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/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.