Mining GWAS mountains for missing heritability

What is missing? The catchy term “missing heritability” refers to a long-standing issue in human genetics that is particularly relevant to common diseases that are thought to have complex genetic architecture. Even though we know several thousands of risk factors for common diseases, the sum of all these risk factors only explains a small proportion of the genetic risk for disease. Where is all the remaining genetic disease risk hidden? A recent publication in PLOS Genetics suggests that known association peaks in genome-wide association studies (GWAS) may harbor more than one risk variant, turning GWAS peaks into mountain ranges. Also, this publication provides an interesting state-of-the art review on the role of common and rare variants with respect to missing heritability. Let’s turn back the clock and start with the decade-old debate on common versus rare variant models of human disease. Continue reading

Rare variants and olive trees

Epic dimensions. 5,000 years ago, human civilization was getting off the ground in Mesopotamia. At some point, the early human pioneers decided to use pictures as letters and human writing was invented. Ox became aleph, which became alpha, which turned into literature, which finally turned into blogging. At around the same time that the Mesopotamian people invented the direct precursor of modern day tweets and text messages, rare genetic variants started spreading through the human population. In fact, all the rare variation that we see in humans today, had probably not been present prior to the chiseling of the first human words. Continue reading

Spooky, scary, phantom heritability

Twilight zone. Admittedly, Halloween is already a few weeks behind us, but I was reminded of it a week ago when I stumbled across the concept of phantom heritability. And guess what, this concept has already been out there since early 2012 and, scarily enough, we didn’t notice it. So what is this mysterious conspiracy behind phantom heritability? Well, it’s about things out there beyond our understanding and the fact that we might already know more than we think we know. But be warned, if you decide to read this post, your understanding of genetic architecture might be changed forever. And there is no going back. Boo! Continue reading