2009 © Institute for Molecular Medicine Finland FIMM
Palotie Group
Professor Aarno Palotie, MD, PhD
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.
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, sequencing and novel tools of statistical genetics. Primarily Finnish clinicians headed by Dr. Mikko Kallela have collected well-phenotyped large study samples with a family history of migraine. Using these unique study samples and extensive international collaborations we aim to identify genes and gene variants contributing to episodic CNS disorders such as migraine and subsequently understand their impact on the disease outcome.
Dr. Palotie’s group 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. These 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. The strong connection and collaboration with large genome centers such as the Wellcome Trust Sanger Institute and the Broad Institute makes this aims realistic. Dr. Palotie is a faculty member at the Sanger Institute and a visiting faculty at the Broad Institute.
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 (http://www.headachegenetics.org/index.html). We have performed 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 collaborative work with Dr. Leena Peltonen-Palotie’s and Janna Saarela’s groups in 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.
Key publications:
McCarroll SA, Bradner JE, Turpeinen H, Volin L, Martin PJ, Chilewski SD, Antin JH, Lee SJ, Ruutu T, Storer B, Warren EH, Zhang B, Zhao LP, Ginsburg D, Soiffer RJ, Partanen J, Hansen JA, Ritz J, Palotie A, Altshuler D. Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nat Genet. 2009 Dec;41(12):1341-4.
Jakkula E, Rehnström K, Varilo T, Pietiläinen OP, Paunio T, Pedersen NL, deFaire U, Järvelin MR, Saharinen J, Freimer N, Ripatti S, Purcell S, Collins A, Daly MJ, Palotie A, Peltonen L. The genome-wide patterns of variation expose significant substructure in a founder population. Am J Hum Genet. 2008 Dec;83(6):787-94.
Nyholt DR, LaForge KS, Kallela M, Alakurtti K, Anttila V, Färkkilä M, Hämaläinen E, Kaprio J, Kaunisto MA, Heath AC, Montgomery GW, Göbel H, Todt U, Ferrari MD, Launer LJ, Frants RR, Terwindt GM, de Vries B, Verschuren WM, Brand J, Freilinger T, Pfaffenrath V, Straube A, Ballinger DG, Zhan Y, Daly MJ, Cox DR, Dichgans M, van den Maagdenberg AM, Kubisch C, Martin NG, Wessman M, Peltonen L, Palotie A. A high-density association screen of 155 ion transport genes for involvement with common migraine. Hum Mol Genet. 2008 Nov 1;17(21):3318-31.
Anttila V, Nyholt DR, Kallela M, Artto V, Vepsäläinen S, Jakkula E, Wennerström A, Tikka-Kleemola P, Kaunisto MA, Hämäläinen E, Widén E, Terwilliger J, Merikangas K, Montgomery GW, Martin NG, Daly M, Kaprio J, Peltonen L, Färkkilä M, Wessman M, Palotie A. Consistently replicating locus linked to migraine on 10q22-q23. Am J Hum Genet. 2008 May;82(5):
Wessman M, Terwindt GM, Kaunisto MA, Palotie A, Ophoff RA. Migraine: a complex genetic disorder. Lancet Neurol. 2007 Jun;6(6):521-32.