Polygene

• Through most of human history, our species has had to cope with food scarcity.
• When food was abundant, our bodies stored excess energy in the form of fat to draw upon when food was not available.

Ancient metabolism in a modern world

• Our brains enabled our species to develop an easier, more comfortable life and a steady supply of food to support population growth.
• Later, they invented machines to move ourselves and our belongings from place to place, and life became even easier.
• Today, mountains of calorie-rich (and often nutritionally poor) food and lakes of sugary beverages are readily available in much of the world.

The brain’s role in obesity

• For far too long society has treated obesity as a personal failing while in reality it’s a biological, physiological, environmental, chronic disease.
• The fact is that for many, trying to lose excess fat is very difficult without help.
• People living with obesity may have a genetic predisposition toward a heightened reward system associated with food.
• Glossy packaging, aggressive marketing (often targeting children), delicious but nutrient-poor foods, drive-through windows and online delivery services all enable this.

Effective treatment

• That begins with accepting that polygenic obesity is a disease and not a matter of willpower.
• Rather than blaming and shaming one another for our size, we should be more understanding and educate ourselves about obesity, to help take stigma and judgment out of the equation.
• It’s important to recognize that when obesity does impair one’s health, it needs treatment, and effective treatment is available.
• She has participated in the development and delivery of continued medical education with pharmaceutical companies who have obesity medications including Novo Nordisk and Eli Lilly.

• In a recent article from Nature Genetics_, scientists raise concerns over the social impacts of recent advances in genomics - i.e.
• the study of genomes, or in other words, the genetic material of an individual or species.
• In passages bringing to mind the dystopian sci-fi film Gattaca, they describe a near future in which one’s DNA could foretell one’s physical and intellectual abilities and near-perfect children be conceived in vitro.

What is a GWAS?

• The markers can be considered as small flags planted along the genome, each flag having two possible colours (the alleles).
• The idea behind GWAS is that an association between a marker and a trait allows for the detection of genetic factors independently of environmental factors.

A new market

• 23andMe managed to keep its doors open by changing its approach and collecting DNA to map out the geographical origins of people’s ancestors.
• An important part of these DNAs has been made available to scientific teams, allowing them to perform and publish GWAS on huge samples.
• Four years later, a study based on 3 million individuals found the number of genetic factors multiplied by 4.

The mistaken assumptions behind Polygenic Risk Scores

• The problem is that these conclusions are based on erroneous assumptions and misinterpretation of associations between the traits to be predicted and genetic markers.
• Indeed, Polygenic Risk Scores are specifically based on assumptions put forward in 1965 by Douglas Scott Falconer.

Misinterpretations of the GWAS studies

• Another problem is that Polygenic Risk Scores are based on a flawed interpretation of the GWAS studies.
• For if the link between a trait and genetic marker could indeed indicate a genetic factor, this remains to be confirmed by subsequent family and functional studies.
• For example, a GWAS study comparing people in France who consume salted butter with those who consume unsalted butter would show a large number of genetic markers associated with this trait.

Sociological consequences

• The IQ variable was originally thought out as a tool to measure the adequacy of a child to a given school programme.
• It is not a universal and timeless measure of cognitive abilities, or even of intelligence.

Ethical implications

• In his presidential address to the American Society of Human Genetics in 2015 [https://pubmed.ncbi.nlm.nih.gov/26942276/ref], geneticist Neil Risch mischievously commented the approach and conclusions.
• He calculated the scores of Craig Venter (pioneer of human genome sequencing) and James Watson (co-discoverer of the DNA structure).
• Risch humorously concluded that a below-average score was enough to land a Nobel Prize or the Medal of Science.

A flawed genetic model

• But they merely raise ethical issues, failing to stress, in the process, that the root of the problem remains an inappropriate genetic model and the misinterpretation of associations with genetic markers.
• Yet to deny the validity of genetic predictions of complex traits is not to deny the effect of genetic factors on these traits.

• Integrated polygenic risk score can more accurately identify people at high risk of developing coronary artery disease across diverse ancestries over a commonly used clinical tool.
• Featured as one of only 20 "Rapid Fire" presentations is the development and validation of an integrated polygenic risk score that improved coronary artery disease prediction.
• Most tests and tools that assess risk for coronary artery disease (CAD), the leading global cause of death, have been validated on a narrow population.
• To support diverse ancestries, MyOme developed and validated an integrated risk score (IRS) that combines a cross-ancestry PRS (caPRS) with ASCVD-PCE.

• MENLO PARK, Calif., Oct. 27, 2022 /PRNewswire/ -- MyOme , a clinical whole genome platform analysis company, today announced new data on its cross-ancestry integrated risk score (caIRS) for breast cancer risk assessment that will be presented at the 2022 American Society of Human Genetics (ASHG) Annual Meeting in Los Angeles.
• In a study on more than 270,000 women across multiple ancestries, data showed that there was a significant increase in breast cancer risk assessment performance when a cross-ancestry polygenic risk score was integrated into the standard of care risk prediction tool.
• Hispanic women showed the largest improvement in remaining lifetime breast cancer risk; 44% increase in odds ratio per unit standard deviation (increase from 1.31 to 1.88)
  "Commonly used breast cancer risk assessment tools based on clinical and family history are not well calibrated for women of certain ancestries.
• Breast cancer is the most common cancer among women and a leading cause of cancer mortality.