Genetics of common neurological diseases

The genetics of common neurological diseases team, headed by Aarno Palotie, is investigating variations in the DNA sequences of people suffering from three common neurological complaints, namely migraine, multiple sclerosis and intracranial aneurism.

The team is attempting to find small variations in the DNA sequence (variants) that commonly arise in these people and to link them to susceptibility to the conditions. All three projects are based on the use of large, well-characterised special populations and large family samples. Using family-based studies and subsequent fine DNA mapping strategies the group has been involved in the identification of several new regions of DNA linked to the diseases. In collaboration with international groups, large-scale genetic studies are in progress. The wealth of multiple large study samples enables the group to use different study designs for genome variant identification and verification and for the estimation of the size of the effect contributed by the variants.

Background

Many common neurological traits such as migraine and multiple sclerosis (MS) have a strong genetic component. However, despite extensive research the detailed molecular background of the genetic susceptibility to these traits has remained relatively unclear.

Research

So far, the best insight of underlying genetic alterations causing migraneous symptoms is provided by the Mendelian forms of migraine, Familial Hemiplegic Migraine (FHM), where all identified variants are in genes coding for ion transporters. However, current evidence suggests that variants in these genes do not play a major role in common forms of migraine: migraine with aura (MA) and migraine without aura (MO). Although family studies by us and others have identified several loci linked to migraine with and without aura, no genes have been convincingly associated to these common forms of migraine. We have specifically monitored allelic diversity of 155 known ion transport involved genes in human genome and failed to show a major impact of any of them on common forms of migraine. Our current work is based on a large international effort that has accumulated one of the largest collections of migraine patients in the world. We are performing a genome-wide association scan to test whether common variants associated to common forms of migraine could be identified in these large study samples of more than 5000 migraine cases.

In multiple sclerosis (MS) the role of the HLA as a susceptibility locus has long been well-established. The role of predisposing non-HLA loci is less well-understood. Our family-based positional cloning studies have identified the protein kinase A (PRKCA) gene as one susceptibility candidate gene outside the HLA region and recent large international genome-wide association studies identified interleukin-2 receptor - and interleukin-7 receptor -genes as susceptibility genes for MS. These are exciting, new discoveries shedding light on basic mechanism of MS pathogenesis. However, it is evident that non-HLA susceptibility loci identified thus far explain only a very small fraction of the variance of disease susceptibility to MS. It is likely that we need a more comprehensive understanding of the full allelic diversity of susceptibility genes as well as genes involved in these pathways. Our genome-wide association study aims to identify rare alleles enriched in a population isolate of Finland with a high disease prevalence.

The overall goal of our group is to improve our understanding of pathogenetic mechanisms underlying common neurological diseases such as migraine and MS. Our strategy has been to combine best possible phenotyping in large samples with cutting edge genetic techniques, including high-throughput genotyping and novel tools of statistical genetics. Primarily Finnish clinicians have collected well-phenotyped large study samples with a family history of migraine or MS. Using these unique study samples and extensive international collaborations we aim to identify genes and gene variants contributing to migraine and MS and subsequently understand their impact on the disease outcome.

Selected Publications