Localization of a Susceptibility Gene for Common Forms of Stroke to 5q12

Abstract

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.

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

“…The control group for the SNP association study was population-based and comprised of 624 unrelated males and females 20-90 years of age whose medical history was unknown. The stroke and PAOD cohorts used in this study have previously been described [32][33][34] . For the stroke linkage analysis, we used genotypes from 342 males with ischemic stroke or TIA that were linked to at least one other male within and including six meioses in 164 families.…”

“…We carried out a genome-wide scan as previously described 33 , using a set of 1,068 microsatellite markers. We used multipoint, affected-only allele-sharing methods 36 to assess the evidence for linkage.…”

The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology

“…In the past few years it became feasible to genotype cheaply large pedigrees with much greater numbers of microsatellites than were previously used for genome scans, and statistical programs that are now available permit efficient computation of linkage even in complex pedigrees 28,29 . These advances allowed a substantial increase in the scale of pedigree-based linkage studies 2,4,[30][31][32][33][34][35][36][37][38] . Inadequate technology and statistical methodology have similarly hindered implementation of alternatives to pedigreebased mapping.…”

Linkage of Essential Hypertension to Chromosome 18q

“…The Allegro program, a linkage program, calculates logarithm of odds (LOD) scores based on multipoint calculations. [23][24][25] Our baseline linkage analysis, as previously described, 19 uses the S pairs scoring function, 24,26 the exponential allele-sharing model, 25 and a family-weighting scheme that is halfway on the log scale between weighting each affected pair equally and weighting each family equally.…”