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  • A first stage genome-wide screen for regions shared identical-by-descent in Hutterite families with multiple sclerosis.

    24 October 2018

    The complexity of multiple sclerosis (MS) genetics has made the search for novel genes using traditional sharing methods problematic. In order to minimize the genetic heterogeneity present in the MS population we have screened the Canadian MS population for individuals belonging to the Hutterite Brethren. Seven Hutterites with clinically definite MS were ascertained and are related to a common founder by eight generations. Six of the 7 affected individuals and 21 of their unaffected family members (total = 27) were genotyped for 807 markers. Haplotypes were then inspected for sharing among the six MS patients. There were three haplotypes shared among all six MS patients. The haplotypes were located at 2q34-35, 4q31-32, and 17p13. An additional 15 haplotypes were shared among five of the six Hutterites MS patients. The HLA Class II region was one of the highlighted regions; however, the shared MHC haplotype bore the DRB1*04 allele and not the MS-associated DRB1*15 allele providing further evidence of the complexity of the MHC. Additional genotyping to refine the haplotypes followed by screening for potential variants may lead to the identification of a novel MS susceptibility gene(s) in this unique population.

  • Significant linkage to migraine with aura on chromosome 11q24.

    24 October 2018

    Migraine with aura (MA) is a prevalent neurological condition with strong evidence for a genetic basis. Familial hemiplegic migraine, a rare Mendelian form of MA, can be caused by mutations in the calcium channel gene, CACNA1A or in the ATP1A2 gene, a Na+/K+ pump. Susceptibility genes for the more prevalent forms of migraine have yet to be identified despite several reports of linkage including loci on 4q24, 1q31, 19p13 and Xq24-28. We have undertaken a genome-wide screen of 43 Canadian families, segregating MA with families chosen for an apparent autosomal dominant pattern of transmission. Diagnosis was based upon International Headache Society Criteria. Parametric linkage analysis revealed a novel locus on 11q24 with a two-point LOD score of 4.2 and a multi-point parametric LOD score of 5.6. We did not find any support for linkage at previously reported loci. The lack of consensus amongst linkage studies, including this study, is probably an indication of the heterogeneity that is inherent for MA. Nevertheless, the finding of a highly significant locus with a LOD score of 5.6 is powerful evidence that a gene increasing susceptibility to MA resides on 11q24. Several candidate genes map to this region of the genome including a number of ion channel genes such as GRIK4, SCNB2, KCNJ5 and KCNJ1.

  • A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo

    24 October 2018

    Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl-tRNA synthetase (HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed. © 2012 Wiley Periodicals, Inc.

  • Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease.

    24 October 2018

    Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.

  • New directions in migraine.

    24 October 2018

    Migraine is a highly prevalent neurological disorder imparting a major burden on health care around the world. The primary pathology may be a state of hyperresponsiveness of the nervous system, but the molecular mechanisms are yet to be fully elucidated. We could now be at a watershed moment in this respect, as the genetic loci associated with typical forms of migraine are being revealed. The genetic discoveries are the latest step in the evolution of our understanding of migraine, which was initially considered a cerebrovascular condition, then a neuroinflammatory process and now primarily a neurogenic disorder. Indeed, the genetic findings, which have revealed ion channels and transporter mutations as causative of migraine, are a powerful argument for the neurogenic basis of migraine. Modulations of ion channels leading to amelioration of the migraine 'hyperresponsive' brain represent attractive targets for drug discovery. There lies ahead an exciting and rapidly progressing phase of migraine translational research, and in this review we highlight recent genetic findings and consider how these may affect the future of migraine neurobiology and therapy.

  • New directions in migraine.

    24 October 2018

    Migraine is a highly prevalent neurological disorder imparting a major burden on health care around the world. The primary pathology may be a state of hyperresponsiveness of the nervous system, but the molecular mechanisms are yet to be fully elucidated. We could now be at a watershed moment in this respect, as the genetic loci associated with typical forms of migraine are being revealed. The genetic discoveries are the latest step in the evolution of our understanding of migraine, which was initially considered a cerebrovascular condition, then a neuroinflammatory process and now primarily a neurogenic disorder. Indeed, the genetic findings, which have revealed ion channels and transporter mutations as causative of migraine, are a powerful argument for the neurogenic basis of migraine. Modulations of ion channels leading to amelioration of the migraine 'hyperresponsive' brain represent attractive targets for drug discovery. There lies ahead an exciting and rapidly progressing phase of migraine translational research, and in this review we highlight recent genetic findings and consider how these may affect the future of migraine neurobiology and therapy.

  • Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds.

    24 October 2018

    The age of onset of Huntington's disease (HD) is inversely correlated with the CAG length in the HD gene. The CAG repeat length accounts for 70% of the variability in HD age of onset. However, 90% of individuals worldwide with expanded alleles possess between 40 and 50 CAG repeat lengths in their HD gene. For these people, the size of their repeat only determines 44% of the variability in their age of onset. Once the effect of the CAG repeat has been accounted for, the residual variance in age of onset is a heritable trait. Targeted candidate gene studies and a genome scan have suggested some loci as potential modifiers of the age of onset of HD. We analyzed the large Venezuelan kindreds in which the HD gene was originally identified. These kindreds offer greater analytic power than standard sib-pair designs. We developed novel pedigree-member selection procedures to maximize power. Using a 5,858-single-nucleotide-polymorphism marker panel, we performed a genomewide linkage analysis. We discovered two novel loci on chromosome 2. Chromosome 2p25 (logarithm of the odds ratio (LOD)=4.29) and 2q35 (LOD=3.39) may contain genes that modify age of onset. A third linkage peak on chromosome 6q22 (LOD=2.48) may confirm the most promising locus from a previous genome scan. Two other candidate loci are suggestive on chromosome 5 (LOD=3.31 at 5p14 and LOD=3.14 at 5q32). All these regions harbor candidate genes that are potential HD modifier genes. Finding these modifier genes can reveal accessible and promising new therapeutic pathways and targets to ameliorate and cure HD.

  • Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development.

    24 October 2018

    β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.

  • Collaborators

    10 January 2018

    Information and links to our collaborators (both internal and external)