Publications of the week – 15q13.3 deletions, POLG1 and liver failure, and twins

Update. In the last few weeks, we have tried to catch up with some recent publications in the field that mainly focused on autism spectrum disorder. This week’s publications, in contrast, cover a wide range of topics including the phenotypic spectrum of the 15q13.3 microdeletions, the importance of POLG1 in valproate-induced liver failure, and the most recent updates on epilepsy and twins. Continue reading

Should we stop talking about heritability in 2014?

Genetic epidemiology. Long before the first epilepsy gene was discovered, clinicians and researchers were wondering about a genetic contribution to epilepsy. Some epilepsy syndrome were found to run in families in an autosomal dominant or recessive pattern. In other epilepsies, there was an obvious excess of affected family members in the immediate or extended family. And this is how we got stuck with the concept of heritability. Let’s review the perils and pitfalls of heritability and ask the question whether we should retire this concept in the current era of genomic medicine. Continue reading

The genetic architecture toolkit – modeling polygenic disease with rare variants

Architecture. Even though we often write about novel gene findings in the epilepsies, we assume that most epilepsies are complex genetic or polygenic. Polygenic inheritance suggests the genetic architecture is composed of multiple interacting genetic risk factors, each contributing a small proportion to the disease risk. However, when using the phrase genetic architecture, sometimes I am not quite sure what I actually mean by this. For example, how many genes are needed? This is why I wanted to build a model genetic architecture and explore what happens if we build a genetic disease solely from rare risk variants. Follow me to a brief back-of-the-envelope calculation of how this might work.

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The familial risk of epilepsy – revisited

Missing heritability. The concept of missing heritability is often invoked to demonstrate that existing genetic techniques only identify a fraction of the overall genetic risk for human diseases including the epilepsies. This statement implicitly assumes that we have a good and solid understanding of what the magnitude of genetic risk actually is. However, when looking at the epidemiological studies that have investigated familial risk of epilepsy, some of these studies have inherent problems, including small sample sizes, different phenotype definitions, recruitment bias, and lack of controls. A recent study in Brain now reassesses the familial risk of epilepsy in a population-based cohort of the Rochester Epidemiology Project. There are few instant classics in the field of epilepsy genetics – this study is one of them. Continue reading

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

FS and FS+ are two distinct diseases, as suggested by twins

GEFS+ reloaded. The genetics of Febrile Seizures (FS) is one big mystery. Even though large families have been reported and multiple linkage studies have been performed, no single susceptibility gene for Febrile Seizures is known. This is somehow surprising, given that FS is by far the most common epilepsy syndrome. In contrast to common FS, genetic research has been very successful in families with Genetic Epilepsy with Febrile Seizures Plus (GEFS+), where Febrile Seizures Plus (FS+) are the most striking feature in families.  Ever since the definition of the GEFS+ spectrum was established, the distinction from common FS has been a matter of debate. Now a twin study in Epilepsy Research suggests FS and FS+ might actually be two very distinct diseases with little genetic overlap. Continue reading

Genetic Generalized Epilepsy might be less genetic than you think

Ceci n’est pas une pipe. The painter René Magritte was known for his series of paintings that he called The Treachery of Images. He basically painted objects such as pipes, but then felt compelled to point out that the image actually betrays you. It’s not a real pipe, but only an image of it. For some reason, Magritte’s pipe comes to my mind when I read or hear the term Genetic Generalized Epilepsy. Again, the treachery of images. Ceci n’est pas une épilepsie génétique. Continue reading

The heritability of schizophrenia, as told by common SNPs

Heritability 2.0. Genome-wide association studies (GWAS) have acquired a slightly negative connotation in the last two years as the results of the enormous efforts were moderate at best. Even though several hundreds of variants have been identified as susceptibility genes for various diseases, the identified genetic risk factors only explain a tiny fraction of the risk for these diseases. Much of what causes common and rare diseases is still unknown – there is a vast discrepancy between population estimates of the genetic contribution and the contribution explained through identified genetic risk factors. This phenomenon has been labeled the “missing heritability”. Now, a recent study using novel statistical tools for GWAS data finds that there is not that much missing after all… Continue reading

Autism – the shared environment strikes back

Autism and environment. A much talked about recent twin study from California finds a significantly lower heritability in autism than previously estimated, reducing the heritability estimate from >80% to less than 40% and attributing much of the liability of autism to shared, probably prenatal environment. At first, this study may seem to add to the growing pessimism in the genetics field given the lack of explanatory findings from exome sequencing studies. However, things are not that simple and you don’t have to put your exome sequencers on Ebay yet. Also, don’t mention vaccinations again. Let me explain… Continue reading