the paradigm for the genetics of complex diseases is changing

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One of the themes of this blog is that living things are complex and making clinical gains from areas of research such as genetics is just plain hard. There’s been a lot of questioning of genetic research lately, but, as I’ve tried to point out, there are many factors other than plain ol’ DNA involved in finding the way genes manifest in disease. That basic situation got a better expectation this past week when two highly respected genetics researchers at the University of Washington, Mary-Claire King and John McClellan, published an essay in Cell titled, “Genetic Heterogeneity in Human Disease.”

For decades the basic genetics paradigm held that common diseases are caused by common variants (CDCV). That is, to look for genetic causes for cancers the reasonable thing would be to identify genetic variations (mutations) found most often in cancer cases. That makes sense, but it turns out that finding these common genetic variations is not enough to explain all the disease. King and McClellan say:

…from the perspective of genetics, we suggest that complex human disease is in fact a large collection of individually rare, even private, conditions…In molecular terms, we suggest that human disease is characterized by marked genetic heterogeneity, far greater than previously appreciated. Converging evidence for a wide range of common diseases indicates that heterogeneity is important at multiple levels of causation: (1) individually rare mutations collectively play a substantial role in causing complex illnesses; (2) the same gene may harbor many (hundreds or even thousands) different rare severe mutations in unrelated affected individuals; (3) the same mutation may lead to different clinical manifestations (phenotypes) in different individuals; and (4) mutations in different genes in the same or related pathways may lead to the same disorder.

There’s a huge idea here: Complex human diseases involve sets of complex genetic variations, so many, in fact, that each person’s case of a disease may have individual characteristics. We accept the idea that each individual is unique, but it’s perhaps surprising to think that your case of cancer, for instance, may bear individual characteristics.

The overall magnitude of human genetic variation, the high rate of de novo mutation, the range of mutational mechanisms that disrupt gene function, and the complexity of biological processes underlying pathophysiology all predict a substantial role for rare severe mutations in complex human disease. Furthermore, these factors explain why efforts to identify meaningful common risk variants are vexed by irreproducible and biologically ambiguous results.

Next-generation sequencing provides its own challenges. Whole-genome sequencing strategies detect hundreds of thousands of rare variants per individual (McKernan et al., 2009). Biological relevance must be established before a mutation can be causally linked to a disorder. The critical question is not whether cases as a group have more rare events than controls; but rather which mutation(s) disrupting a gene is responsible for the illness in the affected person harboring the variant. Variable penetrance, epistasis, epigenetic changes, and gene-environment interactions will complicate these efforts. It will be fun to sort out. [Emphasis mine.]

So, as I’ve remarked before, life is complicated. Living systems are the most complex things we know of in the universe, and we’re only now beginning to explore them in detail. We want results to save us now! But it’s going to be some time before we fully understand diseases like cancer and then a long time ’till effective therapies are widely available. Moreover, we have no idea what it’s all going to cost, and, as our recent rancorous debate on health care demonstrates, cost is no trivial matter.

The family genes

I’ve written several posts about how there’s been a lot of criticism this year of the meager results of gene sequencing in finding therapies for diseases. The genetic keys to diseases have proven elusive to the point there has been discouragement in the field. But there’s perhaps a more positive note in today’s NY Times about two studies being published in journals on Friday. For the last decade the operating assumption of genetics and disease is that common diseases like cancer come from common mutations in genes. But a lot of tests on the connection between genetic mutations commonly seen and common diseases was not strong. Instead the conclusion has been emerging that diseases are really linked to rare mutations. So all those news headlines you’ve seen over the last 10 years of so that declare “gene for depression found” were wrong. It’s not that simple.

For three diseases — Charcot-Marie-Tooth disease, Miller syndrome and ciliary dyskinesia – it turns out that the genetic inheritance comes from more obscure genetic changes by way of Mendelian family inheritance. The studies sequenced the whole genomes of not only the children with expressions of the disease but the parents as well. So they got what you might call the whole-family genome. Identifying diseases that manifest differently depending on the mix of genes coming from mom and dad means that the genomes of the whole troop might be needed.

Fortunately the cost of doing a whole genome is dropping, fast. Complete Genomics of Mountain View, Calif., did the genomes in one of the studies at $25,000 each. That’s a whole lot better than the $3 billion for the first genome ten years ago. They’re promising the $10,000 genome to be followed by the $5,000 genome. Remember, the holy grail is $1,000.

I said in my previous post about the 21st century medical model that our personal health record will need to contain our whole genome. This suggests that linking the genomes of the rest of the family will make the assessments of lifetime disease risk a lot better.

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• Genomes for the whole family (scientificamerican.com)