We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke.
We identified a marker in LINGO1 showing genome-wide significant association (P = 1.2 × 10−9, odds ratio = 1.55) with essential tremor. LINGO1 has potent, negative regulatory influences on neuronal survival and is also important in regulating both central-nervous-system axon regeneration and oligodendrocyte maturation. An increase in the number of fusiform swellings of Purkinje cell axons in LINGO1 knockout models highlights the potential role of LINGO1 in essential tremor pathophysiology.
Essential tremor (ET), the most common movement disorder in humans, appears to be inherited as an autosomal dominant trait in many families. The familial form is called familial essential tremor (FET), which seems similar to sporadic essential tremor. ET is a cause of substantial disability, particularly in the elderly. The prevalence of Parkinson's disease and dystonia may be increased in families with ET, but other movement disorders are seldom encountered in these families. Here we report the results of a genome-wide scan for FET genes in 16 Icelandic families with 75 affected individuals, in whom FET was apparently inherited as a dominant trait. The scan, which was performed with a 10-cM framework map, revealed one locus on chromosome 3q13 to which FET mapped with a genome-wide significance when the data were analysed either parametrically, assuming an autosomal dominant model (lod score = 3.71), or non-parametrically (NPL Z score = 4.70, p < 6.4 x 10(-6).
Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P=3.9 x 10(-6)). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as "STRK1," does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.