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“A man needs a name” and that man is Riccardo Sabatini. Serious games of -omes happening at Human Longevity.

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Pillow talk

Her: Why haven’t you asked me to try that one thing that you really want to try, but haven’t tried yet?

Him: It’s not something you can just “do” Honey. It takes time to learn. You know how I always overestimate how difficult it will be to learn something new? and then my prefrontal cortex – hippocampal connections go and mediate a rapid-fire one shot kind of learning?

Her: Awwww, don’t be embarrassed Dear. I am glad you are an ZNF804A  rs1344706 heterozygote. If I had to choose between too quickly or going on and on for hours … well, let’s just say, my favorite part is always the hugging afterwards. Mmmmkay?

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sattestcomic

Don’t worry about your general cognitive ability genes. Otherwise, check out this study led by Drs. Joe Trampush and Anil Malhotra from the Feinstein Institute showing that the less frequent and non-ancestral (A) alelle of rs1906252 was associated with higher Spearman’s General Intelligence (g-factor) scores.  This SNP sits 700 kilobases upstream of a putative ubiquitin ligase subunit (FBXL4) connected to severe psychomotor retardation. Loss-of-function in other ubiquitin ligase subunits have also been implicated in mental retardation.

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mosquito

It’s summer people. We live in the genome age. Check your rs309375 genotype.

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They say information wants to be free, but maybe it’s more that people want to be free and crave information that helps them acquire freedom. So maybe there is a simple test to apply to any subsequent blog posts here.

Does this post contain information that might help someone on their quest toward personal freedom or self-determination?

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unemploymentline

The  genetics of economics and economics of genetics are really freaky topics.

On the one hand, we spend most of our lives making economic decisions … how to spend time? money? affection? You know, “He’s cute, but has a lame job” and, “I feel like I’m getting a better deal at Five Guys because they give away the peanuts for free.” Genetic research seems to be “worth it” because variation in genetic data might underpin variation in economic behavior (particularly in the healthcare marketplace).

On the other hand, genetic data seems to have little or no economic face value. I mean, they are practically giving the data away at $100 for your SNP-ome and $1,000 for your full genome.

So it seems that consumers are now part of an experiment where they may freely access their personal genetic information and try to figure out how to use it in some sort of economically advantageous way. Meanwhile scientists can (with consent) meta-analytically track the genotypes of these consumers and discover what genotypes are associated with good economic decisions. It’s freaky. It’s fascinating. It’s big data. Whatever.

The downside to “consumer as guinea pig” is that the free marketplace is full of liars and exploiters, and will soon be awash in every sort of hokey “geno-” this and “geno-” and “g’s” fused with all sorts of words that begin with “en”. I mean, have you ever not been paralyzed in the salad dressing aisle? Do we really need “specially formulated for rs1234567 AA” geno-dressings?

Which is why I really think anyone who describes himself as a genoeconomist and founder of a gentrepreneurship consortium, really needs to take it down a couple of notches. This type of self-branding is what the liars and exploiters do.

Hundreds of millions of people are desperately looking for work. The liars and exploiters have wrecked the global economy for decades to come. People are suffering. The publication of meta-analytic studies that show that self-employment, while somewhat heritable, is a complex polygenic trait (um, no shit) feels to me like an insensitive slap in the face to people who are unemployed through no fault of their own.

Rant over.

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meme23andmedudeohyeahmeme

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American Omic

funkyamericangothic

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… except for the genes that allow us to totally reset our expectations about social rejection.

Thank you Jia Jiang for helping me to take everything I had learned about the psychology, neurobiology and genetics of social rejection and rejection sensitivity … and throw it in the garbage.

Apparently the best part of having a human brain is that we have the biological predisposition to transcend our own biological predispositions.

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legarement

The “T” allele of rs1378810 in your DNAJC13 gene has been associated with a slight benefit (less than 0.4% variance) in general cognitive ability. You can check your 23andMe profile.*  What? You’re a TT? Ooooh … nobody is impressed. But let’s not make light of our DNAJ genes just yet.

Consider the critical role of DNAJC5, a so-called cysteine-string protein (because it encodes a protein with an array of cysteine residues). This protein helps synaptic vesicles fuse and un-fuse so that your neurons can release and re-cycle tiny packets of neurotransmitters – which is how neurons send signals to one another. Yeah, vesicle fusion is really important … and is happening like a quadriillion times right now in your brain.

Mutations in the cysteine string of DNAJC5 have been associated with Huntington’s disease.

[artwork credit]

*Interpreting 23andMe data here can be confusing because 23andMe lists an A or T as possible alleles but one isn’t always sure which strand the research literature refers to and if that strand is the same strand that 23andMe is reading from. Luckily SNPedia points out that an rs1378810 TT is in tight linkage disequilibrium with rs2133692 TT (T or C alleles) so you can check this genotype on 23andMe to infer your rs1378810 genotype. My 23andMe profile says AA at rs1378810 and TT at rs2133692, so I think I have the slightly beneficial TT genotype … but I’m really not sure. Confused? Me too. But like the research suggests, this genotype really doesn’t add much to one’s general cognitive ability.

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Meme genes: ALBA

albamuscle

Mo’ Jessica ALBA, mo’ muscle? Actually no. “Serum albumin demonstrated modest and inconsistent trends with loss of muscle mass and function. Low serum albumin within the normal range is not a risk factor for this process among elderly men.” More on your ALBA gene here.

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rg3genes

Have you read The Sports Gene? Maybe you are wondering if your child might be the next Lionel Messi? Or maybe you’re wondering why you were always picked last for kickball? Was it the genes? the practice? or a combination of the two?

We all know kids who seem to have been born with a baseball bat or tennis racquet in their hands. Tall kids, strong kids, fast kids and kids with great hand-eye-coordination. As far back as 1978, the German Tennis Federation had identified 9-year old Steffi Graf as a top recruit based upon her lung capacity, ability to sustain concentration, running speed and her competitive desire. Other kids discover late in life that they have a genetic gift. On a whim, Donald Thomas leaped for his first EVER high jump in 2006 and promptly won the World Championships in 2007.  Chrissie Wellington (world tri-athelete champion) also accidentally discovered her genetic gift late in life (outpacing sherpas on her bicycle while vacationing in Nepal).

As described by David Epstein, the 1996 Olympic games in Atlanta, saw 7 women out of the 3,387 competitors carrying the Y-chromosome-linked SRY gene. 21-hydroxylase deficiency also causes the overproduction of testosterone and is over-represented among top female athletes. The GIANT research consortium has discovered hundreds of “sports genes”, such the rs9930506 SNP in the FTO gene, that contribute to body shape and size. Even more numerous are the complex genetics of height where each genetic variant adds a mere 2-6 millimeters toward NBA stardom. Elite sprinters are more likely to carry 2 functional variants of the fast-muscle-twitch ACTN3 gene. Lastly, an extended network of genes associated with muscle development can – when artificially overexpressed – induce muscle growth: insulin-like growth factor-I (IGF-I), growth hormone (GH), erythropoietin, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and myostatin blockers, such as follistatin.

Sports genes. Few of us are born with them (I was luckily born with the non-obese TT genotype at rs9930506 in the FTO gene, but alas, this allele is associated with a lower response to exercise). Fewer still might be intent upon purchasing a genetic endowment via the taboo art of sports gene doping, especially if they carry the right UGT2B17, CYP17 and PDE7B genotypes. Most of us, however, would just like to maximize our paltry genetic endowments the old fashioned way.

Practice.

Justin Durant of the Sports Science Institute of South Africa is quoted, “I’ve never seen a boy who was slow become fast” but how about late-blooming middle distance runner Jim Ryun whose practice regimen carried him from 21rst on his Wichita East track squad (in 10th grade) to an Olympian and 1-mile world record holder just a single year later? Epstein explores how each of us has an inherent genetic endowment for “trainability” ie. the extent to which our bodies and abilities respond to training. And yes, here too, molecular genetics researchers have identified more “sports genes” in a so-called training responsive transcriptome consisting of genes, including RUNX1, SOX9 and PAX3 whose expression is associated with exercise-dependent muscle growth and CREB1 whose expression is associated with improvements in heart rate and blood pressure.

Sports crazed parents should take note. Your child is probably totally average. Probably like self-described “totally average guy” Dan McLaughlin, who has slogged some 5,500+ hours into his personal experimental journey of “deliberate practice” hoping to land a spot on the PGA tournament by the time he reaches his 10,000th hour of practice. Will he make it? Or will he discover the oft-misconstrued “10,000 hour rule” is more like 4,000 for some and 40,000 hours for others. We wish Dan the best of luck on his quest, but also wish parents to use their children’s precious 10,000 hours for reading, writing, mathing and playing sports for fun rather than trying to attain an NCAA scholarship through mastery of a niche sport.

Will genetic counselors soon be found in pro sport locker rooms or at your local fantasy league draft party? Doubtful, but in 2005, according to Epstein, the Manly Sea Eagles of Australia’s National Rugby League became the first pro sports team to admit that it was genotyping players at ACTN3 and training them differently based on their genotypes.

I loved reading The Sports Gene! Have you ever noticed that NOBODY wants to read a blog or talk about genetics and medical illness, while EVERYBODY loves to talk about sports? Find me a graduate student who can understand (and stay awake while reading) medical GxE research and I will find 1,000 parents who are obsessed with finding the perfect sporting niche and coach for their child.

Whether it be medical treatment or athletic training, a good doctor/coach will seek to optimally match the patient/player’s genetic endowment with treatment/training. The Sports Gene by David Epstein is thus a wonderfully fun and timely playground for readers to explore the complexities of personal genomes and GxE interactions!

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GTFO

rage1

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BeFunky_OldPhoto_12

Have you ever read the DSM and thought you had EVERYTHING? Me too.

And that, sort of,  has always been a big problem … that it is really hard to separate the normal experience of anguish and suffering as part of our everyday mental and emotional lives from what is labelled a “disorder”. At the same time, however, patients, doctors and payors need some type of common reference so as to keep the diagnosis and treatment of mental suffering in-line with the way other medical illnesses are handled. So, everyone (in psychiatry, at least) knows the DSM will always be highly flawed and yet also highly necessary … so, you know, just try and live with it … but don’t expect, for a moment, to search for and find discrete genetic variants that correspond to DSM categories of mental disorders. No … because the DSM categories do not correspond well to the underlying biology of the CNS … the DSM does not “cut nature at its joints” so to speak.

Russ Poldrack provides a glimpse into what the future of diagnosing mental illness might look like using slightly more objective, quantifiable and biologically relevant measures of the brain’s physiological processes.

Also, I stumbled onto an awesome read about the creation of DSM-5 entitled, The Book of Woe

The overall thrust of the manual [DSM-5], the BPS complained, was to identify the source of psychological suffering “as located within individuals” rather than in their “relational context,” and to overlook the “undeniable social causation of many such problems.”  The APA could hardly deny any of this. As Regier had told the consumer groups on the conference call, the manual’s new organizational structure was designed to reflect “what we’ve learned about the brain, behavior, and genetics during the past two decades.” It doesn’t get much more “within the individual” and outside the “relational context” than that. (p. 239)

“Dereification is just as dumb as reinfication,” he [Allen Frances] told me. “A construct is just a construct – not to be worshiped and not to be denigrated.” Psychiatry, he was saying, has to live in the tension between the desire for certainty about the nature of our suffering and the impossibility of understanding it (or ourselves) completely. A DSM that tries to end this tension by turning itself into a living document was bound to collapse into chaos; that was the cardinal error of the incompetent DSM-5 regime. (p. 279)

“What [Dr. Thomas] Insel [Director of NIMH] heard “over and over again” on his tour was that psychiatrists were tired of being trapped by the DSM. “We are so embedded in this structure,” he told me. He and his colleagues had spent so much time diagnosing mental disorders that “we actually believe they are real. But there’s no reality. These are just constructs. There’s no reality to schizophrenia and depression.” Indeed, Insel said, “we might have to stop using terms like depression and schizophrenia, because they are getting in our way, confusing things.” Thirty years after Spitzer burned down DSM-II and built the DSM-III in its ashes, psychiatry might once again have to “just sort of start over.”” (p.340)

Yikes! after reading The Book of Woe, DSM-5 sounds, um, totally wack … if not a tool flagrantly designed to further commodify human suffering for the benefit of a medico-industrial complex. NIMH Director Thomas Insel’s recent announcement that, “NIMH will be re-orienting its research away from DSM categories.” suggests a future where diagnosis will based on biological measures and treatments are directed toward specific circuits.

Treatment for specific circuit dynamics sounds very promising. However, I thought Dr. Allen Frances, as quoted in The Book of Woe made a great point (p.346) that, “The trick is to develop a healing relationship, to care for the person not just the disorder, to diagnose and treat cautiously, and to see the healthy part of the person not just the sick.”

* Maybe that is the hope of this blog also … to take out and explore the intricate biological & molecular parts … but also to try and place them back into their original evolutionary, living, breathing, copulating (or more often the case of just thinking about copulating) “whole” human being.

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ntbd

Studies on adopted children raised by parents in hostile marriages: show (obviously) that frustration and anger begets frustration and anger … irrespective of genes.

“Although there was no direct association between birth mother anger/frustration and toddler anger/frustration, as noted above, birth mother anger/frustration significantly moderated the relation between adoptive parent marital hostility and later toddler anger/frustration. This genetic moderation is consistent with the premise that children whose birth mothers report higher levels of anger/frustration inherit an emotional lability, making them more susceptible to the negative impact of marital hostility.”

But, for an unfortunate few … the doubly unfortunate experience of having an “inherited emotional lability” while being raised in an emotionally harsh environment, can mean a lifetime of emotional anguish, stress-related-physical suffering and falling through the cracks of society.

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groom

Learning to read emotions and faces is important for our well-being.  For some of us, the act of gazing into another person’s eyes is innately rewarding … especially if they are smiling.  New mothers and their infants can be found locked in each others smiling countenance … thus strengthening the developing neural pathways upon which the infant’s future social skills will grow.

One component of these neural pathways is the CNR1 gene expressed in the striatum and other brain regions that process rewarding and positively-reinforcing stimuli.  For most of us, a happy smiling face is positively rewarding … moreso with certain CNR1 genotypes.

From Drs. Baron-Cohen and Chakrabarti:

“A comparison of these results with those from our earlier fMRI study reveals that for the SNP rs806377, the allelic group (CC) associated with the highest striatal response is also associated with the longest gaze duration for happy faces. For rs806380, the allelic group associated with the highest striatal response (GG) is also associated with the longest gaze duration for happy faces.”

My 23andMe profile shows both the long-gaze CC and GG genotypes for rs806377 and rs806380.  Mmmmkay … I guess this would be a good time to apologize to all the girls I inappropriately stared at in the cafeteria back in college … even though you weren’t usually smiling back at me.  I guess my CNR1 and striatum were pretty overactive.

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tumblr_lfbl0vftbD1qc38e9o1_400

The above images are eigenfaces … which are statistically distilled basic components of human faces … from which ANY human face can be reconstructed as a combination of the above basic components.  It’s a great mathematical trick – particularly if you’re into the whole mass surveillance and electronic police state thing.

If you are more into the whole, helping people and medical care thing, check out the global consortia at ENIGMA who have been carrying out massive genetic and brain scanning studies – like this one involving 437,607 SNPs in 31,622 voxels in 731 subjects using their new method, vGeneWAS, to study Alzheimer’s Disease:

“We hypothesized that vGeneWAS would, in some situations, have greater power to detect associations than existing SNP-based methods. One such situation might be when a gene contains many loci with weak individual effects. In addition, we expected that vGeneWAS would have greater overall power than mass SNP-based methods, like vGWAS, because of the drastic reduction in the effective number of statistical tests performed.”

The vGeneWAS method relies on the calculation of “eigenSNPs” which are eigenvectors that describe a matrix of n subjects by m SNPs in an individual gene (an n-x-m matrix of 1’s,0’s,-1’s for aa, aA, AA genotypes).  EigenSNPs are sort of like eigenfaces insofar as eigenSNPs (which are not actual SNPs) capture the majority of variance, or the basic essence of an individual gene … but seriously, you should read the original article ’cause every stats test I ever took totally punched me in the face.

In any case, the eigenSNP-by-voxel method pulled out some legit results such as rs2373115 (where the G-allele confers risk) in the GAB2 gene  which has repeatedly been implicated in the risk of age-related late-onset Alzheimer’s Disease (in folks who carry ApoE4  rs429358(C) alleles).  The authors found that the genetic risk of AD conferred by GAB2 may arise by way of GAB2’s effect on brain structure in the periventricular areas, which have been known to be among the first brain regions to show AD-related changes (time-lapse movie of AD tissue loss in the brain).

Picture 2

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6377650365_0a712cf431_z

Genes that confer risk for illness are ideal targets for prevention and treatment.  So, also, are genes associated with natural or treatment-based RECOVERY from illness.  In a search for “recovery genes”, association studies in women who have recovered from eating disorders (ED) vs. those who are still struggling to recover reveals that the C-allele of rs17536211 is associated with recovery.

From Bloss et al.:  “Given the substantial genetic component in the etiology of EDs in general, it follows that there may be genetic variants that contribute to the likelihood of recovery.”

“These were women who were over age 25 years, carried a lifetime diagnosis of either AN, BN, or ED-NOS (ie, subthreshold AN or BN), and for whom data were available regarding the presence (n=361 endorsed ongoing ED symptoms in the past year and considered ‘ill’) or absence (n=115 no ED symptoms in the past year and considered ‘recovered’) of ED symptoms.”

“rs17536211, an intronic SNP in GABRG1 on chromosome 4, showed the strongest statistical evidence of association with a GC-corrected p-value of 4.63 × 10−6, which corresponds to an FDR of 0.021 (Figure 1). The odds ratio (OR) observed for this SNP is 0.46, suggesting that possession of copies of the minor allele [C] is protective from long-term chronic illness (ie, it is associated with recovery).”

How might this SNP confer a protective effect?  The authors review data on the role of GABRG1 subunits in the un-learning of conditioned fear responses [“GABRG1 subunits are found in the lateral inputs, a region that arises from the intercalated cells masses, and is thought to be responsible for mediating inhibition of amygdala output during extinction of conditioned fear (Likhtik et al, 2008)”] and suggest that individuals with the protective C-alleles may be slightly more able to uncouple eating from a very real and debilitating fear response.

*photo credit

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This chart from John Hawks shows how brain volume (y-axis) has increased gradually during the past 2 million years of human evolution. brainsize  rs31480 is an interesting SNP because individuals homozygous for the ancestral “C” allele have slightly smaller cranial volumes than TT individuals (well, at least the individuals in this particular study do).  The SNP is located in the IL3 gene which regulates proliferation in a variety of cell types including neural progenitor cells – thus possibly influencing the development of overall brain size.

Personal sidenote – I have a kind of a big head – literally – but 23andMe does not cover rs31480.  So, yeah, that whole mystery remains. 

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lie_robot

Let’s be honest.  We are all great liars … to ourselves, and others.  The big blatant lies (I swear I never had sex with Monica Lewinsky) and the little well-meaning lies (No honey, that dress does not make your butt look big) and especially the lies that contain just enough truth as to seem believable on a global scale (Lowering taxes on the rich will spur economic growth) … are what make our lives, and daytime TV, so interesting.

Pity the poor human brain … for some people think that IT cannot tell a lie. Scientists in collaboration with law enforcement have been measuring the  P300 brain wave  as a sort of lie detector (here, here, here) more specifically  “an accurate, and countermeasure (CM)-resistant P300-based Guilty Knowledge Test.”

Interestingly, the properties of the P300 neural biomarker are highly heritable and associated with a variety of genetic polymorphisms – including rs521674 located in the noradrenergic receptor ADRA2A gene (functions in the alerting and stress response elicited when lying/trying not to lie).

I’m an AT heterozygote at rs521674 and proud of my pro-deceitful suppressed P300 … because sometimes all you have to cling to are the lies you tell yourself.

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