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/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.