Abstract for presentation at 11th International Congress of Human Genetics

Searching predisposing variants for MS and migraine by combining data from human and experimental species

  • Dr Aarno Palotie, Finnish Genome Ctr, Univ of Helsinki and Broad Institute, Boston, Finland
  • Dr Janna Saarela, Natl Public Health Institute, Helsinki, Finland
  • Dr Mikko Kallela, Dept. of Neurology, University of Helsinki, Finland
  • Dr Pentti Tienari, Dept. of Neurology, University of Helsinki, Finland
  • Dr Maija Wessman, Finnish Genome Ctr, Univ of Helsinki and Folkhälsan Research Ctr, Finland
  • Dr Dale Nyholt, Queensland Inst of Med Research, Brisbane, Australia
  • Dr Leena Peltonen, Natl Public Health Inst and Univ of Helsinki and The Broad Insitute, Boston, Finland
  • Dr Aarno Palotie, Finnish Genome Ctr, Univ of Helsinki and The Broad Inst of Harvard and MIT, Boston, Finland

    • We have used a study design integrating families of population isolates and across species comparisons to identify predisposing loci and gene variants behind neurological diseases. Large, well-characterized family cohorts were ascertained from the ethnically homogenous Finnish population for Multiple Sclerosis (MS) and migraine. In parallel, genome-wide expression data (Affimetrix GeneChip) was collected from peripheral lymphocytes of patients and primary, CNS-originating cells, from rodent models to identify positional candidate genes and involved pathways. The MS patient cohort consists of about 500, the migraine cohort of almost 700 families. For MS we utilized an internal isolate in Western Finland where the prevalence of MS is higher than in the rest of the country. Migraine is evenly geographically distributed but using genealogical data we formed large pedigrees in Northern Finland. Genome wide scans for both MS and migraine revealed linked loci. MS families from the high risk isolate provided association to the allelic variants of the PRKCA gene on Chr 17q using clinical MS and neuroimaging as end point diagnosis, demonstrating the power of the ethnically homogenous samples. Expression data from peripheral lymphocytes demonstrated that transcript levels correlated to genotypes. Association to PRKCA was subsequently detected also in a more heterogeneous Canadian sample. Using end diagnosis migraine with aura, linkage to Chr 4q24 was detected. When individual symptoms of migraine were used as traits, the Chr 4q24 locus was linked to photophobia and to phonophobia, a locus on 17p13 was linked to pulsation and 18q12 to the C-trait combination defined in IHS. This demonstrates the strength of a deeply phenotyped sample for identification of susceptibility loci. Expression profiles of primary neurons and glial cells from the CACNA1A tottering mouse mutant were used to identify positional candidate genes for the linked migraine loci. Allelic variants of these genes are tested in a case control sample of 1800 subjects. Such studies demonstrate the power of well ascertained clinical and genealogical data as well as integration of the data from human and experimental species in search of complex disease genes.

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