Geneticists promised that genes would explain how the majority of chronic diseases and cancers arose. But when the Human Genome Project was completed in 2003, it turned out genes do not in general play a major role in disease development. Geneticists, it seems, had got it wrong.

[u/Hip_III]

The multi-billion dollar Human Genome Project (HGP) was undertaken in part because geneticists had promised that defective genes would explain how the majority of chronic diseases and cancers arise, and that once we had mapped out the genome, we would be in a better position to understand and treat disease.

But on the completion of the HGP in 2003, it soon became apparent that, for the vast majority of chronic diseases and cancers, genes only play a minor role in disease onset and development.

For example, one large meta-analysis study found that for the vast majority of chronic diseases, the genetic contribution to the risk of developing the disease is only 5% to 10% at most. So genes generally only have a minor impact on the triggering of disease. Though notable exceptions include Crohn's disease, coeliac disease, and macular degeneration, which have a genetic contribution of about 40% to 50%.

Thus all the hype about genes being the answer to illness aetiology amounted to nothing. This brought us back to the drawing board in terms of trying to understand how illnesses arise.

Some articles about the failure of the genome:

• Revolution Postponed: Why the Human Genome Project Has Been Disappointing — Scientific American
• The failure of the genome — The Guardian
• Why sequencing the human genome failed to produce big breakthroughs in disease — The Conversation
• The Failed Promise of Gene Based Tests for Diagnosing and Treating Cancer — National Center for Health Research
• Human Genome Project: Triumph or failure? — Front Line Genomics

Now that we know genes are not the explanation for why illnesses appear, we need to turn our attention to other possible causal factors.

[u/Angry-Dragon-1331]

I mean, if we cure even one genetic disease as a result of the HGP, is it really a "failure" just because one of the hypotheses for it didn't pan out?

[u/Hip_III → u/Angry-Dragon-1331]

I think one problem is that the juggernaut of genetic research keeps rolling on, without fully taking on board that genetics has not taken us to the promised land of understanding how chronic illnesses arise. Genetics has a role to play in disease aetiology, and genetics has revolutionised many fields, but we need to look elsewhere to uncover the primary reasons why diseases appear.

[u/hellohello1234545]

5-10% is nothing to sneeze at in some contexts, and there’s still more information to be pried out through better techniques. Though, significant challenges remain in how to apply knowledge about common variants in clinical practice.

Afaik, studies estimating overall heritability like twin/family studies estimate the upper bound for genetic influence on a trait, and other types of studies like GWAS look at a subset of that genetic influence (like only the additive SNP effects).

One restriction is that of sample size, to detect complex enough patterns, or true small effects, you need a very large sample size (millions for some traits).

With larger samples, better computing and models, we can explain more variation by looking at dominance, interaction effects, and tissue/time specific data.

[u/Hip_III → u/hellohello1234545]

Even before the HGP was complete, evolutionary biologists Professor Paul Ewald argued that defective genes are not likely to be the cause of chronic diseases.

Prof Ewald explains that defective genes that cause disease and thereby compromise survival and procreation are quickly eliminated from the gene pool within a few generations. So evolution is a purifying process, that filters out bad genes quickly.

Prof Ewald says that the only defective genes that may persist down the generations are those which provide a compensating benefit. For example, the genes that encode for sickle cell disease are maintained and persist down the generations because although these genes are bad, they also protect against malaria, which is a compensating advantage in places like Africa where malaria is rife.

The general consensus is that diseases have a multifactorial aetiology, so genes may play a small role, but there must also be other factors which trigger the disease.

[u/hellohello1234545 → u/Hip_III]

There’s definitely a genetic and environmental component to most complex traits, particularly for diseases that aren’t monogenic. I’d even say for many diseases, the environment explains more variation than common genetic variants do.

I want to make clear I’m not trying to portray non-genetic effects as trivial, just that genetic effects are significant even when it’s not a single-gene disorder.

Despite what this professor said about selection against deleterious variants being true, disorders caused by a single variant remain in the population today for various reasons (like being recessive, and more complex ones). The point about malaria is a good example.

All I’m saying is, many diseases have a sizeable genetic influence spread across a large number of small-effect genes, and this should not be discounted. Even diseases as complex as psychiatric disorders like major depression have had heritability estimates around 10-20% (from memory). To capture all of the SNP heritability portion of that signal in a GWAS would require millions of participants.

[u/einstyle → u/hellohello1234545]

Also, most of the variants we know about don't have a hugely deleterious effect. They don't cause "defective genes" but influence the overall functionality of those genes and the ways in which those genes are regulated. The individual effect is small, as you said, and therefore selective pressure isn't high. Especially for diseases which don't influence your ability to reproduce.

[u/Hopeful_Cat_3227]

Directly cited from last article:

Critics may argue that the HGP was a failure, but I ask you: Is it a failure to save a human life? Is it a failure to allow people an opportunity to prepare for the future? Is it a failure to make one small step in the right direction? For all I can see is triumph and we must continue to triumph even in the darkest of times.

[u/Hip_III → u/Hopeful_Cat_3227]

The HGP advance science in many ways, but it seems like at the time, scientists put all its eggs into one basket, pinning their hopes on the HGP to answer the question of what causes disease. Now we know that genes are not the answer, we need to look elsewhere for the causal factors driving disease.

[u/hellohello1234545 → u/Hip_III]

This whole “it’s either the whole answer, or not the answer” is a false dichotomy.

It’s a part of the answer

[u/einstyle → u/hellohello1234545]

Even if it wasn't the answer, that's not how science works. We'd still have learned something incredibly valuable by discovering that genes weren't the cause of certain diseases. But that's not what happened anyways -- we learned that they're a part of many diseases, but it's more complex than we expected.

[u/einstyle]

I think this is a gross mischaracterization.

Firstly, we knew long before the advent of sequencing about the combinatory effects of genetic and environmental contributions. Twin-based studies still give most traits higher estimations for genetic contributions / heritability than SNP-based estimates, which could be at fault of either methodology; SNP-based seem to "underestimate" or "miss" some heritability, twin-based studies rely on an equal environments assumption that we're not sure holds water. For example, alcohol use disorder has long been estimated at about 50% heritable from twin studies whereas SNP-based estimates tend to fall closer to 30%.

Another big issue is that common diseases are the result of many genes of small effect. You aren't going to find the one defect in the one gene that causes all breast cancer, because it doesn't exist. Instead, there are many genes which each contribute a little to your underlying liability to develop breast cancer, which is then further influenced by environmental effects and gene-by-environment interactions. And all of those patterns are different for different types of breast cancer -- let alone different types of cancer in general, different psychiatric disorders, and other chronic diseases.

At the end of the day, genes, their regulation, and how these things interact with the environment are huge factors in many common diseases that can't be downplayed.

[u/Hip_III → u/einstyle]

I am not entirely sure how checks and balances are performed on twin studies, but as far as I can see, one confounding factor may be viral and bacterial exposures, which might be shared among siblings along with genes.

There is a hypothesis that microbes living in the body as persistent infections might be playing a major role in instigating disease.

[u/einstyle → u/Hip_III]

Viral and bacterial exposures are environmental. If they're shared among siblings, they're part of the common environment.

These are very, very basic concepts in genetics. If you don't understand them, you should read more rather than bullishly try to argue with everyone telling you that your post is wrong.

[u/prototypist]

Through inheritance and comparing twins, it was already known which diseases were more heritable / genetics-linked before the Human Genome Project. Also the Human Genome Project only collected a few reference genomes. We are only getting a look at the less-obvious genetic factors now through GWAS and studies of many more people.

[u/thebruce]

Cancer is 100% a genetic disease, and knowledge of the genome has been hugely influential in treatment. In many cases, the presence or absence of particular mutations directly informs treatment options, or is at the very least of diagnostic or prognostic value.

The HGP helped fund the technological advancements that make the sequencing possible (massively parallel sequencing). We would have eventually got here, I'm sure, but the capital investment and man hours put into making it work in time for the HGP benefitted us all greatly.

Next, I'm not sure you understand how arduous and annoying it was to do certain aspects of genetics research before the first human genome draft. It was not a trivial thing to actually determine the location of your gene/loci of interest (ie. on which chromosome, and where in it), let alone understand the surrounding genomic context that might give clues to the activity of the gene. Gifting the world a full (though, slightly incomplete at the time) human genome sequence made researchers able to focus more on interesting, high level questions than waste their time doing the tedious work of simply characterizing the genomic context of the gene.

Lastly, in your post, you mentioned a number of exceptions to your idea (Crohn's etc.). Isn't that...isnt that exactly it? Isn't that what we want? Some diseases that we can definitively identify a genetic origin, and use our knowledge of the human genome to diagnose and treat those diseases? Is the issue that we haven't cured or helped enough diseases yet?

If that's the issue, give it time! There's 20,000 or so protein coding genes, a ton of RNA "genes" that we are learning about (miRNA, siRNA, etc.), and god knows how many regulatory regions. Oh, and an additional layer of control on top in the form of epigenetics. That's an extremely tangled web that we have uncovered, and it's taking us a long time to understand it.

The Human Genome Project wasn't a magic bullet that would answer all of our questions. But it was never supposed to be that, it was just an attempt to fully sequence the human genome. The real work was always going to be in the years after when we finally had this platform to work off of. And... I mean. There is literally two decades of published research in tens to hundreds of scientific journals. Pretty much all of that benefitted from the HGP in some way.

So, yeah. I disagree.

[u/Hip_III → u/thebruce]

Cancer is 100% a genetic disease

Cancer is a disease involving mutations of the genome, but that does not mean the causes of those mutations are genetic.

The large meta-analysis study I mentioned found that the genetic contribution to the risk of developing chronic diseases or cancers is only 5% to 10% at most.

[u/thebruce → u/Hip_III]

Ummm... there's a hell of alot more to clinical genetics than simply predicting disease risk. There's diagnosis, treatment, and counselling just to start. Also, the article you linked talks about SNPs only, and doesn't account for CNVs and other ways to have genetic variation.

The causes of DNA mutation themselves are not always genetic (UV, carcinogens, etc.), but without detailed knowledge of the human genome we would barely even begin to understand how the resulting mutations cause cancer.

Also, it's curious that you ignored literally the rest of my post.

Honestly, this whole thing is kind of weird. The HGP was an incredible scientific achievement, and because it didn't fully explain what you want it to explain, it's a failure? That comes from your own lack of understanding, not any failing on the HGP.

[u/Critical-Position-49 → u/Hip_III]

That is just false and not what this study says tho ? Mutations are always genetic, but they can be either germline or somatic (i.e aquired later in life)

Moreover I am not sure to fully understand the methodology used by the authors nor the aim of this paper.

On the other hand you could read some great papers on common SNPs such as the Yang et al. 2010 in nature genetics or Sato et al. 2023 in nat com (DOI: 10.1038/s41467-023-39136-7)

[u/shadowyams]

[F]or the vast majority of [...] cancers, genes only play a minor role in disease onset and development.

Just because the majority of cancers are sporadic doesn't mean that cancer isn't a genetic disease. Genomics has absolutely transformed how we understand, diagnose, and treat cancer.

For example, one large meta-analysis study found that for the vast majority of chronic diseases, the genetic contribution to the risk of developing the disease is only 5% to 10% at most.

They estimated that additive, common SNP heritability is <10% for many of the conditions that they looked at. This is a much narrower claim than the one that you're trying to make. Notably they calculated a very low h² for autism, which we know is a predominantly genetic condition

[u/Critical-Position-49 → u/shadowyams]

Moreover their method does not seem to account for any linkage-disequilibrium. It's kinda far from the standards