Epistasis Blog

From the Computational Genetics Laboratory at Dartmouth Medical School (www.epistasis.org)

Monday, June 21, 2010

A Statistical Approach to Genetic Epidemiology

I received today my new copy of "A Statistical Approach to Genetic Epidemiology" by Ziegler and Konig [Amazon]. I very much liked the first edition and the new second edition seems to have been nicely updated. I was particularly happy to see an entire chapter devoted to gene-gene and gene-environment interaction. They even highlight our MDR approach. This is a very clearly written book that provides a nice introduction to statistical genetics. I highly recommend it. It is a bit expensive for a paperback though which might make it inaccessible to students ($129.95 list).

Tuesday, June 15, 2010

What we aren't teaching our genetics students

My new copy of Strachan and Read's textbook on Human Molecular Genetics arrived yesterday. I have always thought that this was a clearly written book that provides a nice overview of human genetics from more of a molecular point of view.

The first thing I turned to was the chapter on genetic association studies to see how they present genome-wide association studies (GWAS). The description of what a GWAS is was not bad. However, the context of the discussion was very much the status quo with text on the limitations on GWAS that very much focused on common variants vs. rare variants. There was no discussion whatsoever on genetic arcitecture and the complexity of the genotype-phenotype relationship due to penomena such as epistasis. I immediately went to the index to look for the word epistasis and found one entry on page 71. This turns out to be a very brief mention of epistasis as gene A controlling gene B as a cause of locus heterogeneity. That is it.

It is indeed disappointing to see a modern human genetics textbook fail to rigorously present and discuss the complexity of genetic architecture. Nothing has changed since I was a graduate student in the 1990s. At least the 4th edition lists epistasis in the index. It did not appear at all in the 3rd edition. I guess this is progress.

Monday, June 14, 2010

A Decade Later, Genetic Map Yields Few New Cures

This NYT article highlights the grand failure of GWAS. However, the writer fails to uncover the real reason this hasn't worked - complexity. As I point in a recent Nature Reviews Genetics viewpoint piece (see May 18, 2010 post below), this grand failure should not be a surprise to anyone that marvels at the complexity of genetic architecture. The NYT needs to interview the researchers in the field that are thinking deeply about the problem and not those that are just throwing more technology at the genome.

A Decade Later, Genetic Map Yields Few New Cures [NYT]

Friday, June 04, 2010

Common variants, rare variants or rare combinations of common variants?

Terwilliger and Göring claimed in their 2000 paper "that a larger number of less common alleles is likely to be involved in the etiology of complex disease". They now claim that the grand failure of GWAS and the common variant/common disease(CVCD) hypothesis of Reich and Lander (2001) validates this claim. Their new paper in Human Biology is an interesting read and it is certainly fun to see them slam GWAS. However, I am not yet convinced that the 'missing heritability' is largely due to rare variants. I think it is still highly likely that common variants are important through gene-gene and gene-environment interactions. It is important to note that genotype combinations from multiple common variants are inherently rare in the population. The rare variant effects that everyone is now so excited about might very well be right under our noses. I pointed this out in a recent Nature Reviews Genetics viewpoint piece (see May 18, 2010 post below).

Terwilliger JD, Göring HH. Update to Terwilliger and Göring's "Gene mapping in the 20th and 21st centuries" (2000): gene mapping when rare variants are common and common variants are rare. Hum Biol. 2009 Dec;81(5-6):729-33.

Terwilliger JD, Göring HH. Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design. Hum Biol. 2000 Feb;72(1):63-132.

Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, Nadeau JH. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet. 2010 Jun;11(6):446-50.

Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet. 2001 Sep;17(9):502-10.

Note added June 15: Here is a recent blog post I ran across on the same paper: Getting Genetics Done