The Sequence 12/19-12/25
Discoveries on the Genetics of Alzheimer’s Disease, Animated Digital Messages in Facilitating Familial Genetic Testing, Whole Genome Sequencing in Adults, How Synonymous Mutations Make an Impact
New discoveries on the genetics of Alzheimer’s disease
Studies have been published recently that 1- identified a couple of new genes associated with Alzheimer’s disease, and 2- found a correlation between ADHD and Alzheimer’s disease.
Let’s start with a reminder of what we already knew about the genetics of Alzheimer’s disease
We already knew that individuals that are homozygous for, i.e. have two copies of, what we call the E4 allele in the APOE gene are at an increased risk for Alzheimer’s. This testing is even casually available on 23andme; see my post about that here. And to be clear, when I say this, I mean ‘regular’ Alzheimer’s, the one that’s onset after 75 years old. There is a different set of genes responsible for Early-onset Alzheimer’s, which starts in the 40s or 50s.
We also knew about the importance of studying protein interactions in Alzheimer’s disease.
And, we also knew about a host of other potential Alzheimer’s-associated genes that have been discovered but really need to be further studied. Article 1 that i’m reviewing here adds two more potential genes to that list.
Cool. Tell me more.
So firstly, let’s discuss the two new Alzheimer-associated genes. Holstege et al. discovered that rare variants in ATP8B4 and ABCA1 may increase risk of developing Alzheimer's disease. They did this by doing a rare-variant burden analysis (described in more detail here using the term ‘collapsing analysis’) by comparing the ‘burden’, i.e. amount, of rare damaging variants in exome sequencing data from 32,558 individuals. In the end, there was a significant burden of rare variants in the ATP8B4 and ABCA1 genes in patients with Alzheimer’s and not in those without.
Now, secondly, a study by Leffa et al. found a correlation between ADHD and Alzheimer’s disease. They did this by assigning polygenic risk scores for ADHD (polygenic risk scores are ways to predict the change a genetic condition will happen; you can read about another one here), and then noting that the patients in their study with Alzheimer’s disease also had higher PRSs for ADHD. Specifically, the researchers show that a high ADHD PRS was associated with greater cognitive decline and the development of Alzheimer's disease brain pathophysiology over six years.
What’s the takeaway?
By understanding genetic variants that predict Alzheimer’s disease- be it single genes like ATP8B4 and ABCA1, or PRSs that include multiple genes- we are steps closer to empowering individuals at a higher risk of cognitive decline to take control of their health at an earlier age.
Image credit: Copyright © 2017. The Ohio State University. BRCAShare.
Use of animated digital messages in facilitating familial genetic testing
Aeilts et al. studied questionnaire responses from 373 adults after they had watched an animated digital message (ADM) (i.e. a video) conveying information about the meaning of positive vs. negative test results from a hereditary breast and ovarian cancer (HBOC) syndrome test. The purpose was to understand how the use of an ADM impacted participants’ likelihood to pursue genetic testing.
Tell me more.
This is the thing: when someone has a mutation, or a harmful change in the DNA, that puts them at greater risk for a genetic condition, that person is no longer the only one impacted. That’s how genetics works. Since genes are passed down in families, other family members are at risk of having the same mutation, i.e. ‘carrying’ the mutation.
As a practicing genetic counselor, I can tell you that in many cases, a person who just received a positive genetic testing result is not thinking about their family members receiving genetic testing- the last thing on their minds is how they’re going to convey this information to family members. Explaining a new genetic diagnosis as well as its risk to family members, in a way that is both factual and empathetic, is a lot. So, the existence of a video they can just text or email to a relative that explains everything would be monumentally helpful.
That is exactly why in this case, surveying people with no personal history of breast cancer about HBOC syndrome test was perfect. They had no context or background information, which in reality is what it’s normally like for a family member of someone just diagnosed with a genetic condition.
So was the online decision aid helpful?
Yes! Based on the survey results, the video would prompt more than three-quarters of participants to pursue their own genetic testing, if such cascade testing came with a price tag of $100 or less.
What’s the takeaway?
The use of an ADM seemed to get across the seriousness and potential benefits of HBOC test results. A simple intervention like a video may be extraordinarily useful in communicating risks of a genetic condition to family members at risk.
Utility of whole genome sequencing in adults
Blanco et al. looked at the diagnostic rate of whole genome sequencing in adult patients to understand the clinical utility of genome sequencing among adults with rare, but undiagnosed diseases. ‘Adult’ is important here because whole genome sequencing has already increasingly been suggested as a first-tier test for children with suspected genetic disorders; diagnostic yield in children has already been proven.
What is whole genome sequencing?
Whole genome sequencing (WGS) is a test that looks at all of an individual’s DNA for a mutation, or harmful change in the DNA, that may be causing their condition. I’m emphasizing all here, because this is a big deal- whole exome sequencing, for example, is another genetic test that is thorough, but doesn’t look at all of the DNA; only the protein-coding portions.
Why is this important?
There’s something we call the ‘diagnostic odyssey’ in genetics. This is the incredibly frustrating and disheartening journey people with a rare genetic disorder go on before finally receiving a diagnosis. Since WGS is such a thorough test, it has the highest chances of shortening that diagnostic odyssey. However, since its utility hasn’t been proven in adult populations, it’s often not covered by insurance, remaining inaccessible to many.
Gotcha. What did the study find?
The diagnostic yield was 18 percent for participants who previously underwent exome sequencing but did not receive a diagnosis from that testing, and was highest among patients with neurological symptoms.
What's the takeaway?
These findings reflect an increased diagnostic yield among patients with previous uninformative genetic testing, and according to the authors, "supports the expansion of practice guidelines needed for widespread adoption and clinical implementation of [genome sequencing] in the adult population."
How synonymous mutations make an impact
In arguably one of the most groundbreaking studies of the year (to me), Jiang et al. unlocked some of the ways in which synonymous mutations make an impact in the body.
What is a synonymous mutation?
Let’s start from the beginning. DNA codes for protein in biology what we call ‘The Central Dogma’. No, i’m not making that up. The central dogma says that DNA codes for → RNA which codes for → protein. So let’s break that down further:
DNA is made up of letters, called ‘bases’. Those letters are A, T, C and G, and they string together like beads on a string. To become RNA in step 2 of the Central Dogma, each letter is transcribed into an RNA letter instead. A becomes T, C becomes G, G becomes G, and T becomes U.
Now, visualize this long string of RNA letters. To become protein in step 3 of the Central Dogma, groups of three letters at a time (aka ‘codons’) turn into amino acids. So let’s take a few examples:
CAG = Glutamine
CCG = Proline
ACA = Threonine
UUU = Phenylalanine
If you’re with me so far, you’re ready to understand what a ‘synonymous variant’ is:
Take the first example, how CAG = glutamine. Well, CAA also = glutamine. Different sets of nucleotides can make up the same amino acid.
Now, most genetic mutations, or harmful changes in the DNA, are caused by letter (aka nucleotide) changes that change the amino acid. Synonymous mutations, on the other hand, are caused by letter changes that do not change the amino acid.
Ok got it. What did they find?
Historically, synonymous variants have been disregarded in considering gene-disease associations: why would a genetic variant that makes the same amino acid cause a disorder? It’s the same amino acid, right?
Well, according to Jiang et al., maybe not. The group found that synonymous mutations may actually have a greater impact than we thought. How? By impacting the speed at which the protein is made. Kinetics. By speeding up and slowing down the process of going from RNA to protein, called ‘translation’, the group made the protein travel through the cell faster or slower. One finding, for example, was that faster translation resulted in a 20 percent decrease in protein activity compared to its normal version. They had similar findings for slower translation.
What’s the takeaway?
For the first time, we see that changing the codons that encode a protein, even when the protein is the same, can make proteins fold faster or slower. This will surely change the landscape of genetic variant interpretation and gene disease mechanisms in the future.