biomarker-driven mental health 2.0

Join with fellow citizens and the ACLU to stop warrantless government wiretapping … else, today your phone conversations and tomorrow (or, well, today, actually) your health records and genome.

Just re-posting from Gizmodo … this looks like a positive step … a medical chumby.

James Schummers, Hongbo Yu and Mriganka Sur present their measurements of Ca++ dynamics in response to visual stimuli in the awake ferret and reveal highly refined patterns of astrocyte activity in their paper, “Tuned Responses of Astrocytes and Their Influence on Hemodynamic Signals in the Visual Cortex” (DOI: 10.1126/science.1156120). The genetic regulation of neurovascular coupling is key to understanding the way in which genetic variation may regulate brain function (or at least function as measured by the BOLD response).  A closer look at BOLD response and genetic pathways that mediate astrocyte function would be music to my ears - or at least my auditory cortex astocytes.

Amidst his hectic schedule managing the ongoing credit crisis, the New York Times notes that Federal Reserve chairman Ben Bernanke opened a bipartisan symposium which will, “lay the groundwork for what leaders of both parties predict will be a major push for health care legislation next year.” From the article, it seems that since healthcare accounts for such a large (and growing) slice of the federal budget pie, fixing inefficiency and disparity in healthcare will assuredly involve more legislation and regulation on a growing scale. The article bummed me out since I suppose it portends new and shifting regulatory layers that will just make it harder for entrepreneurial consumer-driven and health2.0 innovations to establish themselves. Coincidental bummer that this symposium was taking place on the day NY and CA were stifling a new genetic testing industry.

Just checked for my status at UGT2B17 - locus of a 150kb deletion variant covered here in the Economist - to see whether I might have missed my chance to inject ‘roids and claim international sports glory without getting busted by the World Anti-Doping Agency. Unfortunately, the 23andMe profile provides data for the flanking genes YTHDC1 and UGT2A3 on chromosome 4, but not this specific gene. Doesn’t quite seem to validate my choice to couch-potato-dom though.

Amidst all the genome-wide ’snp-ing’ going on of late (my 23-and-me data should arrive in a couple of weeks), Walsh and colleagues provide an incredible trove of structural variation (deletions/insertions in the size range of more than 100kbp but less than 100Mbp) that is 3- to 4-fold enriched in patients with adult onset and childhood onset schizophrenia.  Their paper, “Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia” (DOI 10.1126/science.1155174) uses a variety of genome hybriziation techniques to map novel variants and finds, amazingly, that many of the hits are within genes that function in common pathways of brain development and synaptic function.  The authors admit that it is hard to ascribe a population risk value to any one of these variants, but the biochemical pathways suggest that the genes that were identified by this method deserve a great deal of attention in the basic and clinical genetic research community.

Attention Deficit Hyperactivity Disorder is one of the most widespread psychiatric diagnoses in children.  Parents who are faced with the decision to medicate or not medicate their children may wonder if their child - given a bit more time - won’t just “grow out of it”, as many children seem to do.  With this in mind, it would obviously be helpful to have biomarkers that could predict whether certain children are more likely to simply acquire better attentional control on their own, and those children that might not.  In their paper, “Polymorphisms of the Dopamine D4 Receptor, Clinical Outcome, and Cortical Structure in Attention-Deficit/Hyperactivity Disorder” (Arch Gen Psychiatry Vol 64 (no. 8), Aug 2007) a veritable dream team of child developmental neuroscientists working across several medical institutions report on two such biomarkers.  One biomarker is the thickness of the orbitofrontal cortex and posterior parietal cortex.   MRI-based measurments of these parts of the brain (just about 5mm thick!) show that children who carry a diagnosis of ADHD have a thinner cortical sheet in these regions.  Another biomarker is genetic variation in an intracytoplasmic loop of the G-protein coupled dopamine D4 receptor (DRD4).  Children with ADHD are more likely to carry a longer 7-repeat version of this VNTR polymorphism than the more common 4-repeat.  Interestingly, the research team found that healthy children who carry the 7-repeat genetic variant also have slightly thinner cortex in the orbitofrontal and posterior parietal cortex, suggesting that this genetic variant may influence the risk of ADHD by way of an effect on cortical development.  Additionally, the research team found that the cortex of ADHD children who carry this 7-repeat genetic variant “catches up” from age 8 and eventually falls within the range of healthy children by age 15. Lastly, the team reports that ADHD children who carry the 7-repeat had better clinical outcomes (albeit, many of the ADHD children in this study were treated with medication).  Nevertheless, it appears that some progress has been made in identifying biomarkers that might predict favorable developmental trajectories.

Every student can recall at least one stereotypical professor who - while brilliant - kept the students amused with nervous and socially inept behavior. Let’s face it, if you’re in academia, you’re surrounded by these - uh, nerds - and, judging by the fact that you are reading (not to mention writing) this blog right now - probably one of them. So, its natural to ask whether there might be a causal connection between emotionality, on the one hand, and cognitive performance on the other. Research on the neuromodulator serotonin shows that it plays a key role in emotional states - in particular, anxiety. Might it exert effects on cognitive performance ? In their paper, “A functional variant of the tryptophan hydroxylase 2 gene impacts working memory: A genetic imaging study“, (DOI: 10.1016/j.biopsycho.2007.12.002) Reuter and colleagues use a genetic variation a G to T snp (rs4570625) in the tryptophan hydroxylase 2 gene, a rate limiting biosynthetic isoenzyme for serotonin to evaluate its effect on a cognitive task. They ask subjects (who are laying in an MRI scanner) to perform a rather difficult cognitive task called the N-back task where the participant must maintain a running memory queue of a series of sequentially presented stimuli. Previous research shows that individuals with the GG genotype show higher scores on anxiety-related personality traits and so Reuter and team ask whether these folks activate more or less of their brain when performing the N-back working memory task. It turns out that the GG group showed clusters of activity in the frontal cortex that showed less activation than the TT group. The authors suggest that the GG group can perform the task using by recruiting less of their brains - hence suggesting that perhaps there just might be a genetic factor that accounts for a possible negative correlation between efficient cognitive performance and emotionality.

The selection and dosing of medication in psychiatry is far from scientific - even though a great deal of hard science goes into the preclinical design and clinical development. One reason, among many, has to do with the so-called ‘inverted-U-shaped’ relationship between the dose of a psychoactive compound and an individuals’ performance. Some folks show dramatic improvement with a given dose (their system may be functioning down at the low side of the inverted U mountain and hence, and added boost from medication may send their system up in performance), while others may actually get worse (those who are already at the peak of the inverted U mountaintop). How can a psychiatrist know where the patient is on this curve - will the medication boost raise or topple their patient’s functioning ? Some insight comes in the form of a genetic marker closely linked to the DRD2 gene, that as been shown to predict response to a dopaminergic drug.

Michael Cohen and colleagues, in their European Journal of Neuroscience paper (DOI: 10.1111/j.1460-9568.2007.05947.x) entitled, “Dopamine gene predicts the brain’s response to dopaminergic drug” began with a polymorphism linked to the DRD2 gene wherein one allele (TaqA1+) is associated with fewer DRD2 receptors in the striatum (these folks should show improvement when given a DRD2 agonist) while folks with the alternate allele (TaqA1-) were predicted to show a falling off of their DRD2 function in response to additional DRD2 stimulation. The research team then asked participants to perform a cognitive task - a learning task where subjects use feedback to choose between a ‘win’ or ‘not win’ stimulus - that is well known to rely on proper functioning of DRD2-rich frontal and striatal brain regions.

Typically, DRD2 agonists impair reversal learning and, as expected, subjects in the low DRD2 level TaqA1+ genetic group actually got “more” impaired - or perseverated longer on rewarding stimuli and required more trials to switch on the go and figure out which stimulus was the “win” stimulus. Similarly, when differences in brain activity between baseline and positive “you win” feedback was measured, subjects in the drug treated, TaqA1+ genetic group showed an increase in activity in the putamen and the medial orbitofrontal cortex while subjects in the TaqA1- showed decreases in brain actiity in these regions. The authors suggest that the TaqA1+ group generally has a somewhat blunted response to positive feedback (sore winners) but that the medication enhanced the frontal-striatal reaction to positive feedback. Functional connectivity analyses showed that connectivity between the frontal cortex and striatum was worsened by the DRD2 agonist in the TaqA1+ genetic group and improved in the TaqA1- group.

Although the interpretations of these data are limited by the complexity of the systems, it seems clear that the TaqA1 genetic marker has provided a sort of index of baseline DRD2 function that can be useful in predicting an individual’s relative location on the theoretical inverted-U-shaped curve.

I was just browsing the recent paper “Natural selection has driven population differentiation in modern humans” by  Barreiro and colleagues (doi:10.1038/ng.78) and noticed in their supplementary table that the autism risk factor CNTNAP2 (as blogged about earlier here) contains at least one non-synonymous or 5′-UTR SNP with a high Fst value.  Yann Klimenidis has a great post on this paper.

Dr. Scott Shreeve has a great post on the launch of “Carol” a new, open & transparent healthcare marketplace.  With DNA Direct offering services there, its easy to see how biomarkers and biomarker-driven care can work within a consumer-driven business model.  Exciting to see the future today !!

The publication of positive genetic association results is always something to cheer about although most of us know that on a different day, with a different sample, the results could just as easily been flat. So when a meta-analytical paper appears that actually supports a previous finding, you have to savor the sweet joy of it. So it is that Marcus Munafo and colleagues under the leadership of Jonathan Flint - one of the best meta-analytical assessors in the biz - report that the “C” allele of rs1800955 in the dopamine d4 receptor (DRD4) gene (doi: 10.1016/j.biopsych.2007.04.006) survives an analysis of several dozen studies on genetics and personality. Although small, “The evidence from our final meta-analysis indicatest hat the true effect size of the C-521T polymorphism on novelty seeking and impulsivity traits, if genuine, may account for up to 3%o of phenotypic variance.” I, perhaps due to my “C” allele am excited !

MUNAFO, M. (2008). Association of the Dopamine D4 Receptor (DRD4) Gene and Approach-Related Personality Traits: Meta-Analysis and New Data. Biological Psychiatry, 63(2), 197-206. DOI: 10.1016/j.biopsych.2007.04.006

Recent meta-analytical research, “Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy” (N Engl J Med 2008;358:252-60) reveals that while 94% of published antidepressant drug trials show positive findings, only 51% of all such (published and unpublished) trials show positive effects (with a range of effect sizes from 11-69%). This is probably not surprising to patients and physicians (investors? … well, maybe) who often search in vain, using trail and error, for a medication that can provide relief from major depression, one the the top disease burdens world-wide. Many have suggested that pharmacogenetics may provide a key to understanding the tremendous variability in medication response. For example, variations in the ABCB1, ATP-binding cassette sub-family B member 1, gene seem to predict who may show a response to certain antidepressants (citalopram, paroxetine, amitriptyline, and venlafaxine) medications, that are shuttled across the blood-brain-barrier endothelial membrane by ABCB1. In a pharmacogenetic medication trial involving 443 inpatients with depression who were treated at the Max Planck Institute of Psychiatry, the SNPs 2032583, rs2235015, rs2032583 and rs2235015 predict significantly different time course of response to treatment over 6 weeks. The paper, “Polymorphisms in the Drug Transporter Gene ABCB1 Predict Antidepressant Treatment Response in Depression” (doi: 10.1016/j.neuron.2007.11.017) is an example of pure and applied science at is best. The results pose a vexing dilemma for “really big” pharma however since the market size of genetic responders is obviously much smaller than market at large. Nevertheless, it seems inexorable change is underway.

Welcome to the 24th edition of Gene Genie!! During these grey winter doldrums, it is all too easy to hunker down and withdraw from the blogosphere into the minutiae of grant writing and lab management (brrr- I haven’t posted in weeks). So it is with true delight that I present and thank our contributors for brightening the season.

Firstly, a new paper by Mercer et al., in PNAS showing that presumed spurious transcriptional slop, does not appear to be as sloppy, spurious or incidental as predicted - and hence - may have possible functionality (in the brain at least) has sparked some interesting exchanges among our contributors. Genomicron gives some insightful critiques to the proposition that “God, as they say, don’t make no junk” in his article, Is most of the human genome functional ? After reading Greg Laden’s post, Genes are only part of story: ncRNA does stuff, I think there is good reason to put these neuronally expressed ncRNA’s to use and think harder on their possible functions. Skeptical biologist Larry Moran rightly cautions us in his Sandwalk blog to think clearly about the basic biochemical pathways of the Central Dogma before over-hyping a new paradigm of functionality of spurious transcripts. Junk or no junk - THE CENTRAL DOGMA STANDS !

Next, on to the core mission of Gene Genie - a few articles on personalized genetics and the continued unfolding of genetic functionality of individual genes such as SCH9, CNTNAP2, GDF5, ELA2 and others in healthcare.

In what will certainly be one of the most notable findings of 2008, Ouroboros covers the recent paper showing that mutations in the kinase SCH9, combined with intervention in the RAS and TOR genetic pathways can greatly extend the life cycle of budding yeast. Apparently, there is an important connection between genome stability and longevity and the, as yet undetermined, key regulators of stability in humans will be of tremendous interest to all of us.

The discovery of new genetic loci gives hope to parents of autistic children. As reported in Mapping new autism gene(s) to chromosome 16, a small region containing about 25 genes in the p11.2 region of chromosome 16 contains a risk factor that will shed light on the developmental origins of this disorder. Furthermore, as has long been observed, there are epigenetic phenomena related to the risk of autism as reported in Autism Vox of a recent study showing that maternal inheritance of CNTNAP2 confers greater risk than paternal inheritance. Such parent-of-origin effects can be tricky to pin down in mapping studies and trickier still to explain evolutionarily. In Sunday syndrome #5: The anarchist that wasn’t, cotch dot net provides some in-depth coverage of these epigenetic phenomena. The new genetics hasn’t quite pinned down the mechanisms of epigenetic regulation (there are ncRNAs involved as in the case of the h19 igf2 system) but personalized genetic services are well advised to offer assessments of epigenetic risk. A sobering account, as reported by DNA and You, of a different type of parent-of-origin effect - that donor sperm from the same individual transmitted a mutation in the ELA2 gene to 5 separate children, giving them a condition called severe congenital neutropenia - heightens one’s awareness of the potential of personalized medicine to screen for severe developmental risk factors. Apparently, insurance companies see the promise and are moving closer to valuation, payment and implementation strategies as reported on by DNA Direct Talk. Congratulations to the state of Wisconsin for their new offering of screening newborns for Severe Combined Immune Deficiency (SCID) as reported in ScienceRoll.

The GDF5 gene, as reported on by Genetics & Health is a regulator of long bone length (height) as well as common variants recently have been tied to susceptibility to osteoarthritis of the hip and knees in Asian and European populations.

Other large population genome association studies found “seven new genes that influence blood cholesterol levels, a major factor in heart disease, and confirmed 11 other genes previously thought to influence cholesterol”. Gene Sherpas covers the possible role of such genes in the context of the recently flopped ENHANCE trial.

If you are interested in these and many other genetic variants and are considering shelling out the cash and diving into the new personalized genetic era in medicine, the Genetic Genealogist provides a great up-to-date summary of folks’ experience with the 23andMe service.

If you happen to be a male with hair (or at least a male with hair seeking a mate who wonders whats in store for said hair), you may wish to forgo the 23andMe expense and put your money down elsewhere as Eye on DNA reports that men can obtain an highly predictive genetic test for baldness. Whew, I’m glad my wife did not know about this test before we were married (and my genetic program subsequently ran its sad inexorable course). More amusing still, is the video on gene chip conspiracies posted by evolgen - amusing, that is, unless Illumina does actually take over the world.

Amidst the rise of personalized medicine, GrrlScientist covers a recent econo-genetic analysis of the pricing of “stud fees” in the high-stakes horse racing marketplace Nature versus Nurture: Are Champion RaceHorses Born Or Made? posted at Living the Scientific Life. The data show convincingly that pricing strictly based on one’s genetic heritage (and ignoring the role of training in performance) is invalid. As an aside, I couldn’t help but chuckle reminded of Eric Roberts in “The Pope of Greenwich Village” who bet it all on a horse whose paternal genome was acquired via - lets just say - handily creative - means. He and Micky Rourke could have used this paper ! Horse racing (and Eric Roberts’ great hair) aside, as personalized medicine continues apace, the basic science lesson should be well heeded amidst the many new personal genome rollouts. THE ENVIRONMENT IS JUST AS IMPORTANT AS THE GENOME !!

And lastly, this edition also received a number of thoughtful articles that highlight the far reaching impact the new genetics is having on the cultural and spiritual well-being of homo sapiens. Our human genome is an amazing historical document. Each gene tells a story of who we are and what we might become - thanks to our contributors for teaching us how to read it !

Mike Haubrich, FCD probes a deep and fundamental human struggle concerning religion and human origins in his review of a recent PLoS article and also of Richard Dawkins’ book in Ancestor Tales and Gene Loss Adaptation posted at Tangled Up in Blue Guy. A valuable resource in gaining perspective on this debate is reviewed by GrrlScientist in Science, Evolution, and Creationism — The Free Download.

Aardvarchaeology covers some of the more recent - albeit equally passionate - issues of genetic history and ethnic identity in his critique on the origins of Slavic people in his Genes and Peoples article. Clearly we all will be re-thinking our ethnic identities as each of us discovers our own genetic legacy. Thanks to Dr. Rundkvist for giving us a great example of how to do this.

Sudip Ghosh reminds us - it will be a sad day indeed when our evolutionary genetic heritage - in the form of “designer” genetic variants - are mere commodities for sale in A Step Closer to the Great “Gene” Sale? posted at GNIF Brain Blogger. Certainly, the value of the genome is worth more when it can enhances our humanity and dignitiy rather than as a monetized commodity. Thanks for this Sudip!

Alvaro Fernandez’s posts an interview in Learning & The Brain: Interview with Robert Sylwester at SharpBrains. As a parent of two very different little tykes (independent assortment is no joke!), I much enjoyed this post and concur that paying more attention to basic mechanisms of how children develop empathy and social-emotional awareness as an interaction between genes and environment leads to a more fulfilling experience for parent, educator and child alike.

Well, this issue was a welcome dose of interest during an otherwise bleak winter! I hope your new year is off to a good start. Please share your thoughts and insights with the next Gene Genie issues by posting here. If you’d like to host an edition, don’t hesitate to contact berci.mesko [at] gmail.com. Thanks to Ricardo Vidal for the Gene Genie logo!

*** Don your crampons and ascend to the summit with Gene Sherpas for the next edition of Gene Genie ***

All the very best, John