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So, what happens if I publish my genome sequence online … does anyone else get a benefit? or incur a cost?  My children?  My siblings?  What if I were an identical twin?

Do twins favor being more similar? … in which case, maybe, they might see positive externalities?

Are the epigenomes of identical twins similar?

How does your genome influence your economic behavior?

just a pointer to a great SciVee episode – Genetic Contribution To Variation In Cognitive Function In Twins

Their data suggest that genetic influences on cognitive function act outside of the brain areas most commonly activated during cognitive tasks.  The areas where genes seem to exert influence on brain activity are quite variable from person to person (which is why they don’t show up in group-level analyses).  Thus folks with different genetic variability use slightly different brain areas to accomplish the same cognitive task.

It sounds simple on paper – just collect lots of folks with disorder X and look at their genomes in reference to a demographically matched healthy control population.  Voila! whatever is different is a candidate for genetic risk.  Apparently, not so.

The missing heritability problem that clouds the birth of the personal genomes era refers to the baffling inability to find enough common genetic variants that can account for the genetic risk of an illness or disorder.

There are any number of reasons for this … (i) even as any given MZ and DZ twin pair shares genetic variants that predispose them toward the similar brains and mental states, it may be the case that different MZ and DZ pairs have different types of rare genetic variation thus diluting out any similar patterns of variation when large pools of cases and controls are compared …  (ii) also, the way that the environment interacts with common risk-promoting genetic variation may be quite different from person to person – making it hard to find variation that is similarly risk-promoting in large pools of cases and controls … and many others I’m sure.

One research group recently asked whether the type of common genetic variation(SNP vs. CNV) might inform the search for the missing heritability.  The authors of the recent paper, “Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls” [doi:10.1038/nature08979] looked at an alternative to the usual SNP markers – so called common copy number variants (CNVs) – and asked if these markers might provide a stronger accounting for genetic risk.  While a number of previous papers in the mental health field have indeed shown associations with CNVs, this massive study (some 3,432 CNV probes in 2000 or so cases and 3000 controls) did not reveal an association with bipolar disorder.  Furthermore, the team reports that common CNV variants are already in fairly strong linkage disequilibrium with common SNPs and so perhaps may not have reached any farther into the abyss of rare genetic variation than previous GWAS studies.

Disappointing perhaps, but a big step forward nonetheless!  What will the personal genomes era look like if we all have different forms of rare genetic variation?

Humans are spiritual creatures – there’s no denyin’.  How & why we got this way is one of THE BIG questions of all time.  Since our genome shapes the development of our brain and its interaction with our culture, its not a surprise to see that, from time to time, folks will look for and find genetic links to various forms of spiritual and religious behavior.  Here’s a recent paper from Kenneth Kendler’s research team at the Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine entitled, “A Developmental Twin Study of Church Attendance and Alcohol and Nicotine Consumption: A Model for Analyzing the Changing Impact of Genes and Environment” [link to abstract].  An analysis of more than 700 pairs of twins found that the correlation between alcohol and nicotine consumption and church attendance (more church predicts less smokin’ and drinkin’) is more than 50% influenced by genetic factors – in adults.  In children and teens, the genetic contribution to the correlation is much less and the strength of the correlation stems more from shared environmental factors (parents, school etc.).  Is there a gene for going to church? Nope.  Are there genes that shape a person’s inclination toward novelty or conscientiousness? More likely so.  Are they distributed across all races and cultures? Yep.  Lots to ponder next Sunday morning.

Just a pointer

One term, CHREOD, combines the Greek word for “determined” or “necessary” and the word for “pathway.” It describes a system that returns to a steady trajectory in contrast to homeostasis which describes a system which returns to a steady state.  Recent reviews on the development of brain structure have suggested that the “trajectory” (the actual term “chreod” hasn’t survived) as opposed to any specific time point is the essential phenotype to use for understanding how genes relate to psychological development.  Another term, CANALIZATION, refers to the ability of a population to produce the same phenotype regardless of variability in its environment or genotype.  A recent neonatal twin study found that the heritability of grey matter in neonatal humans was rather low.  However it seems to then rise until young adulthood – as genetic programs presumably kick-in – and then decline again.  Articles by neurobiologist Jay N. Giedd and colleagues have suggested that this may reflect Waddington’s idea of canalization.  The relative influence of genes vs. environment may change over time in ways that perhaps buffer against mutations and/or environmental insults to ensure the stability and robustness of functions and processes that are both appropriate for survival and necessary for future development.  Another Waddington term, EPIGENETIC LANDSCAPE, refers to the limitations on how much influence genes and environment can have on the development of a given cell or structure.  Certainly the environment can alter the differentiation, migration, connectivity, etc. of neurons by only so much.  Likewise, most genetic mutations have effects that are constrained or compensated for by the larger system as well.

Its amazing to me how well these evolutionary genetic concepts capture the issues at the nexus of of genetics and cognitive development.  From his lecture, it is clear that Waddington was not unaware of this.  Amazing to see a conceptual roadmap laid out so long ago.  Digging the book cover art as well!

Coping with fear and anxiety is difficult.  At times when one’s life, livelihood or loved one’s are threatened, we naturally hightenen our senses and allocate our emotional and physical resources for conflict.  At times, when all is well, and resources, relationships and relaxation time are plentiful, we should unwind and and enjoy the moment.  But most of us don’t.  Our prized cognitive abilities to remember, relive and ruminate on the bad stuff out there are just too well developed – and we suffer – some more than others  (see Robert Saplosky’s book “Why Zebras Don’t Get Ulcers” and related video lecture (hint – they don’t get ulcers because they don’t have the cognitive ability to ruminate on past events).  Such may be the flip side to our (homo sapiens) super-duper cognitive abilities.

Nevertheless, we try to understand our fears and axieties and understand their bio-social-psychological bases. A recent paper entitled, “A Genetically Informed Study of the Association Between Childhood Separation Anxiety, Sensitivity to CO2, Panic Disorder, and the Effect of Childhood Parental Loss” by Battaglia et al. [Arch Gen Psychiatry. 2009;66(1):64-71] brought to mind many of the complexities in beginning to understand the way in which some individuals come to suffer more emotional anguish than others.  The research team addressed a set of emotional difficulties that have been categorized by psychiatrists as “panic disorder” and involving sudden attacks of fear, sweating, racing heart, shortness of breath, etc. which can begin to occur in early adulthood.

Right off the bat, it seems that one of the difficulties in understanding such an emotional state(s) are the conventions (important for $$ billing purposes) used to describe the relationship between “healthy” and “illness” or “disorder”.  I mean, honestly, who hasn’t experienced what could be described as a mild panic disorder once or twice?  I have, but perhaps that doesn’t amount to a disorder.  A good read on the conflation of normal stress responses and disordered mental states is “Transforming Normality into Pathology: The DSM and the Outcomes of Stressful Social Arrangements” by Allan V. Horwitz.

Another difficulty in understanding how and why someone might experience such a condition has to do with the complexities of their childhood experience (not to mention genes). Child development and mental health are inextrictably related, yet, the relationship is hard to understand.  Certainly, the function of the adult brain is the product of countless developmental unfoldings that build upon one another, and certainly there is ample evidence that when healthy development is disrupted in a social or physical way, the consequences can be very unfortunate and long-lasting. Yet, our ability to make sense of how and why an individual is having mental and/or emotional difficulty is limited.  Its a complex, interactive and emergent set of processes.

What I liked about the Battaglia et al., article was the way in which they acknowledged all of these complexities and – using a multivariate twin study design – tried to objectively measure the effects of genes and environment (early and late) as well as candidate biological pathways (sensitivity to carbon dioxide).  The team gathered 346 twin pairs (equal mix of MZ and DZ) and assessed aspects of early and late emotional life as well as the sensitivity to the inhalation of 35% CO2 (kind of feels like suffocating and is known to activate fear circuitry perhaps via the ASC1a gene).   The basic notion was to parcel out the correlations between early emotional distress and adult emotional distress as well as with a very specific physiological response (fear illicited by breathing CO2).  If there were no correlation or covariation between early and late distress (or the physiological response) then perhaps these processes are not underlain by any common mechanism.

However, the team found that there was covariation between early life emotion (criteria for separation anxiety disorder) and adult emotion (panic disorder) as well as the physiological/fear response illicited by CO2.  Indeed there seems to be a common, or continuous, set of processes whose disruption early in development can manifest as emotional difficulty later in development.  Furthermore, the team suggests that the underlying unifying or core process is heavily regulated by a set of additive genetic factors.  Lastly, the team finds that the experience of parental loss in childhood increased (but not via an interaction with genetic variation) the strength of the covariation between early emotion, late emotion and CO2 reactivity.  The authors note several limitations and cautions to over-interpreting these data – which are from the largest such study of its kind to date.

For individuals who are tangled in persistent ruminations and emotional difficulties, I don’t know if these findings help.  They seem to bear out some of the cold, cruel logic of life and evolution – that our fear systems are great at keeping us alive when we’ve had adverse experience in childhood, but not necessarily happy.  On the other hand, the covariation is weak, so there is no such destiny in life, even when dealt unfortunate early experience AND genetic risk.  I hope that learning about the science might help folks cope with such cases of emotional distress.

I’m wondering how much physical and/or social stress is enough to cause changes in the epigenome?  Does the concern about epigenetics only apply to exposure to severe stress?  or run of the mill forms of stress?  How much do we know about this?

This year, I hope to explore this line of inquiry further.  For starters, I came across a fantastic paper by Fraga et al., entitled, “Epigenetic differences arise during the lifetime of monozygotic twins” [doi:10.1073/pnas.0500398102].   The group carries out a remarkably straightforward and time honored approach – a twin study – to ask how much identical twins differ at the epigenetic level.  Since identical twins have the same genome sequence, any differences in their physiology, behavior etc. are, strictly speaking, due to the way in which the environment (from the uterus to adulthood) shapes their development.  Hence, the team of Fraga et al., can compare the amount and location of methyl (CH3) and acetyl (OCCH3) groups to see whether the environment has differentially shaped the epigenome.

An analysis of some 40 identical twin pairs from ages 3-74 years old showed that – YES – the environment, over time, does seem to shape the epigenome (in this case of lymphocytes).  The most compelling evidence for me was seen in Figure 4 where the team used a method known as Restriction Landmark Genomic Scanning (RLGS) to compare patterns of methylation in a genome-wide manner.  Using this analysis, the team found that older twin pairs had about 2.5 times as many differences as did the epigenomes of the youngest twin pairs.  These methylation differences also correlated with gene expression differences (older pairs also had more gene expression differences) and they found that the individual who showed the lowest levels of methylation also had the highest levels of gene expression.  Furthermore, the team finds that twin pairs who lived apart and had more differences in life history were more likely to have epigenetic differences.  Finally, measures of histone acetylation seemed consistent with the gradient of epigenetic change over time and life-history distance.

Thus it seems that, as everyday life progresses, the epigenome changes too.  So, perhaps, one does not need extreme forms of stress to leave long-lasting epigenetic marks on the genome?  Is this true during early life (where the team did not see many differences between pairs)?  and in the brain (the team focused mainly on lymphocytes)?  Are the differences between twins due to the creation of new environmentally-mediated marks or the faulty passage of existing marks from dividing cell-to-cell over time?  Will be fun to seek out information on this.

Whether you are a carpenter, plumber, mechanic, electrician, surgeon or chef, your livelihood depends on a set of sturdy, reliable, well-honed, precision tools.  Similarly, neuroscientists depend on their electrodes, brain scanners, microscopes and more recently their genome sequencers.  This is because they are not just trying to dissect the brain – the physical organ – but also the psychological one.  As the billions of neurons connected by trillions of synapses process electrical impulses – a kind of neural information – it is the great endeavor of cognitive-molecular-neuro-psychology (or whatever you wish to call the art) to figure out how all of those neurons and connections come into being and how they process information in ways that lead to your personality, self-image, hopes, dreams, memories and the other wonderful aspects of your mental life.  How and why does information flow through the brain in the way it does? and how and why does it do so in different ways for different people? Some, for instance, have informally related Sigmund Freud‘s models of mental structure to a kind of plumbing wherein psychic energy was routed (or misrouted) through different structural aspects of the mind (pipes as it were).  Perhaps such a model was fitting for the great industrial era in which he lived – but perhaps not in today’s highly information-based, inter-connected and network-oriented era.  If our understanding of mental life is a product of our tools, then perhaps we should be sure that our modern tools are up to the job.

One recent paper reminded me of how important it is to double check the accuracy and precision of one’s tools was the research article, “Quantifying the heritability of task-related brain activation and performance during the N-back working memory task: A twin fMRI study” [doi:10.1016/j.biopsycho.2008.03.006] by Blokland et al..  In this report, the team summarizes the results of measurments of the brain activity – not structure – but rather activity as measured by their chosen tool, the MRI scanner.  This research team, based in UCLA and known as one of the best in the field, asks whether the so-called BOLD response (an indirect measure of neural activity) shows greater concordance in identical (monozygotic) vs. fraternal (dizygotic) twins.  To generate brain activity, the research team asked the subjects to perform a task called an N-back  workng memory task, which entails having to remember something that happend “N” times ago (click here for further explanation of N-back task or play it on your iphone).  If you’ve done this, you’ll know that its hard – maddeningly so – and it requires a lot of concentration, which, the researchers were counting on to generate activity in the prefrontal cortex.

After looking at the brain activity patterns of some 29 MZ pairs and 31 DZ pairs, the team asked if the patterns of brain activity in the lateral frontal cortex were more similar in the MZ pairs vs. the DZ pairs.  If so, then it would suggest that the scanning technology (measurement of the BOLD response) is sufficiently reliable and precise enough to detect the fraction of individual differences in brain activty that arise from additive genetic variation.  If one actually had such super-precise tool, then one could begin to dissect and tease apart aspects of human cognition that are regulated by individual genetic variation – a very super-precise and amazing tool – that might allow us to understand mental life in biologically-based terms (and not Freud’s plumbingesque analogies).  If only such a tool existed! Somewhat amazingly, the scanning tools did seem to be able to detect differences between the BOLD response correlations of MZ pairs vs. DZ pairs.  The BOLD response correlations were greater for MZ vs. DZ in the middle frontal gyrus, angular gyrus, supramarginal gyrus when activity for the 2-back task was compared to the 0-back task.  The team were cautious to extend these findings too far, since the standard deviations are large and the estimates of heritability for the BOLD response are rather low (11-36%), but, overall, the team suggests that the ability to use the fMRI methods in conjunction with genetic markers shows future promise.

Meanwhile, the literature of so-called “imaging-genetic” findings begins to grow in the literature.  I hope the tools are reliable and trustworthy enough to justify conclusions and lessons about human genetic variation and its role in mental life.  Will certainly keep this cautionary report in mind as I report on the cognitive genetics literature in the future.

Here the research team – members of the Biomedical Informatics research Network – have carried out the largest and most comprehensive known twin study of brain structure.  By performing structural brain imaging on 404 male twin pairs (important to note here that the field still awaits a comparable female study), the team examined the differences in identical (MZ) vs. fraternal (DZ) pair correlations of the structure of some 96 different brain regions.  The authors now provide an updated structural brain map showing what structures are more or less influenced by genes vs. environment. Some of the highlights from the paper are that genes accounted for about 70% of overall brain volume, while in the cortex, genes accounted for only about 45% of cortical thickness.  Much of the environmental effects were found to be non-shared, suggesting, as expected, that individual experience can have strong effects on brain structure.  The left and right putamen showed the highest additive genetic influence, while the cingulate and temporal cortices showed rather low additive genetic influences (below 50%).

If you would like to play around with a free brain structure visualization tool, check out Slicer 3D, which can be obtained from the BIRN homepage or directly here.  I had fun this morning digitally slicing and dicing grey matter from ventricles and blood vessels.