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From the Department of Clinical Neurosciences (Drs. Hassan and Markus), St. George’s Hospital Medical School, and Division of Psychological Medicine (Dr. Sham), Institute of Psychiatry, London, United Kingdom.
Address correspondence and reprint requests to Prof. Hugh S. Markus, Department of Clinical Neurosciences, St. George’s Hospital Medical School, London SW17 ORE, UK; e-mail: h.markus{at}sghms.ac.uk
Background: Identification of stroke risk genes in humans has relied on case-control methods to determine the association between candidate genes and disease. Alternative approaches include linkage analysis using affected sibling pairs, transmission disequilibrium testing (TDT), and sibling TDT (S-TDT). Despite theoretical benefits, the feasibility of these methods in stroke remains unknown.
Methods: Family history was determined in 727 patients with ischemic stroke and 623 control subjects. These data were used to estimate the number of stroke patients required for the different study designs.
Results: A family history of any stroke occurring at 
65 years was an independent risk factor for ischemic stroke at all ages (OR 1.47, 95% CI 1.02 to 2.12, p = 0.04) and a stronger risk factor for young (65 years) ischemic stroke (OR 2.25, 95% CI 1.43 to 3.55, p < 0.0001). For early-onset ischemic stroke, the sibling risk ratio was estimated to be 3.08. Assuming three major stroke loci, collection of 953 affected sibling pairs (both 65 years) would be needed for a linkage study, and 115,472 ischemic stroke patients would have to be screened to achieve this sample size from the authors’ population. The predicted sample sizes for association studies to detect a gene conferring an OR of 2.0 were case-control methodology (414), TDT (414), and S-TDT (617), which would require screening of 820, 31,680, and 3,062 cases.
Conclusion: Alternative genetic approaches are feasible, but TDT and linkage studies using the affected sib-pair methodology may require large multicenter collaborations. S-TDT approaches appear more practical. These estimates will aid in planning of such studies.
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