Tag Archives: Genetics

Divorce is More Genetic than Environmental

That the children of divorced parents are more likely themselves to get divorced than the children of parents who stayed together, is not in doubt. The relative risk, however, varies widely, ranging from approximately 1.25 to over 3.

However, no study finds no association. The question is the cause – genes versus environment. This is always a tricky issue because genes act through the environment. Nevertheless, components of the variance in the overall effect can be teased apart, recognising that the relative contributions might themselves be ephemeral quantities. A Swedish linkage study of national registries shines light on this topic.[1] These Swedish registers are vast – big data personified. A recent study examined 8,500 adopted siblings and 53,000 biological siblings. The adoptees resembled the biological siblings, not those of their birth family, in their propensity to get divorced. The authors also found that the risk of divorce in an adopted person was more closely related to the divorce rate of their biological parents rather than to the divorce rate of their adoptive parents.

Of course, all sorts of biases can creep into a study like this. For example, homes are carefully screened before adoption is permitted. Nevertheless, taken in the round, these results do suggest a strong genetic component to divorce. I suspect that the genetic alleles responsible will be unmasked in due course.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Salvatore JE, Larsson Lönn S, Sundquist J, Sundquist K, Kendler KS. Genetics, the Rearing Environment, and the Intergenerational Transmission of Divorce: A Swedish National Adoption Study. Psychol Sci. 2018; 29(3): 370-8.
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Vaccine in Pill Form

Storage of vaccines is an issue faced in a number of low- and middle-income countries due to the need for constant refrigeration. Some sites may have intermittent power or outages, they may simply not have the storage space for the necessary number of vaccines, or there may be difficulty in maintaining a cold temperature during transportation. A recent proof-of-concept study by Miles, et al.[1] may offer hope in the future though. The team based at Cardiff University produced a prototype oral polypeptide vaccine that was able to provide protection against the ‘flu in a mouse model. Previous polypeptide vaccines had poor stability, which hindered transport and thus therapeutic potential. For this vaccine the researchers created highly stable antigenic ‘mimics’ that did not exist in nature. It was stable in both human serum and gastric acid, was able to stimulate and prime an immune response specific to human ‘flu that was as effective as the standard biological equivalent, and remained immunogenic after being administered orally. Although there is still quite a way to go, it is worth keeping an eye on development of these encouraging findings.

— Peter Chilton, Research Fellow

Reference:

  1. Miles JM, Tan MP, Dolton G, et al. Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry. J Clin Invest. 2018.

On the Origins of Sickle Cell Anaemia

Nearly every biology and medicine student will have learnt about the link between sickle cell anaemia (SCA) and protection from malaria. If a person inherits two faulty alleles of the haemoglobin gene then their red blood cells will be sickle shaped, which can result in pain, anaemia, swelling, infections and stroke. If they inherit only one faulty allele then the other, non-mutated allele, will ensure they are unlikely to have any symptoms of SCA – they will only be a carrier. If a SCA carrier is infected with the malaria parasite it is unable to reproduce in their red blood cells and so the person is less likely to develop malaria, or will suffer less severe symptoms.

Authors of a recent paper [1] in the American Journal of Human Genetics have traced the origin of the sickle allele through the use of whole-genome-sequence data from around 3,000 people. There are five main haplotypes of the sickle allele that cause varying severity of SCA, but it is unknown if these were caused by relatively recent independent occurrences of the same mutation, or a single mutation a longer time ago, from which they all originated. It turned out that there was a single mutation, which occurred 259 generations ago, or roughly 7,300 years ago, most likely in either the Sahara or west-central Africa. From this it spread to other areas in Africa, probably due to the protection it afforded against malaria, and then beyond. It is hoped that this finding will allow better medical care to be provided, and to predict the severity of a patient’s SCA.

— Peter Chilton, Research Fellow

Reference:

  1. Shriner D & Rotimi CN. Whole-Genome-Sequence-Based Haplotypes Reveal Single Origin of the Sickle Allele during the Holocene Wet Phase. AJHG. 2018.

A Very Interesting Paper Using Mendelian Randomisation to Determine the Effect of Extra Years of Education on Heart Disease

It turns out that there are a number of genes, all associated with aspects of neurodevelopment, that predict how many years a person will spend in formal education.[1] It is already very well established that more years of education are associated with large reductions in coronary heart disease (CHD) (mediated by behaviour such as lower calorie intake, less smoking, more exercise).[2] So the authors of a recent well-written and most interesting BMJ paper did the obvious thing.[3] [4] They related the (random) presence or absence of educational propensity genes to CHD. Bingo, they measured a large effect (the genes that predispose to larger durations of formal education associate with reduced CHD). Now, the thing with Mendelian randomisation is that the genotype must not be linked to the outcome (CHD in this case), other than through the putative explanatory variable (duration of education in this case). The authors are aware that it is quite possible that education genes are linked to the outcome (CHD), net of (any) effect on education. To deal with this possibility they perform sensitivity analyses. They examine the association of genetic variates associated with education and the behaviours that lead to CHD. If the effects on education and on CHD behaviours are similar across the genetic variates this suggests that the effect on CHD is through education and not through another variable. And so it was. They also looked to see whether genetic variants already known to be associated with CHD (genes for high cholesterol, etc.) were also associated with education. If the genes associated with education do not associate with these other risk factors, then that favours a cause and effect explanation. There was no association. However, such an association would only be expected if there was a ‘massive’ effect of ‘education genes’ that bypassed education.

This all falls short of proof. Since the educational genes lead to education through mental processes, it is reasonable to suppose that almost all genetic variates that affect education also affect behaviour. Thus, they would affect CHD, even if there was no extra education. The authors say that their conclusion is strongly supported by identical twin studies where one twin stayed longer in education than the other, but this too ignores the fact that these twins are different, for all that their inherited genotype is the same, and so these differences could be the cause of both increased education and decrease in the behaviours that lead to heart disease.

One more point ­– even if years of education really are causative, this might well apply only to people genetically predisposed to more education and may not apply among those not so predisposed – there may be an interaction between the genes that predisposes to education and response to that education. After all, why would one persist in the classroom if you were not predisposed to benefit from the experience? People not predisposed would find being coerced to do so most unpalatable, and such an approach could even have a perverse effect. This is an excellent article and is beautifully presented. But I am a little more sceptical than the authors. I would like to see a debate on the issues.

— Richard Lilford, CLAHRC WM Director

References:

  1. Okbay A, Beauchamp JP, Fontana MA, et al. Genome-wide association study identifies 74 loci associated with educational attainment. Nature. 2016; 533(7604): 539–42.
  2. Veronesi G, Ferrario MM, Kuulasmaa K, et al. Educational class inequalities in the incidence of coronary heart disease in EuropeHeart. 201635895865.
  3. Tillmann T, Vaucher J, Okbay A, et al. Education and coronary heart disease: Mendelian randomisation study. BMJ. 2017; 358: j3542.
  4. Richards JB & Evans DM. Back to School to Protect Against Coronary Heart Disease? BMJ. 2017; 358: j3849.

Three Hits Hypothesis

Quite a lot of diseases are brought about by the conflation of two factors. Mice infected with certain herpes viruses suffer no ill-effect unless a helminth infestation supervenes. Oral allergy syndrome arises when a certain pollen interacts with certain foods (usually raw fruits, vegetables and nuts). The hygiene hypothesis says that lack of exposure to certain gut bacteria sensitises the body to allergic reactions to a range of environmental allergens. The pathway for disease involves three hits:

Genetically predisposed person –> Exposure 1 –> Exposure 2 –> Disease.

An intriguing example of a three-hit condition is the severe disease of children – Burkitt’s lymphoma. This cancer arises in germinal centres of lymph nodes in the neck. It is known that Epstein-Barr (EB) virus infection is necessary for endemic Burkitt’s lymphoma to develop because it prevents apoptosis (cell death) when certain mutations occur in the cell. But endemic Burkitt’s lymphoma only occurs in the malaria belt, and why this is so has been a mystery until the last few years. Now we know that the malaria parasite Plasmodium falciparum ‘upregulates’ an enzyme that causes mutations in DNA in lymph cells. These mutations are a normal part of antibody production since rearrangements of chromosome segments is necessary for antibody specificity. But in people with falciparum malaria, the effect ‘spills over’ to cause mutations of cancer genes. The double hit of EB plus malaria sets the scene for carcinogenesis.[1] Why in the neck – perhaps because lymph cells in the necks of children work particularly hard eradicating throat and ear infections, in which case there is a ‘four hits’ hypothesis!

— Richard Lilford, CLAHRC WM Director

References:

  1. Thorley-Lawson D, Deitsch KW, Duca KA, Torgbor C. The Link between Plasmodium falciparum Malaria and Endemic Burkitt’s Lymphoma—New Insight into a 50-Year-Old Enigma. PLoS Pathog. 2016; 12(1): e1005331.

Can Thinking Make It So?

When we think of risk factors for mortality we properly think behaviours (e.g. smoking / obesity) or genetics (e.g. family history). What about psychological factors – can unhappiness increase your risk of risk of cancer? Well, Batty and colleagues [1] have tackled this problem as follows:

  1. They assembled 16 prospective cohort studies where behaviours and psychological state had been measured and in which participants were followed up to see if cancer developed.
  2. They obtained the raw data and obtained an individual patient meta-analysis.
  3. They adjusted for the usual things known to increase risk of cancer (obesity, smoking, etc).
  4. They calculated relative risk of cancer according to antecedent psychological state.

They found a positive correlation between psychological distress and risk of cancer. But causality might have run the other way – (occult) cancers may have been the cause of psychological distress, not the other way round. So:

  1. They ‘left censored’ the data, thereby widening the gap between the point in time where the psychological state was measured and the point where cancer supervened.

The association between psychological state and cancer death persisted, even when they were separated by many years. What is the explanation?

  1. Failure to fully control for all behaviours (although behaviour could be the mechanism through which the cancer risk is increased in people with depression, in which case they ‘over-controlled’).
  2. Reduced natural killer cell function.
  3. Increased steroid levels, which can apparently affect DNA repair in some way.
  4. Some mechanism yet to be discovered.

In any event, the findings are intriguing, for all that practical implications may be limited.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Batty GD, Russ TC, Stamatakis E, Kivimäki M. Psychological distress in relation to site specific cancer mortality: pooling of unpublished data from 16 prospective cohort studies. BMJ. 2017; 356: j108.

Genetic Testing for Common Non-Communicable Diseases

News Blog readers will know that I am no fan of genetic testing for common conditions, such as asthma or diabetes (see previous post). My argument gains support from recent literature summarised in an editorial in the Annals of Internal Medicine.[1] An obese person with the lowest genetic risk is five times more likely to develop diabetes than a normal weight person with the highest genetic risk, for example. Moreover (and as pointed out in a previous blog), knowledge of genetic risk is ineffective in promoting behaviour change. Private screening not only externalises costs (such as counselling and treating) to the health service, but also results in less satisfied customers whose expectations have been raised to levels that are hard to meet. The libertarian CLAHRC WM Director would not ban direct-to-consumer testing, but would seek to regulate it in the same way as cigarette advertising is regulated. Of course, the threshold where providing information topples over into hype is a tricky one for a regulator to define.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Burke W & Trinidad SB. The Deceptive Appeal of Direct-to-Consumer Genetics. Ann Intern Med. 2016; 164: 564-5.

Service Implications of Personalised Medicine

Personalised medicine is a slightly slippery term, since medicine can be bespoke with respect to a patient’s biological features (affecting probabilities of outcomes) or a patient’s psychology (affecting preferences / values / utilities). Ideally, medicine should, as much as possible, be tailored to both. But in this short blog we will concentrate on medicine that is personalised on the basis of biology (precision medicine, if you like). We select this focus because it is becoming increasingly possible to focus treatment according to different, often genetic, test results. Previously treatment was determined by the clinical diagnosis formed on the basis of clinical and standard tests, such as the ECG, image or biochemistry. However, a much finer level of granularity is increasingly available as a result of genetic testing. This type of precision medicine is increasingly important for cancer where interest has focussed on somatic (acquired), as well as germ-line (inherited), genetic variation. Treatment is no longer based purely on tissue of origin and histological appearance, but on the genetic mutations that are part and parcel of the carcinogenic process and that strongly influence responses to treatment. Treatment is also influenced by genetic factors affecting non-cancer diseases, but in this case it will be inherited, rather than acquired, genetic variations that are salient. Lastly, inherited genetic variations may provide advance warning that certain patients can, or cannot, tolerate certain treatments – pharmacogenetics.

Since CLAHRCs are concerned with how the service must adapt to improve access to safe and effective care, precision medicine is a topic of relevance to CLAHRCs, and a point of contact between service delivery and biomedical researchers.

But what are the service change requirements of precision medicine? Well, many new targetted therapies have no real service implications since they simply involve substitution of one medicine for another. The service implications are nugatory in a health service that already has well developed and smoothly functioning supply chains that can ensure availability of the relevant drugs. However, precision medicine is not always so straightforward, so here are some scenario types where the service may need to be adapted to a degree.

First, genetic diagnosis has an important collateral effect that arises when the laboratory findings have implication for the individual that lie outside the presenting feature. For instance, a genetic test in a patient with breast cancer may show that she has a high risk of cancer of the ovary. Preparing for such a scenario has human resource and educational implications. These might be somewhat modest, but more radical implications arise when a finding in one person may impact other family members who are often scattered across the world. This raises logistical issues in arranging for people to be contacted, counselled and tested. The workload and hence human resource implications are considerable. Currently, a project called the “100,000 genomes project,” is unfolding in England. Genetic samples are being taken from patients with numerous diseases. This is the basis for a tractable research project to model the service implications of enhanced genetic testing. CLAHRC WM collaborators at the Health Services Management Centre, University of Birmingham are investigating this issue with support from the regional West Midlands Academic Health Science Network (WM AHSN). Clearly, the ‘new genetics’ is going to have quite large service implications and we should prepare for it in advance.

Second, patients may obtain testing privately and then present to publically funded services with the results. The service needs to ensure that it has the capacity to respond, at the very least, by ensuring that accurate counselling is available. Continued professional development will be needed to ensure that staff are up to date. The resource implications may be mitigated by making information available online or even establishing online question and answer facilities. Informal testing also has implications for regulatory oversight of providers of genetic testing to ensure high-quality and prevent testing for attributes that society deems it inappropriate to test for.

Third, there are implications for health economic evaluation and the cost-effectiveness of targeted therapies. However, the principle behind precision medicine is that the effect of therapy will be greater when therapy is targeted. That means that companies should be able to charge more for their medicines per patient to recoup costs. However, the general improvement in effectiveness will have disequilibrium effects, meaning that, ceterus parabus, the willingness-to-pay threshold for a QALY will have to deflate. Precision medicine does, of course, have implications for the private insurance industry since they will be on guard to ensure that they are not exposed to moral hazard when people have covert testing and only declare this if their risk is low.

Taken in the round, however, precision medicine would seem to have real, but fairly, modest service delivery implications. But we do need to plan carefully by evaluating the human resource and educational implications of dealing with collateral effects and making sure that necessary testing capacity is scaled to predicted demand.

There is another kind of precision medicine with more radical service implications, and this is the genotypic approach to characterising microbes. This has large implications for two reasons. First, existing microbial typing laboratory procedures will become obsolete (or demand for them will be greatly reduced), with implications for retraining and possible redundancy. Second, testing may well move from the lab back into the ward with large implications for education of the clinical workforce.

Although precision medicine may have rather modest implications for service delivery, there are other lab discoveries with much greater implications. For example, cell therapy has large implications for service delivery, quality control, and methods for up-scaling, and new treatments come along, some of which change pathways completely, such as intracranial thrombectomy for stroke, as discussed in a previous blog.[1]

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford R. Provocative Idea for Thrombectomy Services in Acute Stroke. NIHR CLAHRC West Midlands News Blog. 14 August 2015.

Why Do You Want to Know About Genetic Risks of Disease When the Relative Risk Difference is Moderate?

If you smoke, you increase the risks of certain multi-factorial diseases five- to ten-fold. But various genetic variations carry much smaller risks for these diseases thanks to evolutionary pressures. So why would a person want to know their genetic risk? Smokers should quit even if their genetic risk is low. And non-smokers should continue to abstain, even if their genetic risk is low. Consistent with this observation, a recent BMJ article shows that knowledge of one’s genetic risk does not influence a person’s behaviour.[1] The point in continuing research into genetic associations is to unravel pathophysiological mechanisms on the assumption that this knowledge will translate into better treatments for established diseases. Precision medicine, it seems, does not entail precision preventive medicine.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Hollands GJ, French DP, Griffin SJ, et al. The impact of communicating genetic risks of disease on risk-reducing health behaviour: systematic review with meta-analysis. BMJ. 2016; 352: i1102.

Psychiatry Comes of Age

In a recent post the CLAHRC WM Director opined that psychiatry was taking its first reductive steps – we are starting to understand the neurochemical mechanisms behind diseases that appear in the mind. Well our toddler has started to run and the new era has been ushered in with a brilliant recent publication in Nature.[1] The story starts, as it increasingly does in modern science, with a large collaborative effort – in this case the international Psychiatric Genomics Consortium, which carries out genetic association studies. Their Biobank harbours 39,000 cases of schizophrenia and 45,000 controls. There are many genetic polymorphisms across the genome that are associated with schizophrenia – about 100 in fact, as mentioned in a previous post. But one constellation of polymorphisms stands out in terms of the strength of its association with schizophrenia. This constellation resides in the HLA gene cluster. Genes in this cluster encode proteins that help the immune system identify foreign antigens, such as those found on the cell surface of microbes or transplanted tissue. Polymorphisms in the HLA cluster are associated with autoimmune disease, meaning that the immune system has mistakenly identified an antigen on a normal host cell for attack. Does this mean that schizophrenia might be an autoimmune disease? Well, sometimes perhaps (see below), but there is another mechanism by which HLA variants may predispose to this devastating disease. It turns out that the part of the HLA complex most closely associated with schizophrenia is the gene responsible for one of the complement proteins known as complement component 4. And this molecule is not just active in eliminating pathogens and cellular debris – it also affects nerve cells by directly accelerating the pruning of synapses. Synaptic pruning is a normal part of adolescent brain remoulding, but excessive pruning, associated with over-active complement 4, features as part of the pathogenesis in many cases of schizophrenia.[1] Enter NIHR CLAHRC East of England Director Peter Jones. Jones hypothesises that around 10% of cases of acute onset schizophrenia result from an acute autoimmune brain syndrome. He is testing this hypothesis by means of a RCT involving immunosuppression. Presumably it is no co-incidence that some cases of schizophrenia result from a form of autoimmune disease, and that genes in the HLA constellation are so frequently associated with schizophrenia. If so, much of the damage may have been done when the acute brain syndrome appears – we may need to look for an earlier, more tightly targeted therapy, and we suspect that preventing complement-mediated damage will play a role. Incidentally, this is a further example of massive scientific achievement emanating from an international collaborative effort, rather than the genius of just one individual. The future prominent scientist will increasingly be the one with the social skills to engineer a prominent place for herself on the committees that shape protocols and scientific papers, such as the Global Burden of Disease project discussed in a recent post.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; 530: 177-83.