxious” and not? or does it not work that way?

    Read More
    • Replies: @Sandgroper
    Robert, friend, you flatter me. Almost everything I know about genetics, I have learned at the feet of my teacher Razib, metaphorically speaking.

    But I can tell you that my daughter is CC (not surprising). On occasion she has suffered from quite bad anxiety attacks. Not often, but pretty bad. I have never experienced anything like that, although I tend to be a bit of a worrier.
  5. I’m a AA and so is my maternal uncle, we are both African American, and yes I can say from spending a few years of my life in East and Southeast Asia (Mainland China, Taiwan, Singapore, Japan) that I found a lot of Asians to be…uhm…”neurotic” in the anxious sense…always worried about something, far more than what you find in America, but I chalked this up to culture. To be honest I find most African Americans to be pretty laid back until you anger them.

    Read More
    • Replies: @Jefferson
    "To be honest I find most African Americans to be pretty laid back until you anger them."

    It doesn't seem like it takes much to anger African Americans, hence why they have a higher crime rate than all other races in the U.S.
  6. Razib,

    Your conclusions about the FAAH Genes in Finns is spot on.

    Please review the statistics summarized here:

    1.
    2. http://www.fastcoexist.com/3016661/what-countries-are-most-anxious-about-around-the-world

    So, your looking at Genetic Studies / GWAS studies shows the Finns are less likely to suffer from GAD – General Anxiety Disorder. http://hgdp.uchicago.edu/cgi-bin/alfreqs.cgi?pos=46643348&chr=chr1&rs=rs324420&imp=false

    And also, the above surveys done on a worldwide basis also point to the Finns as being less anxious.

    I have developed a Finnish Tonic to help persons in America and around the World suffering from GAD. Two 12 ounce cans a month for 6 months and you will be over GAD and quite laid back. Your spouse, co-workers, friends should be able to see the change in you in about 3 months.

    Please comment here if you are looking for something like this or wish to invest. Patents are pending.

    Hans

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  7. Cosmo says:

    Interesting. Whatever makes the Finns test as more anxious than other European populations must not be captured by this gene loci. It makes sense that a population with high anxiety due to cause B might have a lower than average frequency of anxiety alleles for cause A. The genetic background would already be tweaked toward anxiety, thus eliminating any advantage for alleles that produce a slight push in the cause A direction. Also, somebody who happens to double up with both cause A and B might be too extreme.

    There must be some kind of rule for this. The presence of alleles of large effect for a given phenotype can almost be inferred to exist in a population if you find a population with an unexpected paucity additive alleles for the given phenotype, who nonetheless exhibit high levels of the phenotype.

    A good place to go hunting for rare alleles of large effect may be those populations that have have an unexplained lack of additive alleles for a given trait.

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    • Replies: @Razib Khan
    thanks for noting that i'm just confused as to whether this phenotype outcome is what the SNP says it is. it's complicated, and the article elided over the confusion. and on facebook people are now going buckwild with the variant ;-)
  8. @Dmitry Pruss
    Long-term fear must be a double-edged sword, essentially helpful in the situations where the danger is real, persistent, and uncontrolled? So it's easy to come up with a hypothesis that the balance between the two alleles may have been maintained in evolution, either through distinct advantages of each allele, or through heterozygous advantage coupled with homozygous fitness loss?

    I would also expect the complex phenotypes such as anxiety or substance abuse to be regulated by multiple loci, some of which may be more important in the populations where rs324420 is fixed...

    re: het advantage. i doubt that. the segregation load problem with overdominance makes me skeptical of any given case of het advantage. it does exist (see: some malaria stuff), but it has to be rare to make any sense. so the chances that this is one of those rare cases is unlikely. but some sort of spatial or frequency dynamics balancing seem feasible.

    Read More
  9. @Cosmo
    Interesting. Whatever makes the Finns test as more anxious than other European populations must not be captured by this gene loci. It makes sense that a population with high anxiety due to cause B might have a lower than average frequency of anxiety alleles for cause A. The genetic background would already be tweaked toward anxiety, thus eliminating any advantage for alleles that produce a slight push in the cause A direction. Also, somebody who happens to double up with both cause A and B might be too extreme.

    There must be some kind of rule for this. The presence of alleles of large effect for a given phenotype can almost be inferred to exist in a population if you find a population with an unexpected paucity additive alleles for the given phenotype, who nonetheless exhibit high levels of the phenotype.

    A good place to go hunting for rare alleles of large effect may be those populations that have have an unexplained lack of additive alleles for a given trait.

    thanks for noting that i’m just confused as to whether this phenotype outcome is what the SNP says it is. it’s complicated, and the article elided over the confusion. and on facebook people are now going buckwild with the variant ;-)

    Read More
  10. Anonymous says: • Disclaimer

    Is there any evidence for action against cancer regarding the A allele? I ask, because it is known that cannabinoids (and endocannabinoid agonists) have strong anti-cancer properties (by causing cells to commit apoptosis), thus it could be possible that possessing any alleles for any genes that reduce the risk of cancers might be positively selected for, without regard for any other of their functions. Considering this mutation seems to help people with focus/learning (which I discovered for myself is what actual Cannabis does), it could well have been of help in our Ancestors’ hunting/gathering lifestyle, since being able to keep one’s wits is important in a crisis.

    BTW, has anyone checked for overlap of this gene’s frequency with areas of endemic Cannabis sativa? Because I suspect in places where pot grows wild, the gene’s frequency would go down, because it would not have the positive selection advantage (and whatever negative properties it has might cause it to be selected against). C. sativa comes from India, where I believe you, Mr. Kahn, mentioned people have low levels of A, and high C. And Chinese medicine (as well as Indian Ayurveda) uses various herbs, including C. sativa, and has done for literally thousands of years. North America, where there is no wild pot, and never had been before Colonial times, has the highest incidence, so… There are a couple-few testable hypotheses here.

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  11. @Robert Ford
    am i correct to assume that an AC would be a "middle ground" between "anxious" and not? or does it not work that way?

    Robert, friend, you flatter me. Almost everything I know about genetics, I have learned at the feet of my teacher Razib, metaphorically speaking.

    But I can tell you that my daughter is CC (not surprising). On occasion she has suffered from quite bad anxiety attacks. Not often, but pretty bad. I have never experienced anything like that, although I tend to be a bit of a worrier.

    Read More
    • Replies: @Robert Ford
    ok, cool, we'll just wait for more info. i sent it to my dad and that's the first thing he asked and i basically said "uh.....I have no idea!"
  12. Robert Ford says: • Website
    @Sandgroper
    Robert, friend, you flatter me. Almost everything I know about genetics, I have learned at the feet of my teacher Razib, metaphorically speaking.

    But I can tell you that my daughter is CC (not surprising). On occasion she has suffered from quite bad anxiety attacks. Not often, but pretty bad. I have never experienced anything like that, although I tend to be a bit of a worrier.

    ok, cool, we’ll just wait for more info. i sent it to my dad and that’s the first thing he asked and i basically said “uh…..I have no idea!”

    Read More
  13. ohwilleke says: • Website

    While phenotype to genotype studies of personality have not been very fruitful (perhaps because phenotypes aren’t very precisely defined and self-assessment of phenotype by paper and pencil survey isn’t very accurate but often used), going in the reverse direction to map genotype to established personality phenotypes looks increasingly fruitful and seems to involve a pretty modest number of large effect genes. I wouldn’t be surprised if twenty years from now if there were two or three dozen genes that could collectively produce a reasonably accurate personality profile.

    This would be remarkable enough, but imagine then going back and looking at ancient DNA both of unknown individuals and of famous ones. That would give you a real feel for the people of the past in a way that no other means could.

    Read More
  14. Jefferson says:
    @Dragon Horse
    I'm a AA and so is my maternal uncle, we are both African American, and yes I can say from spending a few years of my life in East and Southeast Asia (Mainland China, Taiwan, Singapore, Japan) that I found a lot of Asians to be...uhm..."neurotic" in the anxious sense...always worried about something, far more than what you find in America, but I chalked this up to culture. To be honest I find most African Americans to be pretty laid back until you anger them.

    “To be honest I find most African Americans to be pretty laid back until you anger them.”

    It doesn’t seem like it takes much to anger African Americans, hence why they have a higher crime rate than all other races in the U.S.

    Read More

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