Exploring New Scientific Research With My Genotype In Hand

This morning, a single tweet sent me on a 2-hour tour (more, if you count drafting this post!) of my genome.

In the tweet, Mary Carmichael expressed interest in a potential book regarding the orchid/dandelion theory recently described in a December 2009 article in The Atlantic “The Science of Success.”  Before this morning, I was not familiar with either the article or the theory.

The introduction to the article, reproduced below, does a good job of summarizing the main thrust of the very long (but extremely interested and worthwhile) report:

“Most of us have genes that make us as hardy as dandelions: able to take root and survive almost anywhere.  A few of us, however, are more like the orchid: fragile and fickle, but capable of blooming spectacularly if given greenhouse care.  So holds a provocative new theory of genetics, which asserts that the very genes that give us the most trouble as a species, causing behaviors that are self-destructive and antisocial, also underlie humankind’s phenomenal adaptability and evolutionary success.  With a bad environment and poor parenting, orchid children can end up depressed, drug-addicted, or in jail—but with the right environment and good parenting, they can grow up to be society’s most creative, successful, and happy people.”

As the introduction suggests, the article examines the complicated interaction between environment and genetics and suggests that while genetics can present hurdles in life, environmental factors can increase or perhaps even eradicate those hurdles.

Nature v. Nurture

The article begins with a discussion of complex behavioral science experiments using humans or monkeys before bringing in recent studies of genetics that tie into these experiments.  For example, the author mentions the 5-HHTLR gene, which is involved in serotonin processing:

“As I researched this story, I thought about such questions a lot, including how they pertained to my own temperament and genetic makeup. Having felt the black dog’s teeth a few times over the years, I’d considered many times having one of my own genes assayed—specifically, the serotonin-transporter gene, also called the SERT gene, or 5-HTTLPR. This gene helps regulate the processing of serotonin, a chemical messenger crucial to mood, among other things. The two shorter, less efficient versions of the gene’s three forms, known as short/short and short/long (or S/S and S/L), greatly magnify your risk of serious depression—if you hit enough rough road. The gene’s long/long form, on the other hand, appears to be protective.”

From SNPedia:

“5-HTTLPR (serotonin-transporter-linked polymorphic region) is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter. It has been extensively investigated in connection with the behavioral, psychiatric, pharmacogenetic aspects of neuropsychiatric disorders.  In contrast to earlier reports, a June 2009 article in JAMA showed no association between 5-HTTLPR genotype and my depression treatment.”

My 5-HTTLPR Status

Perhaps not surprisingly for anyone who has read The Genetic Genealogist, I was immediately interested in determining my own 5-HTTLPR status.  Based solely on my personal history (for example, I’ve never been overly prone to depression) and family history, I quickly predicted that my status would be S/L.

The author of The Atlantic article was also interested in his 5-HTTLPR status and sent away a saliva sample to a researcher she knew for analysis.  You can read the article to learn his status in the last few terrific paragraphs.

However, being one of the most extensively genotyped people in the world (which still doesn’t require much genotyping; I’ve had whole-genome scans performed by two different companies, along with Y-DNA and mtDNA testing), I turned to the results I already had in hand.

Unfortunately, the main SNPs used to examine the S or L version of 5-HTTLPR are not examined by 23andMe.  However, there has been extensive discussion of the gene in the 23andMe forums, and one member pointed out (here) that a 2009 study associated the CA haplotype of SNPs rs4251417 and rs2020934 is coupled with the short allele of 5-HTTLPR (although not perfectly, with r(2) = .72).

Of these “surrogate SNPs,” 23andMe only tests rs4251417.  A quick glance at my results revealed that I am C/C homozygous at rs4251417, suggesting that I might be 5-HTTLPR S/S, not S/L as I had predicted.  (I should note here that with just the rs4251417 allele and with a combined r(2) of 0.72, it is not clear how well the rs4251417 allele alone predicts 5-HTTLPR status despite the discussions found in the 23andMe forums).

There are a myriad of articles examining the S/L alleles, including research regarding their effect on stress (“We found that the s allele of 5-HTTLPR was associated with depression and perceived stress in patients with coronary disease.”); aggressive behavior in alcoholics (“Data suggests that the presence of s allele may confer a genetic vulnerability factor to the development of aggressive behaviour in alcohol dependent subjects, specially, in interaction with acute alcohol consumption stage”); and my favorite, financial risk (“We find that the 5-HTTLPR s/s allele carriers take 28% less [financial] risk than those carrying the s/l or l/l alleles of the gene.”).  Interestingly, it appears that none of this research considered the environmental factors that appear to be so influential on the 5-HHTLPR genotype, something that is undoubtedly endemic to genotype/phenotype studies.

The Future

Now that my wife has had her genome analyzed, I can do something that I couldn’t do with my results alone; I can predict the possible 5-HTTLR genotypes of our offspring.

This is, of course, tricky business.  I’m still not sure how I feel about purchasing genetic testing for my children, but this is a far cry from buying them a test.  I’m simply using basic genetic techniques to predict possible genotype outcomes, something that high school biology students have been doing for decades (determining the % of blue vs. brown eyed-children using various parental genotypes, for example).

Although an interesting exercise (and one that I’ve been performing often), given the state of the 5-HHTLR science I don’t believe that I’ve gained any useful or actionable information from an estimate of my children’s genotype.  Of course, I’m not even sure exactly how strong the research would have to be to make almost any genotype actionable!

Caveats

This discussion and analysis is for my personal interest only.  Specifically, I’m intrigued by the (as-of-yet unregulated) ability to check my own genotype against the results of new research.  I do not plan to make any lifestyle or parenting changes based on the results discussed in this post, and I do not suggest that you should do so either.  I simply examined my genetic code to determine my allele status and then examined the primary research to review the discussion of that allele status in the literature.  And I certainly hope I will be able to continue to do this in the future.

Edit Before Posting:

I was finally able to obtain a copy of the 2009 study that associated the CA haplotype of SNPs rs4251417 and rs2020934 is coupled with the short allele of 5-HTTLPR.  The authors include the following in their analysis, revealing that the rs4251417 SNP is not a useful proxy for determining your 5-HTTLPR status:

“Unfortunately, rs2020934 has not been genotyped as part of the HapMap project and has not been included on any of the genome-wide SNP platforms.  SNP rs4251417 is included on the Illumina 610K and 1M chips, but on its own, it is not a useful proxy for 5HTTLPR (r2 = .06).”

While this means that the above analysis was not fruitful, it emphasizes three very important points regarding personal genomics: (1) people will increasingly turn to their personal genotype as they read new research; (2) be sure to confirm everything for yourself; and (3) at this stage of the game, you should be prepared for everything you’ve discovered and/or concluded to be turned on its head with new research.