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

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.

Citing Articles

Phosphodiesterase 4 inhibition as a novel treatment for stroke.

Zhong J, Yu X, Lin Z PeerJ. 2025; 13:e18905.

PMID: 39897494 PMC: 11786714. DOI: 10.7717/peerj.18905.

Single-nucleotide polymorphism rs2910829 in is related to stroke susceptibility in Chinese populations: The results of a meta-analysis.

Zhang G, Tang X, Li Q, Lin R Open Life Sci. 2024; 19(1):20220818.

PMID: 38465333 PMC: 10921477. DOI: 10.1515/biol-2022-0818.

PDE4D single nucleotide polymorphism rs918592 is associated with ischemic Stroke risk in Chinese populations: a meta-analysis.

Yu X, Zhang G, Tang X, Lin R BMC Cardiovasc Disord. 2024; 24(1):17.

PMID: 38172709 PMC: 10765709. DOI: 10.1186/s12872-023-03681-2.

Association of plaque enhancement on vessel wall MRI and the phosphodiesterase 4D variant with stroke recurrence in patients with symptomatic intracranial atherosclerosis.

Xu C, Qin J, Yu J, Sun Y, Hu D, Wu G Neuroradiology. 2022; 64(9):1781-1794.

PMID: 35420310 DOI: 10.1007/s00234-022-02948-3.

Associations between SNP83 of phosphodiesterase 4D gene and carotid atherosclerosis in a southern Chinese Han population: a case-control study.

Liu L, Mo D, Li J, Jiang Y, Zhou G, Jiang D Mamm Genome. 2021; 32(2):115-122.

PMID: 33755782 DOI: 10.1007/s00335-021-09857-5.

References

Whittemore A, Halpern J . A class of tests for linkage using affected pedigree members. Biometrics. 1994; 50(1):118-27. View

Bonita R . Epidemiology of stroke. Lancet. 1992; 339(8789):342-4. DOI: 10.1016/0140-6736(92)91658-u. View

Friedlander Y, Kark J, STEIN Y . Family history of myocardial infarction as an independent risk factor for coronary heart disease. Br Heart J. 1985; 53(4):382-7. PMC: 481776. DOI: 10.1136/hrt.53.4.382. View

Levy E, Carman M, Power M, Lieberburg I, van Duinen S, BOTS G . Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990; 248(4959):1124-6. DOI: 10.1126/science.2111584. View

Giglio S, Broman K, Matsumoto N, Calvari V, Gimelli G, Neumann T . Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am J Hum Genet. 2001; 68(4):874-83. PMC: 1275641. DOI: 10.1086/319506. View

Valdimarsson E, Sigurdsson G, Jakobsson F . [Etiology and treatment of cerebral ischemia at the Department of Neurology and Rehabilitation Medicine at Reykjavik City Hospital.]. Laeknabladid. 2009; 84(12):921-7. View

Duffin C . The wellcome trust sanger institute. Nurs Stand. 2015; 29(22):30. DOI: 10.7748/ns.29.22.30.s35. View

Sahoo T, Johnson E, Thomas J, Kuehl P, Jones T, Dokken C . Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet. 1999; 8(12):2325-33. DOI: 10.1093/hmg/8.12.2325. View

Kruglyak L, Daly M, Lander E . Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996; 58(6):1347-63. PMC: 1915045. View

10.

Halpern J, Whittemore A . Multipoint linkage analysis. A cautionary note. Hum Hered. 1999; 49(4):194-6. DOI: 10.1159/000022874. View

11.

Thompson E . Crossover counts and likelihood in multipoint linkage analysis. IMA J Math Appl Med Biol. 1987; 4(2):93-108. DOI: 10.1093/imammb/4.2.93. View

12.

Jousilahti P, Rastenyte D, Tuomilehto J, Sarti C, Vartiainen E . Parental history of cardiovascular disease and risk of stroke. A prospective follow-up of 14371 middle-aged men and women in Finland. Stroke. 1997; 28(7):1361-6. DOI: 10.1161/01.str.28.7.1361. View

13.

Adams Jr H, Bendixen B, Kappelle L, Biller J, Love B, Gordon D . Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993; 24(1):35-41. DOI: 10.1161/01.str.24.1.35. View

14.

Lindenstrom E, Boysen G, Nyboe J . Risk factors for stroke in Copenhagen, Denmark. I. Basic demographic and social factors. Neuroepidemiology. 1993; 12(1):37-42. DOI: 10.1159/000110297. View

15.

Hodge S . The information contained in multiple sibling pairs. Genet Epidemiol. 1984; 1(2):109-22. DOI: 10.1002/gepi.1370010203. View

16.

THOMPSON D, Furlan A . Clinical epidemiology of stroke. Neurosurg Clin N Am. 1997; 8(2):265-9. View

17.

Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop G, Chabriat H . Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet. 1993; 3(3):256-9. DOI: 10.1038/ng0393-256. View

18.

Shea S, Ottman R, Gabrieli C, Stein Z, Nichols A . Family history as an independent risk factor for coronary artery disease. J Am Coll Cardiol. 1984; 4(4):793-801. DOI: 10.1016/s0735-1097(84)80408-8. View

19.

Gunel M, Awad I, Anson J, Lifton R . Mapping a gene causing cerebral cavernous malformation to 7q11.2-q21. Proc Natl Acad Sci U S A. 1995; 92(14):6620-4. PMC: 41570. DOI: 10.1073/pnas.92.14.6620. View

20.

Risch N . Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am J Hum Genet. 1990; 46(2):229-41. PMC: 1684989. View