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Archive for the ‘NRG1’ Category

According to wikipedia, “Jean Philippe Arthur Dubuffet (July 31, 1901 – May 12, 1985) was one of the most famous French painters and sculptors of the second half of the 20th century.”  “He coined the term Art Brut (meaning “raw art,” often times referred to as ‘outsider art’) for art produced by non-professionals working outside aesthetic norms, such as art by psychiatric patients, prisoners, and children.”  From this interest, he amassed the Collection de l’Art Brut, a sizable collection of artwork, of which more than half, was painted by artists with schizophrenia.  One such painting that typifies this style is shown here, entitled, General view of the island Neveranger (1911) by Adolf Wolfe, a psychiatric patient.

Obviously, Wolfe was a gifted artist, despite whatever psychiatric diagnosis was suggested at the time.  Nevertheless, clinical psychiatrists might be quick to point out that such work reflects the presence of an underlying thought disorder (loss of abstraction ability, tangentiality, loose associations, derailment, thought blocking, overinclusive thinking, etc., etc.) – despite the undeniable aesthetic beauty in the work.  As an ardent fan of such art,  it made me wonder just how “well ordered” my own thoughts might be.  Given to being rather forgetful and distractable, I suspect my thinking process is just sufficiently well ordered to perform the routine tasks of day-to-day living, but perhaps not a whole lot more so.  Is this bad or good?  Who knows.

However, Krug et al., in their recent paper, “The effect of Neuregulin 1 on neural correlates of episodic memory encoding and retrieval” [doi:10.1016/j.neuroimage.2009.12.062] do note that the brains of unaffected relatives of persons with mental illness show subtle differences in various patterns of activation.  It seems that when individuals are using their brains to encode information for memory storage, unaffected relatives show greater activation in areas of the frontal cortex compared to unrelated subjects.  This so-called encoding process during episodic memory is very important for a healthy memory system and its dysfunction is correlated with thought disorders and other aspects of cognitive dysfunction.  Krug et al., proceed to explore this encoding process further and ask if a well-known schizophrenia risk variant (rs35753505 C vs. T) in the neuregulin-1 gene might underlie this phenomenon.  To do this, they asked 34 TT, 32 TC and 28 CC individuals to perform a memory (of faces) game whilst laying in an MRI scanner.

The team reports that there were indeed differences in brain activity during both the encoding (storage) and retrieval (recall) portions of the task – that were both correlated with genotype – and also in which the CC risk genotype was correlated with more (hyper-) activation.  Some of the brain areas that were hyperactivated during encoding and associated with CC genotype were the left middle frontal gyrus (BA 9), the bilateral fusiform gyrus and the left middle occipital gyrus (BA 19).  The left middle occipital gyrus showed gene associated-hyperactivation during recall.  So it seems, that healthy individuals can carry risk for mental illness and that their brains may actually function slightly differently.

As an ardent fan of Art Brut, I confess I hoped I would carry the CC genotype, but alas, my 23andme profile shows a boring TT genotype.  No wonder my artwork sucks.  More on NRG1 here.

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slow motion video
Image via Wikipedia

The neuregulin-1 (NRG1) gene is widely known as one of the most well-replicated genetic risk factors for schizophrenia.  Converging evidence shows that it is associated with schizophrenia at the gene expression and mouse model levels which are consistent with its molecular functions in neural development.   However, in several recent genome-wide association studies (GWAS), there appeared nary a blip of association at the 8p12 locus where NRG1 resides.  What gives?

While there are many possibilities for this phenomenon (some discussed here), the recent paper, “Support for NRG1 as a Susceptibility Factor for Schizophrenia in a Northern Swedish Isolated Population” by Maaike Alaerts and colleagues, suggest that the typical GWAS study may not adequately probe genetic variation at a fine enough scale – or, if you will, use a netting with sufficiently small holes.  By holes, I mean both the physical distance between genetic markers and the frequency with which they occur in populations.  While GWAS studies may use upwards of 500,000 markers – that’s a pretty fine scale net for a 3,000,000,000bp genome (about 6,000bp apart) – Alaerts and colleagues set forth with slightly finer-scale netting.  They focus on a 157kb region that is about 60kb upstream from the start of the NRG1 gene and construct a net consisting of 37 variants between the markers rs4268087 and rs17601950 (average spacing about 5kb).  They used the tagger program to select markers that account for all haplotypes whose frequency is higher than 1.5%.  Thus – even though there are still more than 500 possible snps in the region Alaerts and colleagues are exploring, they are using a slightly finer netting than a typical GWAS.

The results of their analysis (using GENEPOP) of 486 patients and 514 ethnically matched control participants from northern Sweden did reveal significant associations in an area slightly downstream (about 50kb closer to the start point of the NRG1 gene) than the location of the “previously often replicated variants”, suggesting that the region does confer some risk for schizophrenia, but, that diagnostic markers for such risk will be different for different populations.  More telling however are the very weak effects of the haplotypes that show significant association.  Those haplotypes with the most significance show meager differences in how often they are observed in patients vs. controls.  For example, one haplotype was observed in 5% of patients vs. 3% of controls. Others examples were, 11 vs. 9, 25 vs. 22 and 40% vs. 35% – revealing the very modest (krill sized) effects that single genetic variants can have in conferring risk toward mental illness.

However, there are potentially lots of krill in the genomic sea!

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Neuregulin 1Image via Wikipedia Nowadays, as many folks peer into the vast tangled thicket of their own genetic code, they, as I, assuredly wonder what it all means and how best to ascertain their health risks. One core theme that emerges from repeated forays into one’s own data is that many of us carry a scads of genetic risk for illness, but somehow, find ourselves living rather normal, healthy lives. How can this be ? A recent example of this entails a C/T snp (c) located in the 5′ flanking region of the neuregulin 1 gene which has been repeatedly associated with schizophrenia. Axel Krug and colleagues recently reported in their paper, “Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with differences in frontal brain activation in a working memory task in healthy individuals” that T/C variation at this snp is associated with activation of the frontal cortex in healthy individuals. Participants were asked to keep track of a series of events and respond to a particular event that happened “2 events ago” . These so-called n-back tasks are not easy for healthy folks, and demand a lot of mental focus – a neural process that depends heavily on circuits in the frontal cortex. Generally speaking, as the task becomes harder, more activity in the frontal cortex is needed to keep up. In this case, individuals with the TT genotype seemed to perform the task while using somewhat less activity in the frontal cortex, rather than the risk-bearing CC carriers. As someone who has tried and failed to succeed at these tasks many times before, I was sure I would be a CC, but the 23andMe data show me to be a non-risk carrying TT. Hmmm … maybe my frontal cortex is just underactive.

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