I think it's sort of. Well, welcome to the ground around today.
It's nice to see a good turnout in her term week, so it's supposed to introduce Dominic Furness and Burke.
Dominic, many of you know, is the only consultant,
plastic surgeon and associate professor graduating at Trinity College Cambridge and then moved to Christchurch, Oxford, studying clinical medicine.
Did DM research degree and in 2012 was awarded the Wellcome Trust Intermediate Fellowship, which was the first to a plastic surgeon.
His research interests were find out of the room to investigate the genetic and non-genetic causes of common hand surgery conditions,
and his interest is in hand surgery and the super microsurgery for the treatment of lymphedema.
So thank very much. This is. So it was the fourth century BCE when Aristotle called the hand the tool of tools.
And of course, we still use the hand to manipulate tools and create the environment around us.
Hands are use for opening doors, both literal and metaphorical.
And we use them increasingly on keyboards like this and more commonly like this.
And almost everyone in this room uses their hands to help heal people who are suffering from illness.
But of course, the hands have a symbolic role as well that can be used to swear an oath.
What's promised to tell the truth? Hand on heart that can be a sign of respect, but also salutes can be used for other purposes.
The right hands can produce moments of sporting genius, or they can help us cling on to life itself.
When applied by the correct brain, they can produce moments of musical genius.
And very intricate carvings and not only a hands use for painting, but they can actually be the subjects of great works of art themselves.
And when we look back to our ancestors, the earliest cave paintings, what do we find that they painted, they painted hands?
And of note here five out of the six hands are left hands,
which suggests that the artist here was right handed and we'll come back to that in a carers talk later.
That could be used to ask for more that can symbolise love and protection.
Hans can give blessings. They can say that things are OK and that things are not OK.
They can symbolise threats or try to placate be a symbol of peace of friendship, and they can be used to end wars.
Fans can show our appreciation for the enormous achievements of others, symbolise our hope for the future.
They might give us the thumbs up or sometimes the thumbs down.
That can be a symbol of victory and also of surrender. Rebellion, but we must always remember when we're imaging the hand to take two views.
And finally, the most remarkable thing that the hands can do is give sight to the blind.
So this reading of braille really relies upon the tremendous connexion that we have between the hand and the brain.
And the brain, of course, is the most complex and wonderful other organ in our body.
And when we look at the sensory homunculus, we can see how overrepresented the hand is compared to its physical size.
And then when we change to the motor homunculus, whereas other organs have shrunk away, the hand still retains its importance here.
A new imaging techniques such as this functional MRI image using tracks holography are showing us the
enormous number of intricate connexions within our brain that then lead down the spinal cord to our hand.
And again, we'll come back to this later in a carers talk. So when things go wrong, you need a hand surgeon.
And this is the kind of thing that we do on a daily basis. We treat trauma such as tendon injuries and fractures.
We sometimes treat tumours of the hand and then in the bottom panel that we commonly treat arthritis.
But I'm going to talk to you today about cheap trends, disease, which many of you will have heard me talk about before.
So this is a fibro proliferative disease of the Palmer fascia,
where excess collagen gets laid down and then contracts by my fibroblasts to form section contractures of the finger.
It's most commonly treated by surgery, as in this case here, where the Egyptians cords been removed.
This allows a finger to straighten surgeries often complicated by recurrence of the disease because it doesn't treat the biology of the condition.
Jeep turns disease is a typical complex genetic disease where multiple genetic factors are multiple,
non genetic factors come together in a single person to cause expression of the disease.
And the way that we study the genetics of such diseases is by a genome wide association study.
So we have about three billion base pairs in our genome,
and each of you differs from the person sitting next to you at about 10 million of those places.
And the vast majority of those variants are called single nucleotide polymorphisms or snips.
So here you can see the person on the left has an a at a particular place and the person on the right has a T.
So when we're thinking about complex disease,
we compare those snips at up to a million places and sometimes more than that across the entire genome in cases and controls.
And if we find that a particular variant is more common in cases than controls,
significantly more common than we can say that that snip and the area around that snake, we call that a locus is associated with a particular disease.
So it's important to say that it's not necessarily that variant that causes the disease because the variants are inherited in blocks together.
And so there may be hundreds of variants in that area, all of which are inherited together,
and you can't tell the difference between them genetically. So this is a marker of where there is some genetic predisposition to a particular disease.
Now, because we're doing a million tests, we can't use a normal P value of nought point nought five to declare statistical significance.
We have to correct that for multiple testing.
So that gives us a generalised threshold for declaring genome wide significance of five times 10 to the minus eight.
So in order to get the power to achieve those kind of P values, he needs thousands of cases and thousands of controls.
So we've done this for cheap trans disease, and last time I spoke to grind around a couple of years ago,
I reported some of the findings that we had from our second genome wide, our bigger genome wide association study, which is now published.
And we found 26 snips 26 loci regions of the genome that predispose to dupe turns disease.
And I'm just going to update you on some of the functional work that we've done on one of those snips,
which we think is going to be a good therapeutic target, not only in Duke trends, but potentially in other diseases.
And this is the snap.
It's on chromosome 14, and it's within a gene called MMP 14, also known as MT1 MMP or memory membrane bound type one matrix Martello protease.
It's the only snip out of those 26 that we found that actually causes a coding change with energy.
So the vast majority that we find are regulatory variants, and they change gene expression and gene regulate and regulation of gene expression,
whereas this one actually changes in amino acid in a protein, and that's pretty rare for genome wide association studies.
The other thing is that, as I said to these variants tend to be inherited in blocks,
and so there might be 20 or 40 or 100 or 200 different variants, which we can't tell which one of those is causative from using genetic means.
Interestingly, with this snip, it was a sole snip. So there were no other snips in that block that could look like they could be causative.
And it's very common. So if we look in the western European population, we find that almost 40 percent of people are heterozygous for this snap,
an almost seven percent of people are homozygous for it. So have we followed this up?
Well, it just so happens that in our department, in end dorms, we have probably the world's expert on empty one MP.
So life is all about happy coincidences. And this is one of those happy coincidences.
So I went to speak Tsuyoshi, and we've done some follow up work.
A lot of the work has been done in his lab. So a little bit more about MTV on MMP, as I said, it's a transmembrane protease.
The important function here to focus on is that it degrades extracellular matrix components, so particularly the fibular collisions.
It also works as a home, a timer, so it needs to time arise in order to be able to digest those loans and habits.
Proteolytic functions. It's important not only in trends, but in the multitude of other diseases.
So it's vital for cellular invasion, and if you culture tumour cells with cancer associated fibroblasts,
then they will invade through a matrix through college and matrix.
If you knock out A. one MMP in those cancer associated fibroblasts, they can no longer invade.
So it's really important for metastasis of cancer.
It's important in the invasion of cartilage in rheumatoid arthritis,
very inflammatory panis to invade through into the cartilage and degrade the cartilage.
And as I said, it's also vital in extracellular matrix homeostasis.
So in the MCU, on MMP knockout mice, they die at about 12 weeks of age and they have generalised musculoskeletal fibrosis.
So it's kind of it's it's a seesaw, really when we think about disease.
So if you have two little mouse, you want MMP function, then you're predisposed to fibrosis.
And if you have too much and you're unlucky enough to get cancer,
then it may well predispose you to having more invasion, more metastasis, etc. And that's an area that we're looking at.
So what about this variant?
So here, top left, you can see a structural model of the catalytic domain of M2 on MMP and where the zinc ion binds, that's the catalytic cleft.
That's where the the protease activity happens and the coloured area on the bottom right.
That's where our particular amino acid is.
So the aspartic acid to aspire gene substitution, you can see on the top right doesn't really give us a major structural change at all.
So we thought, I'm not quite sure what this is going to do to the catalytic activity of empty one MMP.
So we transfected some cos nine cells, which don't express them to you on MMP and then looked at the general catalytic function.
So this doesn't require a timer ization.
This is just gelatine degradation, and you can see that the wild type and mutant form degrade the gelatine in exactly the same way.
Not very promising. We then looked at the ability of the MT1 MMP to activate another Matrix metallic protease programme MP two MP to the active form.
And we did find a reduction in the mutant form of about 50 percent.
And with the heterozygous so the double transfected cells, it was about halfway between.
So quite interesting, but not so amazing.
But what we did find, which was really interesting,
was when we did the collagen degradation assay a big difference between wild type and recent forms.
So on the top left panel, the mock transfected cells don't degrade the college, and it's also the field remains dark.
The wild type cells when you express wild type MT1 MMP, they punch multiple holes in the collagen matrix.
And so the light comes through and you can see it's bright when we look at the mutant form.
You can see that it's hardly able to degrade the collagen at all, which is really interesting.
And the there's the heterozygous form, if you like the double transfected form.
Again, the amount of collagen degradation is severely reduced, and you can see that in graphical form on the right hand side.
So we wondered what happens in real patients. So these are just cells in the lab.
What about cells from patients?
So these are cells derived from trans patients who are operated on and we've grown their my fibreglass in the lab that group by genotype,
and you can see that this is a collagen degradation assay in exactly the same way as the previous slide.
The wild type that goes to great collagen normally,
but both the heterozygous and the homozygous mutant forms are down to about 13 percent of collagen degradation,
and it seems to be working in a dominant negative manner here.
So this fits with the dimerisation theory as well.
So that's roughly where we're at. We've done a few more things now.
What we're interested in next is looking at this relationship between cancer and fibrosis,
and we've approached several several groups who've done genetics studies of big genetic studies of various tumour types.
What we're really interested in is not does MT1 want MMP predispose you to getting cancer in the first place?
But if you got it? What does it do? What does this variant do to your chances of progression?
Your chances of lymph, vascular invasion, metastasis, etc.?
We're planning to perform a chemical library screening in collaboration with a pharma company looking for small molecules that can modify either
to the wild type form to to mimic what happens in the mutant form or to restore collagen journalistic activity to the mutant form itself.
And we're interested in what the structural basis of this is because, as I said,
it's not a big structural change, but it's having quite a big biochemical change.
And so we're collaborating with the Dunn School to look at criterium of that.
So that's where we're at. With just one of those variants we would like to do now is introduce a carer.
So I care why. Berg is DPhil student in my group.
He's an MRC clinical research fellow, and he's going to talk to you about more of the nerve and brain side of the title.
So I'm going to hand over the. I'm going to talk about carpal tunnel syndrome initially,
everyone in this room for me certainly knows the carpal tunnel syndrome is caused by compression
of the median as it enters the hand through an anatomical tunnel and left untreated,
it leads functional impairments in the hand. It affects between five to 10 percent of the population.
So it's a common disease, and it's by far and away the most common entrapment neuropathy.
Over 50000 carpal tunnel operations are performed in England every year, so it's an economically potent disease,
both to society and to the individual and to the health service as well.
What causes carpal tunnel syndrome?
Well, we know that there are associations with other diseases that make you more likely to get carpal tunnel syndrome,
such as diabetes, rheumatoid arthritis, hypothyroidism and gout.
We also know that pregnant women are more likely to get carpal tunnel syndrome, although this tends to be transient and the majority of cases,
and there are some weaker evidence for occupational risk factors such as performing repetitive tasks and the use of racing tools.
But that doesn't tell us why Person A will go on to develop carpal tunnel syndrome.
All things being equal risk Person B will not get carpal tunnel syndrome.
And that's because carpal tunnel syndrome is your typical complex disease with a significant genetic component.
It has a relatively high heritability of 46 percent, and about a third of patients report a family history.
Yet we know next to nothing about the genes that are important in the pathogenesis of carpal tunnel syndrome.
Before we started this research, we asked ourselves, How can your genes confer risk to carpal tunnel syndrome?
And we came up with two competing hypotheses. Either your genes,
also the environment through which the median nerve transits or your genes somehow render the median nerves more vulnerable to increase pressures.
So the aim of this research was to try and answer that question by discovering genes that predispose to carpal tunnel syndrome by performing a glass.
And for us, we use carpal tunnel patients in UK Biobank.
This is a prospective cohort study of about half a million individuals aged between 40 to 69 at the time of recruitment.
And all of these people have had whole genome genotyping undertaken, so we know that genotypes at about 800000 steps.
And we also have access to them medical records in the form of diagnostic codes.
And we have lots of other lifestyle data and also some imaging as well.
And the great thing about UK Biobank is that it's freely available to all researchers around the world,
so it's a profoundly powerful resource for performing this sort of genetic association study.
So we started off with about half a million UK Biobank individuals in about just under 100000
steps on the first and arguably most important step in a glass perform quality control.
And this is a form of curating your data by getting rid of the snips that are either not particularly informative or misleading,
and also getting rid of individuals whose DNA might be contaminated or mixed up, or people who are related to each other.
So after QC, we were left with just under 400000 individuals and just over half a million snips.
We then performed case ascertainment and we phenotype these patients and we decided who is a case or not,
depending on whether they had diagnostic codes for carpal tunnel syndrome. So we used ICD 10 codes, OPEC's codes, the carpal tunnel decompression.
And we looked at self-reported codes for carpal tunnel syndrome and for carpal tunnel surgery.
And this gave us about 12000 cases and about three hundred and ninety thousand controls going into the association study.
I'm going to quickly summarise our key findings. This is called a Manhattan plus, and this is how juicy results are presented.
It's called that because it resembles the Manhattan skyline on the y axis, you have the p value.
In the association study that Don talked about. And on the x axis, you have the chromosome and the genomic position.
The dotted red line represents the threshold for genome wide significance of five times 10 to the minus eight.
So we discovered 16 regions or loci across the genome that are significantly associated with carpal tunnel syndrome.
This is what the results looked like in tabular formats and the first column you have the chromosome where your top snip is located.
You've got the genomic position. You've got the name of the snip.
And as we were saying earlier, there are several steps to the locus, but we're focussing on the top snip as each locus.
Next, we have the odds ratio for developing carpal tunnel syndrome if you have the risk variant and then you have the P value dissociation.
So we run these summary statistics through various points somatic tools and they
tell us which genes are nearby and are likely to be related to these variants.
We discovered there were three genes in particular that we were drawn to initially.
I'm going to talk about this briefly.
We found variants within genes called Adam C17 and Adam Kasten, and both of these happened to be missense variants.
So these are these are genetic variants to lead to an amino acid substitution in your protein products.
So very rare to pick up in a once, and it's another gene called SCMP, one that we were interested in as well.
But we'll start with Adam, 'cause these are a family of proteolytic enzymes related to matrix metallic proteases.
They have a wide range of functions, but importantly, extracellular matrix maintenance, sanitation and migration, and that we picked up in Adam.
C17 causes an amino acid substitution in the protease domain and is predicted to be deleterious mutation since the RNC has 10.
This leads to an arginine to glutamine substitution directly adjacent to an important sites within the enzyme.
And this reduces the enzymes activation efficiency. So these are just zoomed in Manhattan plots, essentially, some of which is two earlier,
and you can see that there aren't many other snips in that region apart from those two steps we picked up.
So we're quite confident that we have actually found the causal variance in these two cases, which is very rare.
Yes, if you want. Codes for a protein called Sibilant three.
And this is a glycoprotein associated with basement membranes, elastic fibres and matrix components.
And it's been associated with various cancers, hernias and also varicose veins.
And the snip that we found is an intranet SCMP ones within the gene, but it's in a non-coding gene, but it's actually an enhancer region,
which means that this variance increases the likelihood of transcription factors binding to it and therefore initiating transcription.
And we certainly know that in skin, which isn't necessarily the tissue, were interested in print skin.
It's been shown that's having the risk. Variants of the people actually produce more of this protein products than the heterozygous.
The people who in turn produce more than the homozygous for the non-racialism, gallium carpenter carpal tunnel syndrome.
We form something called a gene based enrichment analysis, which is where you take all the genes that were implicated in you guys.
You see if they're overrepresented in particular biological pathways or gene ontologies.
And you can see here that there is a lot of enrichment for extracellular matrix related ontologies.
So we went back and looked at our genes and we found that, yes, there was an overabundance of extracellular matrix protein genes.
But where are these genes acting in the context of carpal tunnel syndrome? It's long been suspected that the substance of your connective tissues,
by which I mean the connective tissues around the median and around the flexor tendons
in the carpal tunnel are somehow involved in carpal tunnel syndrome pathogenesis.
And this shows an extended carpal tunnel decompression.
The blue arrow shows the median nerve, and you can nicely see how it becomes quite injects it and quite hyperemesis as it enters the carpal tunnel.
And below that you see one of the flexor tendons. Now flexor tendons are supposed to look like that's that's supposed to be white and shiny.
But in this particular carpal tunnel, patients is covered in an inflamed sign over him,
and this is something you often find when you open up carpal tunnel. So we wondered, are genes expressed in this tissue?
So I extracted RNA from 41 patients who were undergoing carpal tunnel decompression,
from whom tennis on medium was resected and run an RNA seq experiments and found that our three candidate genes are highly expressed in this tissue,
suggesting that they have a plausible biological role and seen as synovial.
Well, there are any practical applications of this in the near future. Well, this sort of thing.
And so here are some key statistics again. These are 16 snips, and this is the risk that increases your risk of developing carpal tunnel syndrome.
Now we all have either zero, one or two copies of each of these aliyu's,
so we can construct a genetic risk score by multiplying the number of risk deals an individual has by the natural logarithm of the odds ratio.
We do this across all 60 snips and some them to create a weighted genetic risk score within the UK Biobank cohorts.
Individuals with carpal tunnel syndrome had a mean genetic score of one point sixty two,
whereas controls had a genetic risk score of one point forty seven. We hypothesised that within those patients who had carpal tunnel syndrome,
those who've had surgery are genetically more predisposed to a more severe phenotype.
And consistent with this, we found that they operated carpal tunnel group had a significantly higher genetic risk score than the unaffiliated group.
Therefore, genetic risk or correlates with disease severity. Our next hypothesis was whether patients with carpal tunnel syndrome.
They have a higher genetic risk than those who have not needed a revision operation and have only had a single operation.
And although we found this was the case, we were underpowered to find statistical significance.
So we can't use this in clinic just yet because our genetic risk score is based on 16 snips.
But as we discover more and more sniffs, our genetic instruments will become stronger for detecting this.
And this is the sort of thing that can be used on an individual level for prognostication.
This was particularly interesting to us when we looked at our results,
we found this four of us snips were previously reported to be genetic determinants of human height.
So we wondered would we see a height difference between carpal tunnel cases and controls in UK Biobank?
And to our amazement, we found that there was a two centimetre difference in height.
The carpal tunnel patients have shorter than controls in both males and females.
And is this simply association or is this causation? And to untangle that relationship, we performed a Mendelian randomisation analysis,
which is a technique that is used to basically establish causation between a putative
risk factor and an outcome using genetic variants as a natural experiments.
And the important thing here is that the negative gradients of the course and the fact that this was highly statistically significant.
And we've demonstrated the highs is inversely causal in the aetiology of carpal tunnel syndrome,
and we calculated that each standard deviation increase in height is associated
with a point seventy six odds ratio for developing carpal tunnel syndrome.
We weren't the first to discover this association between heights and carpal tunnel syndrome,
although we've explained it for the first time, hopefully. But some other people have discovered that carpal tunnel patients are not only shorter,
but they also have shorter hands, wider palms and a greater risk ratio.
So they essentially have a slightly square or around a wrist.
And this actually fits very nicely with our findings because Heights is essentially a proxy for all skeletal growth.
So if you're shorter,
you're probably more likely to have this sort of risk configuration if you go back to the two genes that we talked about earlier.
There is an ardent 10 mutation. In fact, there are several that can cause autosomal recessive vile Nakasone syndrome.
This is characterised by short stature bracket athletes to short fingers and joint stiffness and a similar biomarker.
Sony like syndrome in advancing 70 mutations, which manifests with short stature and iron on these and carpal tunnel syndrome has
been reported in families with biomarker sahni syndrome and even the C children,
which is vanishingly rare in the general population.
So this nice little close closes the loop on the saga between heights, carpal tunnel syndrome and these two genes.
So going back to this slide with our two competing hypotheses how can you genes confer risk carpal tunnel syndrome?
The results this study certainly seem to favour this first hypothesis.
Thus aberrations in your extracellular matrix architecture, either within the carpal tunnel or within the nerve itself,
perhaps or simply being shorter and having altered wrists dimensions.
These seem to be the important genetic determinants of carpal tunnel syndrome.
So in summary, we have performed the status of a glass of carpal tunnel syndrome.
We discovered 16 susceptibility loci.
We identified some biologically plausible candidate genes and found that they are expressed in our tissue of interest, namely the Tino Sino-African.
We developed a genetic risk score that seems to correlate with disease severity,
and we have found this causal role of heights in carpal tunnel syndrome,
and we provided some novel insights into the biology of carpal tunnel syndrome.
And I'm going to finish by quickly talking about something almost completely
different in the career of a plastic surgeon and indeed a plastic surgery trainee.
The question we most commonly ask patients is probably this all you left to right handed.
We can one further and we ask, why are you left right handed?
Because handedness is interesting across all cultures, about 90 percent of humans are right-handed,
and this has been the case since at least the Palaeolithic period.
As we know from cave paintings and looking at tools, the scheme and the distribution of handedness is a uniquely human trait.
And the question of handedness has been culturally loaded for a very long time.
This historically had negative connotations.
It's been associated with evil and malady, so words like sinister and gauche candidate all refer to left handedness.
On the other hand, left handedness is also associated with creativity and genius in popular culture.
So it's certainly something that we've been interested in for a long time. So what do we know about the genetics of handedness?
Well, very little considering it's been debated considerably in many academic spheres for well over a century.
We know from twin studies that there is a heritable component to this. The estimates of 25 percent.
And that's quite a modest heritability us. Perhaps why?
Despite several previous goals, no one has found any genome wide significant associations with handedness in the general population.
So we wondered, can we harness the size and power of UK Biobank to find associations within UK Biobank?
We had about 350000 right handers, about 40000 left handers and about 6000 ambidextrous people, and energy was of right handers versus left handers.
We left out the ambidextrous people to try and capture the two extremes the phenotype,
and we were delighted to discover three genome wide association signals.
We then went on to do a right handers versus non-white Hamdi's G.
So we lumped the ambidextrous participants with the the left handers, and we picked up this extra hit here on chromosome six.
And when we scrutinised these genomic regions for these hits were something very interesting became apparent.
That is this three out of four of our loci, we found genes related to microtubules.
This included top, which codes for beta tubulin map two,
which codes the microtubule associated protein to unmapped map to see which codes for the total protein,
which is fairly well known to be important in the pathogenesis of Alzheimer's disease and
Parkinson's disease and microtubule proteins are very important in neuronal physiology,
their importance in morphology, migration, axonal transport and morphogenesis.
So it's entirely plausible that they should have effective phenotypes such as.
This so we wondered that the disproportionate numbers of these microtubule genes that came up, was that merely a coincidence?
So to try and establish whether that was the case or not, we performed a permutation analysis.
So we looked at all 348 genes in a gene ontology called microtubule and skeletal organisation.
We selected 150000 snips evenly spread across the entire genome, and we randomly permitted them into groups of four.
And we counted how many times a three out of four of these groups of four would be in relatively close proximity to microtubule gene.
We found that this happened in two hundred and ninety nine out of 10000 permutations,
which tells us that there was an empirical probability of three percent of this occurring by chance alone.
We then performed the snip based enrichment study, which is when we took all the snips,
and Augustus showed some degree of association with handedness and correlated them with other genes phenotypes.
And we found that nine out of 10 enrichments were for neurodegenerative phenotypes.
You can see Parkinson's disease right at the top there,
but then wondered whether there was any shared genetic architecture between handedness and these diseases.
So we performed something called Elzie School Regression,
which is basically we were comparing GWAS results with previously published G one summary statistics and looking for areas of overlap in the genome.
And we found significant correlations with Parkinson's disease and schizophrenia,
and interesting sets of schizophrenics are well known to be much more likely to be left handed.
So now that we correlated handedness, Gina Typekit,
the next thing we wanted to know was whether genotype at the handedness snakes could in some way affect your brain structure or function.
So we teamed up with a team of brain imaging experts theme repair in Oxford to try and establish this relationship.
And again, we used UK Biobank because the UK Biobank has detailed brain imaging for about 10000 participants,
and our colleagues have derived the very sort of clever computational pipeline to take the raw imaging data and produce imaging to phenotypes.
And these are distinct individual measures of brain structure and function.
So this might be that the volume of particular brain areas where it might be the connectivity between two areas in the brain.
So when we correlate, it's the genotype.
At our fourth snips with brain imaging, we found that for the snip that was near the total protein gene and mapped gene on chromosome 17,
there were many significant associations and these were particularly in white
matter tracks such as the acute physical and the superior longitudinal cyclase.
And these are tracks that connect language related regions in the brain, such as Broca's area and the plain and temporally and vulnificus area.
So on this on this picture here, the blue represents the these language related tracts and the orange and green are the other grey
matter areas related to language function and can see that they're being connected by the blue tracts.
The next logical thing to do was try and close this triangle by correlating handedness with brain imaging, regardless of genotype.
And here we found that left handers have increased functional connectivity between the right and left.
Functional language networks and functional connectivity in this context refers to the
temporal relation between two corresponding areas lighting up in the two hemispheres.
And interestingly, can these language related tracks, such as the Acute for Cyclase,
have been associated with schizophrenia and auditory hallucinations?
So in conclusion, this is the first ever us to discover genome wide associations with handedness.
And I'm going to caveat that by saying we have not discovered genes that definitely makes you left handed.
We discovered a modest number of associations full of relatively small effect size.
So this whole gene environment paradigm, the environmental factors are still predominant,
saying that we did discover some interesting microtubule related genes and these genes have
biological plausibility in contributing to differences in connectivity between language areas,
which in turn might predispose to left handedness and certain neurodegenerative and psychiatric disorders.
Thank you very much for attention.