Quantifying the Genetic Basis of Complex Diseases

Question

In general, there are 2 types of diseases for which we understand "causality" very well:

1. Infectious disease, where there is some etiological agent that causes the disease and
2. Monogenic genetic diseases (e.g. cystic fibrosis), where there are a set of mutations that make specific proteins that are very important non-functional.

My question is not about these diseases. Rather it's about the diseases like T2D (type two diabetes mellitus). Simply put, are complex, chronic diseases like this always traceable to genetic causes? For a given complex disease state, is there always a set of genotypes that leads to the disease? Large-scale GWA (genome-wide association) studies of course have upturned tons of disease-associated variants in complex conditions like T2D, most with tiny effect sizes.

But is it possible to get the disease with none of the disease associated variants (even assuming that you had a list of all disease associated variants; of course you don't actually have this list, but I'm just trying out an intellectual exercise)? If yes, what is the causal pathway for this way to 'get' the disease?

EDIT: To clarify my question as per comment suggestions: Do all (complex) diseases have a genetical background/causative mutation or can they arise for other reasons?

Answer 1

I'm not sure what you mean by "complex", but many diseases are known to arise due to exposure to toxins or to an absence of essential nutrients in the environment.

Toxic metals:

A good example of this is exposure to some metals including arsenic, lead, and mercury. See for example this information from the US NIH and the wikipedia article on metal toxicity.
In the case of arsenic, some of this poisoning is even "natural" — i.e. due to toxic levels of this metal in ground water that hasn't been contaminated by human activity.

Diseases that have been linked to such exposures include cancer, heart disease, diabetes, and anemia.^1,2

Deficiencies:

Another class of diseases that are more-or-less purely environmental are those due to nutrient deficiencies — i.e. a diet lacking in minerals or vitamins.

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References:

1. Byrns, M. C., & Penning, T. M. (2011). Environmental toxicology: carcinogens and heavy metals. The pharmacological basis of therapeutics. McGraw Hill, New York, 1853-1878.
2. Tolins, M., Ruchirawat, M., & Landrigan, P. (2014). The developmental neurotoxicity of arsenic: cognitive and behavioral consequences of early life exposure. Annals of global health, 80(4), 303-314.