[pfisherman]

One quick piece of semantic and linguistic housekeeping for the commenters…

Heritable != Molecular / Genetic Mechanism

There is a conflation of these terms in popular discourse that does a disservice to the field of statistical genetics, imo. There are mechanisms of inheritance that operate various length / time scales other than that of biological macromolecules. For example, if you tell me what language your parents natively speak I can tell you your primary language with >90% accuracy.

So before we start getting 3 replies deep into any thead, please remember that retrospective observational data measured with unqualified instruments is notoriously confounded and that we can barely infer causal structure in controlled functional genomics experiments (much less a GWAS of phewas). So let’s all please keep an open mind and not be so certain about our beliefs.

[fearmerchant]

This comment reads as if it were dropped into a generic "genetics of lifespan" thread,. The Dynomight article is already making a much more sophisticated version of some of these same points. The article's central argument is precisely that heritability is a contingent observational statistic, not a Platonic form. This particular article isn't conflating heritability with genetic mechanism at all. It's interrogating a simulation model and its assumptions. The warning about "unqualified instruments" and "retrospective observational data" feels off as this paper isn't a straightforward observational study. it's a parametric simulation fitted to twin registry data.

This comment might be very useful in a Reddit thread full of people saying "50% of lifespan is in your DNA," but it's a bit off-target as a response to this particular article.

[tptacek]

I think the comment is speaking to the thread, not responding to the author.

[robwwilliams]

Agreed, the Dynomight article is on-the-mark. I work in this field and was really puzzled when I read this paper. Yes, it is obvious that excluding extrinsic causes of death will increase heritability estimates. But is death from influenza genetic or extrinsic?

The typo on the first page of the Science article is on the authors, not the editors.

[svnt]

The accurate version of the result would be something like: “if you model lifespan as aging + i.i.d. noise and dial the noise to zero, heritability of the aging component is ~40-50% in our model.” Which is barely a finding, since by construction reducing i.i.d. noise has to increase heritability of whatever non-noise remains.

[shevy-java]

This would require an accurate definition of ageing. What is ageing? How is it related to life span? Because in theory, there can be definitions of ageing that are not tied to life span. For instance, do bacteria age? Does this affect life span? What is the life span of a bacterium anyway? Does hydra age? (For those who don't know much about biology: literally everything ages, if you define ageing as functional decline over time. Even viruses would age, if you define it as functional infections possible plotted over time. Does DNA and RNA age? The definitions become blurry; almost no molecule is immune to changes and modifications, so just about anything would age. So it really depends on the definition, and we need to read the definition before we can accept assumptions based on it. Thus: what is ageing and how does it relate to lifespan, as definition?)

[codethief]

OP has another post on the definition of heritability, which I really liked: https://dynomight.net/heritable/

> For example, if you tell me what language your parents natively speak I can tell you your primary language with >90% accuracy.

According to the link above, the heritability of the primary language is zero, whereas the heritability of what language(s) a person speaks in general (whether primary or secondary) is not necessarily zero and varies by language.

[aidenn0]

I believe that your example of "what language your parents natively speak" is incorrect.

Some ways of measuring heritability would have trouble detecting this as environmental, but that is considered a deficiency in those measures, not part of the definition of heritability. Any serious study into heritability of language would quickly find it is largely due to the common environment.

[robwwilliams]

We have many bits and pieces of causal structure for some human traits courtesy of GWAS and PheWAS but you are right that lifespan genetics of humans is seriously compromised by rapid changes in life styles and environments.

[IshKebab]

> Heritable != Molecular / Genetic Mechanism

Hmm let me just check Wiktionary for "heritable"

> Genetically transmissible from parent to offspring

Ok then. Maybe it has some specific meaning in biology? A search for "heritable meaning in biology" let me to this page: https://www.cancer.gov/publications/dictionaries/cancer-term...

> In medicine, describes a characteristic or trait that can be passed from a parent to a child through the genes.

IMO this post is dumb and the paper is perfectly clear to non-pedants.

[rbehrends]

Heritability has a very specific meaning in quantitative genetics [1], which in many ways is not what your intuition would suggest [2]. It is this usage that the article talks about that.

That said, there are plenty of critiques of this definition of heritability, and not just because it is different from what a layperson would expect it to mean.

For example, the way it is used also usually has a big problem in that the standard formula assumes that Cov(G, E) = 0 (or at least is negligible), whereas in practice that is not actually true [3, 4].

This definition of heritability is also mathematically flawed in that it assumes (without evidence) that P = G + E, or at least can be reasonably approximated this way. Given that human development is the result of a feedback loop involving genetic and environmental factors, one would expect a model closer to something like a Markov chain. Proposed justifications of a simple additive model as an approximation (e.g. via the central limit theorem for highly polygenic traits) have to my knowledge never been tested.

More recent genome-wide association studies [5] have actually shown a considerable gap between heritability estimates from genotype data and heritability estimates from twin studies, known as the "missing heritability problem".

[1] https://en.wikipedia.org/wiki/Heritability

[2] https://en.wikipedia.org/wiki/Genetic_variance

[3] https://en.wikipedia.org/wiki/Gene%E2%80%93environment_inter...

[4] https://en.wikipedia.org/wiki/Gene%E2%80%93environment_corre...

[5] https://en.wikipedia.org/wiki/Genome-wide_association_study

[codethief]

OP has another post on the definition of heritability, which I really liked: https://dynomight.net/heritable/ . I'm a layman, though, so since you seem knowledgeable, I would love to hear your thoughts on that article!

For instance, OP's definition H = Var[G] / Var[P] seems to bypass the issues you mentioned:

> For example, the way it is used also usually has a big problem in that the standard formula assumes that Cov(G, E) = 0 (or at least is negligible), whereas in practice that is not actually true [3, 4].

> This definition of heritability is also mathematically flawed in that it assumes (without evidence) that P = G + E, or at least can be reasonably approximated this way.

[rbehrends]

> For instance, OP's definition H = Var[G] / Var[P] seems to bypass the issues you mentioned:

No, this is exactly the definition I am talking about. The problem is that while theoretically you could work with Var(G)/Var(P) even if Cov(G, E) ≠ 0, studies are not designed to capture that.

In fact, the standard ACE model [1] used in twin studies explicitly assumes among other things that there is no gene-environment correlation. This means that it gets silently added to one or more of the ACE components; not because of any ill intentions, but simply because if you included covariance, the resulting system of equations would be underdetermined and could not be solved [2].

But to make matters worse, gene-environment correlation/interaction itself is disproportionately absorbed by the A and C components rather than E. All this can lead to inflated heritability estimates.

And to clarify, I am not making any pronunciations about how much relevance or magnitude that effect has; for all I know, this could in the end be a minor effect. My point here is that there is a lot of mathematical handwaving going on with very limited testability of the modeling.

[1] https://en.wikipedia.org/wiki/ACE_model

[2] If you want to be precise, you need to actually distinguish between gene-environment correlation and interaction and use P = G + E + (G x E), but that makes the system even more underdetermined, because now we have both Cov(G, E) and Var(G x E) to worry about.

[IshKebab]

> Heritability has a very specific meaning in quantitative genetics [1]

Literally the first paragraph of that page is

> Heritability is a statistic used in the fields of breeding and genetics that estimates the degree of variation in a phenotypic trait in a population that is due to genetic variation between individuals in that population. The concept of heritability can be expressed in the form of the following question: "What is the proportion of the variation in a given trait within a population that is not explained by the environment or random chance?"

That matches what I assumed it meant, and it seems like OP and the post are arguing that that is some kind of surprising interpretation.

> OK, but check this out: Say I redefine “hair color” to mean “hair color except ignoring epigenetic and embryonic stuff and pretending that no one ever goes gray or dyes their hair et cetera”. Now, hair color is 100% heritable. Amazing, right?

Uhm, no. That is exactly what I (and I think most people) would expect the answer to be.

[rbehrends]

> That matches what I assumed it meant, and it seems like OP and the post are arguing that that is some kind of surprising interpretation.

The unintuitive part is that in quantitative genetics, heritability is defined in terms of variance in traits at the population level, not as the passing of traits from parents to offspring (that would be heredity [1]). Of course, I may have misinterpreted what you said in your OP when you cited the wiktionary definition of "[g]enetically transmissible from parent to offspring", and if so, I apologize, but at the time it seemed to me that you were talking about heredity.

> Uhm, no. That is exactly what I (and I think most people) would expect the answer to be.

What the article is talking about is that if you fix Var(E) = 0, then Var(P) = Var(G) in the standard heritability model, i.e. all phenotypic variance is explained entirely by genotypic variance (because in that model, Var(P) = Var(G) + Var(E)).

Fun fact (even if only tangentially unrelated): In Western countries, wearing glasses is a highly heritable trait, because wearing glasses is a strong proxy variable for refractive error [2], such as nearsightedness, which is highly heritable. It is often brought up as another example of how the quantitative genetics definition does not match conventional use of the word.

[1] https://en.wikipedia.org/wiki/Heredity

[2] https://en.wikipedia.org/wiki/Refractive_error

[tptacek]

The heritability statistic that occurs in the literature is the ratio of genetic variance to phenotypic variance.

Two corrollaries:

* When discussing heritability results from the literature, we are discussing that statistic, not your intuitive understanding of what the word should mean.

* In the scientific literature, your conception of heritability doesn't operate. In the scientific sense, the number of hands you have has low heritability, despite being genetically determined.

I think you're going to find "let's check Wiktionary" is not the decisive move in these kinds of discussions that it is elsewhere.

[AgentME]

Another great example of the unintuitiveness of heritability is the fact that earrings are highly heritable. Earrings are highly correlated to a specific genetics (being female), so they're very "heritable", even though that correlation is an arbitrary cultural fashion.

[lostmsu]

See my sibling comment. This is misleading for the same reason, but in this case the cause of misleading is narrowing the timespan under consideration to approximately now.

[lostmsu]

> In the scientific sense, the number of hands you have has low heritability, despite being genetically determined.

This is only a surprise because unlike layman the author of this joke insists on considering heritability among humans specifically. While "heritability among humans" sounds like a reasonable comment to a layman, the author of this joke is misleading the layman, because layman (before being mislead) correctly thinks of "heritability" as "heritability among all living things with genes".

[hirvi74]

There is a genetic component to alcohol use disorder, for example. But if one is in an environment where there is no access to alcohol whatsoever, then that person, despite their genes, will not develop an alcohol use disorder. The disorder can still be passed from parent to child, but it's more complicated than just genes.

[IronyMan100]

I heared the same distinction as OP, but it is the other way around, it's the degree to what a trait is inherited from you parents which cannot be explained by the enviroment or Random Chance.

[imtringued]

What you're expecting heritability to mean is essentially "are genes responsible for expressing this trait", which is very different from "can I get this trait from my parents?" which does not impose any particular method for passing on the trait.

If the study doesn't use sequenced genes of parents and children as input into the model, it can't make the distinction between genetic or non genetic influence by parents.

[simiones]

That is exactly wrong. The measure of heritability used in the scientific literature is very much tied to genetics, just not in a very direct way. That is, heritability is a measure of how much of the variance in a trait is explained by genetics vs environment. In this sense, wealth will have a relatively low heritability, because it is weekly tied to genetics, even though it is very much a trait most people inherit from their parents. Skin color will have a high heritability, because the variance in skin color is almost entirely explained by genetics.

The unintuitive part is that traits with almost no genetic variance at all, such as the number of arms, have very low heritability - since, in a population study, almost the entire variance in the number of arms will be explained by environmental factors (very very few families have 1 or 3 arms as a recurring trait - and there are way more people who lose their arms during life).

[kjs3]

"Welcome to science hell, professor. This is IshKebab, he once saw something on the internet about your field of expertise and is going to spend eternity lecturing you on it."[1]

[1] https://www.tomgauld.com/shop/science-hell-print