This week’s new papers

Here’s what we told the world’s journalists last week. You can use Google News to see what they made of our briefing.

Please cite Nature Genetics as the source of the following items. If publishing online, please carry a hyperlink to https://www.nature.com/naturegenetics.

A variant in a gene called GDF5 is associated with the risk of developing osteoarthritis

DOI:10.1038/ng2005

Osteoarthritis is the most common form of arthritis, affecting more than 20 million people in the United States. The disease is caused by the breakdown and loss of the cartilage in one or more joints during ageing, leading to swelling, pain, and limited mobility. Shiro Ikegawa and colleagues analyzed variation across the GDF5 gene and found that one particular variant was significantly more frequent in two independent populations of Japanese individuals with osteoarthritis of the hip compared to disease-free individuals. The same variant was also found to be significantly more frequent in both Japanese and Chinese individuals suffering from osteoarthritis of the knee. Depending on the study, the variant conferred 30%-80% additional risk of developing the disease. The authors showed that this variant probably reduces the amount of GDF5 produced. As GDF5 is a protein that is secreted by cells and is known to be involved in cartilage development, lower levels of GDF5 may affect the maintenance of cartilage in joints.

I’m currently attending the ISN-Nature Genetics Forefronts Symposium on Nephrogenetics in Danvers MA.

If the Human Variome Project were to produce a comprehensive synopsis of all the variants of a single gene important for kidney function, together with all the available evidence for their involvement in human disease, which gene would you choose for them to highlight? The synopsis would cover all the mendelian mutations, association studies with common variants and resequencing for rare variants. Please consider:

1) the prevalence and seriousness of the clinical condition(s)

2) the value added by combining all three types of genetic study listed above

3) the availability of all three kinds of evidence

Please send your recommendations with brief reasons to variome.pub(at)gmail.com which is an email address I have set up to collate responses to this question. If you are not a nephrogeneticist (or even if you are) please don’t restrict your answers to kidney genes, this is an important question for the future of the Human Variome Project. I will attempt to post all answers to the blog and would prefer to publish your name with your contribution. Please let me know if you would prefer the comment to be anonymous.

The gene-based view of human variation is fine for molecular biologists and will help clinical geneticists decide whether a variant is likely to cause disease, but I suspect most physicians will be more interested in a disease-based view. In other words, “how many genes can be mutated to produce this phenotype, and what tests are available to help me distinguish between them?”

At this meeting, the difficulty of producing such a view is obvious since the correspondence between genes and kidney diseases is often many-to-many rather than one-to-one. Mutations in the renin-angiotensin system result in tubular dysgenesis. Mutations affecting cilia and centrosomes mostly produce polycystic kidney disease, Bardet-Biedl syndrome and nephronophthisis. However, mutations affecting glomerular filtration by the podocytes and slit diaphragm rather unpredictably produce different clinical conditions: familial glomerulosclerosis and steroid resistant nephrotic syndrome.

Keynote speaker Richard Lifton (Yale) emphasized that studies of human heredity have shown that the ten mutations that raise blood pressure and nine that lower it all influence salt homeostasis in the kidney. There is every indication that variants in these same genes will be important at the population level.

It is certainly difficult to lower blood pressure simply by restricting salt intake. Some find that regular exercise or losing excess weight is also needed. Many also are prescribed diuretics and beta-blockers or ACE inhibitors on the advice of their physician. But to what extent is salt imposed on us by a food industry that exploits our evolutionary adaptation to crave salt? My co-convenor, Qais Al-Awqati (Columbia) said that it is the practice of the Salt Institute to highlight conflicting publications in order to represent the science of blood pressure regulation as “controversial”. Great argument, “the scientists can’t agree, so salt can’t be that bad, can it?”. Now where did I hear that one before, climate change?

To be fair, the Salt Institute response to Qais’s editorial of May last year can be found here.

This week’s new papers

Here’s what we told the world’s journalists last week. Please cite Nature Genetics as the source of the following items. If publishing online, please carry a hyperlink to https://www.nature.com/naturegenetics.

Mitochondrial point mutations do not limit lifespan

DOI: 10.1038/ng1988

A large number of point mutations in mitochondria — the energy-producing units of the cell — do not have a direct link to the ageing process in mice, according to a study to be published online this week in Nature Genetics. While such mutations have been shown to accumulate during ageing in mice and humans, this result contradicts the notion that such mutations are causal factors in the aging process.

The widely debated mitochondrial theory of ageing postulates that the lifelong accumulation of mitochondrial DNA mutations contributes to the decline of tissue function observed in ageing. Lawrence Loeb and colleagues used a new, highly sensitive approach to determine the rate of single base-pair mutations in mitochondrial DNA in normal ageing mice, and in so-called ‘mitochondrial mutator mice’, which have a 500-fold greater mutation burden than normal mice. While the authors found that normal mice have an 11-fold increase in mitochondrial point mutations with age, the mutator mice did not have any obvious features of accelerated ageing, suggesting that the more modest mutation burden in normal mice is not likely to be contributing to the ageing process. It is important to note that this study does not exclude the possibility that large deletions of mitochondrial DNA contribute to ageing. For example, large deletions in mitochondrial DNA have been correlated with the impairment of certain neurons in aged individuals and in individuals with Parkinson disease.

A follow-up story in The Scientist can be found here.