Better off not knowing? The self-fulfilling risks of genetic testing

Simply knowing you’re at increased genetic risk for an illness can precipitate symptoms of the disease, new research shows.

Researchers from Stanford University’s Department of Psychology ran DNA tests on around 100 adults for two genes associated with obesity – one related to exercise capacity (CREB1), and the other to appetite (FTO rs9939609).

Instead of giving the individuals their actual DNA test results, the researchers randomly told participants they had either “high-risk” or “protective” genotypes.*

In the first experiment, 116 participants were asked to run a treadmill test before and after receiving personalised genetic information on their aerobic exercise capacity.

After being told they had a “high risk” genotype, people exhibited worse cardiorespiratory fitness –poorer metabolic gas exchange (CO2:02) and lower maximum ventilator flow rate compared to baseline, the study found. They also ran a shorter distance before giving up, and also reported feeling more exerted and hotter.

By contrast, individuals who were told they had the protective genotype did not exhibit any significant changes in their treadmill performance compared with baseline.

In the second experiment, 107 participants were given a meal before and after receiving personalised results on the gene linked with appetite.

Those told they had a protective genotype experienced greater satiety at the second meal – measured by self-reported feelings of “fullness” as well as by post-consumption gut peptide physiology (GLP-1 response).

By contrast, participants assigned the “high-risk” genotype experienced no significant changes in post-consumption feelings of fullness or GLP-1 response compared with baseline.

Across both experiments, the size of the effects due to “perceived genetic risk” were sometimes greater than effect sizes associated with actual genetic risk.

A potent mindset

Writing in the journal Nature Human Behaviour this month, the authors warned: “If simply conveying genetic risk information can alter actual risk, clinicians and ethicists should wrestle with appropriate thresholds for when revealing genetic risks is warranted.”

“Receiving genetic risk information has the potential to instil a potent mindset,” they wrote. “Many studies show that providing people with a genetic causal explanation reduces perceived control compared with providing people with an environmental or lifestyle causal account for a range of conditions and situations, including mental illness, maths performance, and obesity.”

The study comes amid an explosion in genetic testing, with genetic risk estimates now available for over 10,000 conditions, according to the authors.

Although the aim of genetic testing may be to motivate patients toward risk-reducing behaviours, its efficacy is dubious. A recent meta-analysis of 18 studies found communicating the genetic risk of disease had no effect on recipients’ motivation to change behavior, or actual engagement in risk-reducing behavior.

Lifestyle and personality

Dr Sarah Edelman (PhD), a Sydney-based clinical psychologist and author of the book Change Your Thinking, said patients who underwent genetic testing needed to be informed that health outcomes were influenced by both genes and lifestyle.

“Whilst we can’t control our genes, we do have control over lifestyle choices,” she said. “When providing test results, genetic counsellors need to focus on the individual’s potential to influence health outcomes and to frame it in terms of how they can make a difference. For example, saying things like: ‘when people do regular exercise and follow [the prescribed] eating guidelines, they reduce their risk by 30%.’”

Personality also plays a role in how people responded to knowing their personal genetic risk, she said.

“For some people, knowing their genetic risk will be a motivator; for others, it will have the opposite effect. For people who don’t believe they can make a difference to the things that happen to them (low self-efficacy), discovering that they have a high genetic risk for a particular condition may reinforce feelings of hopelessness, and may be unhelpful.”

*The researchers noted ethical challenges in their study design – notably, that some participants were falsely informed of their genotype. It was for this reason that the researchers chose to focus on the effects of genetic risk information for obesity, rather than a more emotionally charged disease such as Alzheimer’s or cancer. They also limited the time under which participants would hold a potentially false belief about their genetic risk to around 1 hour, while under clinical supervision.

[World Report] Prince Mahidol awards 2018

This year, the Prince Mahidol awards recognise outstanding achievements that improved chronic myeloid leukaemia treatment, breast cancer genetics, and cholera vaccines. Talha Burki reports.

Call for global bipolar research volunteers

Australian researchers are seeking 5,000 adults who have been treated for bipolar disorder to volunteer for the world’s largest genetic investigation into the chronic illness that can prove devastating.

The Australian Genetics of Bipolar Disorder Study aims to identify the genes that predispose people to bipolar disorder in order to develop more effective, personalised treatments, and ultimately, find a cure for the illness.

QIMR Berghofer Medical Research Institute (QIMR Berghofer) is the base for the Australian arm of the international study, with collaborating centres throughout North America and Europe.

The study aims to recruit 100,000 participants, with Australian researchers hoping to contribute five per cent of the overall study population.

Approximately one in 50 Australians (1.8 per cent) will experience bipolar disorder during their lifetime.

The complex disorder, which occurs commonly in families, typically results from a combination of genetic and environmental influences. Those living with bipolar disorder may be at higher risk of developing other health issues, including alcohol and drug abuse, anxiety, cardiovascular disease, diabetes and obesity. They also carry a 15 times greater risk of suicide than the general population, accounting for up to 25 per cent of all suicides.

Researchers are seeking 5,000 male and female Australian volunteers aged 18 and older, who are currently being, or have been, treated in the past for bipolar disorder. Their involvement will allow researchers to shed light on the genes that predispose people to the illness to ultimately develop more personalised treatments.

Globally, about one in 50 of the population experiences bipolar disorder during their lifetime. In Australia, it is estimated that 1.8 per cent of males and 1.7 per cent of females have experienced bipolar disorder in the previous 12 months.

Participation in the study is free and simple. Volunteers complete a 20-minute online survey, and those who qualify will be asked to donate a saliva sample. Study researchers will analyse DNA from saliva samples to identify specific genes associated with bipolar disorder. The knowledge will be used to improve current, and develop new treatments for bipolar disorder.

Anyone wishing to volunteer for the Australian Genetics of Bipolar Disorder Study should head to www.geneticsofbipolar.org.au, email gbp@qimrberghofer.edu.au or call 1800 257 179.

Artery hardening begins before high school: Australian study

Only a minority of Australian 12-year-olds have ideal cardiovascular health, research shows, with arterial stiffening evident before some children start high school.

A team from Melbourne’s Murdoch Children’s Research Institute assessed the cardiovascular health of 1028 Australian children aged 11-12 using the seven risk factors of the American Heart Association’s Cardiovascular Health (ICVH) score: physical activity, weight, diet, blood glucose, cholesterol, blood pressure and smoking status.

Only 7% of the children (76) had a perfect ICVH score, and only 39% (406) achieved ideal levels in six out of the seven metrics. The median score was 5/7.

For the first time, the researchers demonstrated that ICVH scores in children were associated with vascular function.

Each additional point in a child’s ICVH score was associated with slower carotid-femoral pulse wave velocity (0.07m/s reduction in pulse wave velocity) and greater carotid elasticity (0.009% per mm Hg).

This relationship was largely mediated by BMI and blood pressure, according to the study published this month in the International Journal of Cardiology.

Study co-author, Professor David Burgner of the University of Melbourne told doctorportal: “If parents were aware that even before their child starts high school, risk factors such as increased BMI and raised BP were already associated with stiffer arteries – which increases the chance of heart attack and stroke as adults – then you’d hope that would galvanise families to try to reduce their risk factors.”

“Cardiovascular disease risk occurs from childhood onwards and we already see associations between risk factors and preclinical changes in the arteries by mid-childhood,” he said.

A family problem

The researchers also assessed 1,235 parents of the children – in most cases the mothers.

The median ICVH score in the parents was lower than in children (4/7), and the association with vascular function was stronger, the study found.

ICVH scores in adults were also linked with changes in vascular structure. Each additional point in an adult’s ICVH score was associated with a smaller carotid intima-media thickness (-7.3μm per metric unit), a measure of subclinical atherosclerosis.

The study found children whose parent had non-ideal health in any of the seven metrics had substantially higher odds for non-ideal health in that metric, for all metrics except physical activity and serum glucose. Children typically did more exercise than their parents.

Ideal diet was the metric least likely to be attained by both adults and children.

Family-based interventions

Professor Burgner said the study highlighted the need for family-based interventions to reduce cardiovascular risk from early on in life.

“Clearly many of the risk factors are shared within families, so considering the family rather than the individual as the unit for interventions that address modifiable environmental risk factors such as increased physical activity or diet may have more impact than just focusing on the adult or child in isolation,” he said.

Professor Burgner said it was unknown whether the poorer vascular function seen in children with lower ICVH scores in the study was reversible.

“The adverse changes in children are smaller than in adults and only relate to the elasticity of the arteries. This likely reflects a longer cumulative exposure to risk factors the older you get,” he said. “Certainly the consensus is that children are physiologically more ‘plastic’, so changes are likely to be reversible, but it is not well understood.”

The study cohort was drawn from the Longitudinal Study of Australian Children and Child Health Checkpoint. The authors cautioned that it was likely to have under-represented socio-economically disadvantaged families.

Dr Richard Liu, another co-author of the study, said that BP measurement should be routine in children. However in practice it was rare.

“Arguably all children with a raised BMI should be screened but it is important that it be done appropriately – that abnormal readings are repeated at least twice, the cuff is appropriately sized and equipment calibrated, and values are measured against established centiles for age, sex and height,” he said.

Monstrous: Aussie experts on ‘edited’ bubs

A Chinese researcher has engaged in a monstrous game of Russian roulette if he really has made the world’s first genetically edited babies, Australian experts say.

A chorus of international condemnation has erupted after He Jiankui said he’d altered the DNA of twin girls, born earlier this month, to make them resistant to the virus that causes AIDS.

Australian geneticists and bioethicists are sceptical and say he has offered no proof that he permanently altered the twins’ genetic codes.

But if he is telling the truth, they say it’s a premature and dangerous leap with unknown consequences for future generations.

They accuse him of unethical conduct that flies in the face of a consensus ban on fiddling with the genes of embryos that will result in live births.

That ban exists because any changes that are made are passed on to future generations and not enough is known about the effects of that.

They also say the researcher from China’s Southern University of Science and Technology has shown complete disregard for the welfare of the babies at the heart of his experiment.

Limited use of genetic editing in adults – solely for the purposes of treating serious diseases – has shown that it can have unintended consequences.

Professor Julian Savulescu, a bioethicist with Victoria’s Murdoch Children’s Research Institute says that if He’s claims are proven, he’s engaged in “monstrous” conduct.

“These healthy babies are being used as genetic guinea pigs. This is genetic Russian roulette,” he says.

“Gene editing itself is experimental and is still associated with off-target mutations, capable of causing genetic problems early and later in life, including the development of cancer.”

Associate Professor Darren Saunders is a gene technology and cancer specialist in the School of Medical Sciences at the University of NSW.

He shares Prof Savulescu’s concerns and worries that He’s claims could set back the study of gene editing by decades.

“Most scientists think that the safety concerns around gene-editing in humans are still too big to outweigh any potential benefit,” he said.

But he said it was possible the world had just seen “a huge leap towards editing the human book of life”.

“Some might even suggest this is a step towards eugenics,” he said, referring to a movement that advocates improving the genetic composition of the human race.

He claims to have altered embryos for seven couples during fertility treatments, using CRISPR-Cas9 technology, allowing him to cut-and-paste DNA with the aim of specific outcomes, in this case HIV resistance.

He says one pregnancy has resulted so far, the two girls born earlier this month.

But the Chinese university where he worked until February says it didn’t know what He was doing, and has launched an investigation calling his work a “serious violation of academic ethics and standards”.

More: Q&A about gene-edited babies

Does gender dysphoria have a genetic basis?

Four genetic variants involved in processing sex hormones are over-represented in transwomen, according to Australian research, indicating there could be a genetic basis for gender dysphoria.

Lead researcher Professor Vincent Harley, from the Hudson Institute of Medical Research in Melbourne, told doctorportal that establishing the role that sex hormones have in gender identity contributes significantly to our understanding of the condition.

“We know that if you look at identical twins and one is trans, there is a 25% chance the other twin will be. That’s not 100%, but the chance is higher than what it is between unrelated people.”

“Therefore, this study might be the first small part of the evidence base, as I think there could be many genes involved, like there is in height or blood pressure.”

Study finds significant association between genes and gender dysphoria

The study, published in the Journal of Clinical Endocrinology & Metabolism, set out to explore the likely genetic component of gender dysphoria. The authors hypothesised that gender dysphoria in transwomen is associated with variants in sex hormone signalling genes responsible for under-masculinisation and/or feminisation.

The research involved 380 transwomen (most of whom were receiving hormone treatment at the time of recruitment) and 344 control males. The authors conducted a DNA analysis, focusing on the functional variants in 12 sex hormone signalling genes and their relationship to gender dysphoria in transwomen.

The results showed a significant association between gender dysphoria and ERα, SRD5A2 and STS alleles, as well as ERα and SULT2A1 genotypes. Several allele combinations were also over-represented in transwomen, most involving AR (AR-ERβ, AR-PGR, AR-COMT, CYP17-SRD5A2).

Existing knowledge about sex hormones informed the research

Professor Harley said the approach the team took was biased and informed by channels of existing literature. One aspect of this was the evidence base on sex hormones.

“We know that when males and females smell sex hormones, different brain regions are activated, and trans women have an atypical response to this”, Professor Harley said.

He said this suggested that the receptors of androgen and oestrogen play some role, and this formed the basis of his investigation.

“I didn’t just take neutral variations of genes. The ones I looked at had already previously been implicated in other conditions like breast cancer, prostate cancer and infertility, so I knew they had functional polymorphism – they are things that do tweak hormone pathways.”

Establishing the role genes play could help reduce discrimination

Professor Harley feels his research is making a difference and improving our understanding of gender dysphoria.

“This work has been helpful to trans people – and I get hundreds of emails from trans people and society at large which suggests that.”

He said that when he started his research 20 years ago, the general public knew little about trans people. “I think gender identity is an important part of the spectrum of human diversity”

“When we establish some biological basis for trans, we can educate the public and this knowledge can help reduce discrimination of the trans community.”

Professor Harley said that as far as clinical implications go, a test will not emerge from the study – nor was this ever the intention of his research on gender dysphoria.

“I’m a biologist, so I was interested in looking at why we feel the sex we do, from a basic biology point of view. This research was more about trying to understand the condition.”

DNA to predict disease risk

Scientists have created a powerful new tool to calculate a person’s inherited risks for heart disease, breast cancer, and three other serious conditions.

Reporting on research in the journal, Nature Genetics, the New York Times revealed that, by surveying changes in DNA at 6.6 million places in the human genome, investigators at the Broad Institute and Harvard University were able to identify many more people at risk than do the usual genetic tests, which take into account very few genes.

Of 100 heart attack patients, for example, the standard methods will identify two who have a single genetic mutation that place them at increased risk. But the new tool will find 20 of them.

The researchers are now building a website that will allow anyone to upload genetic data from a company like 23andMe or Ancestry.com. Users will receive risk scores for heart disease, breast cancer, Type 2 diabetes, chronic inflammatory bowel disease, and atrial fibrillation.

People will not be charged for their scores.

A risk score, including obtaining the genetic data, should cost less than $100, said Dr Daniel Rader, a professor of molecular medicine at the University of Pennsylvania.

Dr. Rader, who was not involved with the study, said the university will soon be offering such a test to patients to assess their risk for heart disease. For now, the university will not charge for it.

Dr Sekar Kathiresan, senior author of the new paper and director of the Center for Genomic Medicine at Massachusetts General Hospital, said his team had validated the heart risk calculation in multiple populations.

But DNA is not destiny, Dr Kathiresan stressed. A healthy lifestyle and cholesterol-lowering medications can substantially reduce risk of heart attack, even in those who have inherited a genetic predisposition.

The new tool also can find people at the low end of the risk range for the five diseases. This should prove useful to certain patients: for example, a woman who is trying to decide when she should start having regular mammograms, or a 40-year-old man with a slightly high cholesterol level who wants to know if he should take a statin.

[Seminar] Type 1 diabetes

Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. Interventions to preserve β cells have been tested, and several methods to improve clinical disease management have been assessed. However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden.

The Canadian Partnership for Tomorrow Project: a pan-Canadian platform for research on chronic disease prevention [Research]

BACKGROUND:

Understanding the complex interaction of risk factors that increase the likelihood of developing common diseases is challenging. The Canadian Partnership for Tomorrow Project (CPTP) is a prospective cohort study created as a population-health research platform for assessing the effect of genetics, behaviour, family health history and environment (among other factors) on chronic diseases.

METHODS:

Volunteer participants were recruited from the general Canadian population for a confederation of 5 regional cohorts. Participants were enrolled in the study and core information obtained using 2 approaches: attendance at a study assessment centre for all study measures (questionnaire, venous blood sample and physical measurements) or completion of the core questionnaire (online or paper), with later collection of other study measures where possible. Physical measurements included height, weight, percentage body fat and blood pressure. Participants consented to passive follow-up through linkage with administrative health databases and active follow-up through recontact. All participant data across the 5 regional cohorts were harmonized.

RESULTS:

A total of 307 017 participants aged 30–74 from 8 provinces were recruited. More than half provided a venous blood sample and/or other biological sample, and 33% completed physical measurements. A total of 709 harmonized variables were created; almost 25% are available for all participants and 60% for at least 220 000 participants.

INTERPRETATION:

Primary recruitment for the CPTP is complete, and data and biosamples are available to Canadian and international researchers through a data-access process. The CPTP will support research into how modifiable risk factors, genetics and the environment interact to affect the development of cancer and other chronic diseases, ultimately contributing evidence to reduce the global burden of chronic disease.

[Obituary] Arno Motulsky

Founder of medical genetics and creator of pharmacogenomics. Born on July 5, 1923, in Fischhausen, Germany, he died in Seattle, WA, USA, on Jan 17, 2018, aged 94 years.