Category: Medical Genetics

Ambry Genetics and PRS “equity”

Posted on by Razib Khan

A few people shared with me some screenshots from a message from Ambry Genetics regarding polygenic risk scores (click to enlarge). From what I can gather this seems to indicate that they’ll stop offering polygenic risk scores until they become more equitable by population. The basic issue here is that a prediction for one population may not port over well to another. The standard “solution” to this problem has been to expand population coverage by doing more research on non-European populations.

Perhaps I’m misunderstanding, but the communication here seems to suggest that they will stop giving scores to people of European ancestry until they can provide them to other groups in the interests of equity.

The communication here was shared on genetic counselor Twitter, and the messages were all very supportive. Generally, they were of the form “this is how antiracism is done!”

If I understand this correctly, I am not supportive. The traditional means by which these sorts of inequities were remediated is through addition, not subtraction. Not providing a polygenic risk score that might be actionable and useful to white Americans would be like simply rejecting using standardized tests because there is a gap between races.

There are two major issues here. First, “white Americans” are heterogeneous socioeconomically. White American life expectancy is declining. This decline is driven by social and class stratification. A focus on racial equity masks this reality. Due to the interaction of the environment with genetic risk improving equity through subtraction will increase class inequity. The white Americans who could benefit the most from polygenic risk scores because of all their environmental risks are probably Hillbilly Elegy whites.

Second, there has and will be progress in diversifying the training sets with non-Europeans. We can’t get worse than where we are. The issue is not racism in the classical sense, but various structural and historical forces (outside of East Asia most of the studies have been done in the USA and Europe). And, you can’t chalk up all the blame to Americans and Europeans. India and the Middle East in particular have great possibilities in the domain of biomedical genetics due to inbreeding and endogamy but have not leveraged their natural advantage in this area due to bureaucratic inaction and lack of execution. The scientists in these nations want to “go” but the political and institutional support is not there, or slows them down.

I must also add that I have heard privately from some researchers who are white that they have made a private decision to shy away from research on non-Europeans due to the possibility of controversy. Basically, some activists may not believe it is a “good look” for white people to be doing research on datasets of “people of color,” so on a personal level of decision-making, some white scholars are just leaving the work to nonwhite scholars. This is not a good trend in my opinion, though I understand why individuals with really diverse career options would choose the maximum gain for the minimum risk.

Problems in PRS?

Posted on by Razib Khan

Variable prediction accuracy of polygenic scores within an ancestry group:

Fields as diverse as human genetics and sociology are increasingly using polygenic scores based on genome-wide association studies (GWAS) for phenotypic prediction. However, recent work has shown that polygenic scores have limited portability across groups of different genetic ancestries, restricting the contexts in which they can be used reliably and potentially creating serious inequities in future clinical applications. Using the UK Biobank data, we demonstrate that even within a single ancestry group, the prediction accuracy of polygenic scores depends on characteristics such as the age or sex composition of the individuals in which the GWAS and the prediction were conducted, and on the GWAS study design. Our findings highlight both the complexities of interpreting polygenic scores and underappreciated obstacles to their broad use.

For my podcast, I recently talked to the first author of Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood. He turned out to be pretty sanguine about this result. We’re in the early years of the polygenic risk scores. There’s going to be a lot to learn…

Not happening at genomic speed: diversification of GWAS panels

Posted on by Razib Khan

 
One of the things that is evident and the norm when you are interested in genetics and genomics is that things happen fast. There are some sciences which proceed at a normal and conventional pace. But, because genomics is fundamentally driven by the synergy of two technologies, modern automated sequencing, and computation, the field has been moving at faster than the speech of light. A single whole genome sequence is now cheaper than $1,000, whereas the first whole genome 20 years ago cost $3,000,000,000!

People who point to a paper in 2010…well, in genomics that’s ancient history. Take a look at the initial HapMap papers from the mid-2000s if you want to have a laugh!

But, there’s one area that it seems “genomic speed” hasn’t applied: and that’s the attempts to increase population diversification necessary in GWAS panels to maximize insight. The figure to the right is from a new preprint, Current clinical use of polygenic scores will risk exacerbating health disparities. To my surprise, over the last few years, the proportion of people of European ancestry, which mostly means Northwest European ancestry, in genome-wide association studies has actually increased. The absolute number increases are still heartening, as a a lot of the low-hanging fruit can probably be picked at sample sizes of thousands.

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Cystic fibrosis as the sickle-cell anemia of the north

Posted on by Razib Khan

Cystic fibrosis is one of those ‘classical’ recessive diseases you learn about in medical genetics. It’s frequent enough that doctors will always be interested in it, and its inheritance pattern is relatively simple, following a rough Mendelian pattern of recessive expression. The reality is a little more complicated than that though, as there are different mutations in the CFTR gene, and some variants can complement so that two carriers don’t necessarily have a risk of producing a child which expresses the disease.

But CF is also interesting from an evolutionary perspective. Why is such a lethal disease present at such high frequencies in Northern Europeans? On the order of 1 out of 25 Northern Europeans carry a mutant allele on CFTR. Apparently, 1 in 19 Irish carries a mutation for CF, while Finland it’s prevalent at a frequency of around 1 in 90, which is actually in the range of non-European populations.

Though it is well known that inbred populations can manifest high frequencies of deleterious alleles, as a whole Northern Europe is not an inbred population. So what’s going on? One hypothesis is that heterozygotes for CF (carriers) have a higher fitness than wild-type individuals, so the low but persistent frequency of CF expressing individuals is an outcome of this overdominant effect. The analogy then presents to sickle-cell anemia.  Heterozygotes are more resistant to malaria, an endemic and pervasive disease in much of the tropics and subtropics.

So what might be causing the high frequency of mutant CF alleles in Northern Europe? One candidate has been tuberculosis, a very common disease in the recent past in Europe. A new paper out of Brazil supports this contention with epidemiological methods, Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary selective advantage based on data from the Brazilian territory:

Applying spatial epidemiology, we studied the link between CF carriership rate and tuberculosis (TB) incidence in Brazil. We corrected for 5 potential environmental and 2 immunological confounders in this relation: monthly income, sanitary provisions, literacy rates, racial composition and population density along with AIDS incidence rates and diabetes mellitus type 2. Smoking data were incomplete and not available for analysis.

…

A significant, negative correlation between CF carriership rate and TB incidence, independent of any of the seven confounders was found.

The immediate objection is that one may not have controlled for all the confounds. Though do note there are molecular biological rationales for why CFTR heterozygotes may be more fit when infected with tuberculosis.

All that being said Brazil is a diverse place, and it is hard to imagine there might not be a confound out there geographically. Fortunately, we won’t be doing a randomized controlled field trial by infecting individuals with tuberculosis, so we’re just going to have to keep looking at these correlational studies.

Something has to be driving selection for this nasty disease as part of the genetic correlation.