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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A polygenic trickle of rare disruptive variants in schizophrenia

Polygenic. Schizophrenia is a complex neurodevelopmental disorder that is assumed to be caused by a mixture of genetic and non-genetic factors. The genetic component in schizophrenia is thought to be polygenic, i.e. due to the interaction of multiple genetic factors. Rare variants may play a particular role in this presumable polygenic genetic architecture, but so far this component of the genetic morbidity has been hard to pin down. Now, a recent study in Nature explores the role of rare, disruptive mutations in schizophrenia using large-scale population-based exome sequencing. Let’s find out about a new level of exome-wide honesty and why even a gene with 10 disruptive mutations in cases and none in controls is only mentioned in passing. Continue reading

The age of mega-genomics, type 2 diabetes, and protective variants in SLC30A8

Sequence first. There are larger genetic studies but not too many. In a recent study in Nature Genetics, roughly 150,000 individuals were genotyped to assess the importance of rare, disruptive variants in SLC30A8 in type 2 diabetes. This genomic tour de force was made possible by available and curated databases that could be tapped to extract the necessary genetic information. Also, this study highlights some of the surprises that we can expect by mining the human genome for disease-related information. Rare, disruptive variants in SLC30A8 protect against type 2 diabetes. Let’s review why these rare, protective genetic factors might be particularly important for biomedical research and what kind of studies we need to identify them. Continue reading

GPHN deletions in IGE and mutation-dependent recessive inheritance

Bild1Living in Cologne is a little tough at the moment. Currently, we are in the middle of the Cologne Carnival, the world’s oldest carnival, which started in 1829. Until the upcoming Wednesday the entire city is one big festival. In addition to the 1 million Cologne citizens probably another million tourists will join. Due to this (positive) distraction I will write less than usual. However, I still consider this week’s publications noteworthy. Continue reading

Papers of the week – Encephalitis-antibodies, FAN1, Art and Parent-of-Origin Effects

Dennis' paper of the week

Biggest surprise this week: Imprinted genes interact with non-imprinted genes frequently. But first sequencing reports, statistical frameworks for rare variants analyzes and an impressive translational result.

A novel encephalitis with seizures and the analysis of the effects of antibodies. In their study published in LANCET NEUROLOGY Petit-Pedrol and coworkers characterized serum and CSF samples for antigens in 140 patients with encephalitis, seizures or status epilepticus as well as antibodies to unknown neurophil antigens. High titres of serum and CSF GABAA receptor antibodies are reported to be associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both, which could be exploited for immunotherapy with 15 patients.

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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

Transmission of rare variants in parent-offspring trios – power or no power?

My untested assumption. Recently, I have boasted quite a bit about the power of the trio design, i.e. the inclusion of patients and parents in the analysis of rare genetic variants. Rare variants, in contrast to monogenic variants that arise de novo, are usually transmitted from unaffected parents and are the big unknown of modern day genetic studies. Much of the missing heritability may be accounted for by rare variants, but identifying these variants from genomic noise is difficult. Power calculations for association studies usually suggest that thousands, if not tens of thousands, of patients are necessary to identify these variants with sufficient statistical certainty, a sample size that the field of epilepsy research may never arrive at. So what about switching to parent-offspring trios? Would this help us? Follow me on a brief statistical journey through the land of rare variants. Continue reading

Cold fusion – joining exome datasets to identify autism genes

Mergers and acquisitions. Invariably, genetic research in neurodevelopmental disorders is moving towards joint analyses of large datasets. While the methodology of meta-analysis is well established for genome-wide association studies, the joint analysis of exome datasets comes with many question marks. Now, a recent paper in PLOS Genetics pioneers the field of joint exome data analysis for association studies in autism. This paper highlights some unexpected facets of rare variant analysis. 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

Recessive mutations in autism – the return of hidden metabolic disorders

My wrong guesses of 2012. Two weeks ago during a presentation, I had to admit that there is little evidence for a large contribution of recessive or compound heterozygous mutations in epileptic encephalopathies. At the beginning of 2012, I had initially suggested that recessive or compound heterozygous mutation of known neurometabolic disorders could be identified through exome sequencing in sporadic epileptic encephalopathies. However, as of 2013, there is little evidence for this in our data or the data from other consortia. Now, two papers in Cell suggest a significant contribution of recessive mutations in autism including a revival of the “hidden neurometabolic hypothesis”. Continue reading